Myofibroblasts. I. Paracrine cells important in health and disease
Abstract
Myofibroblasts are a unique group of smooth-muscle-like fibroblasts that have a similar appearance and function regardless of their tissue of residence. Through the secretion of inflammatory and anti-inflammatory cytokines, chemokines, growth factors, both lipid and gaseous inflammatory mediators, as well as extracellular matrix proteins and proteases, they play an important role in organogenesis and oncogenesis, inflammation, repair, and fibrosis in most organs and tissues. Platelet-derived growth factor (PDGF) and stem cell factor are two secreted proteins responsible for differentiating myofibroblasts from embryological stem cells. These and other growth factors cause proliferation of myofibroblasts, and myofibroblast secretion of extracellular matrix (ECM) molecules and various cytokines and growth factors causes mobility, proliferation, and differentiation of epithelial or parenchymal cells. Repeated cycles of injury and repair lead to organ or tissue fibrosis through secretion of ECM by the myofibroblasts. Transforming growth factor-β and the PDGF family of growth factors are the key factors in the fibrotic response. Because of their ubiquitous presence in all tissues, myofibroblasts play important roles in various organ diseases and perhaps in multisystem diseases as well.
a growing body of literature over the last decade has made it evident that there is phenotypic heterogeneity among fibroblasts and that some express features of smooth muscle differentiation (73, 136, 214, 216). These smooth-muscle-like cells, or myofibroblasts as they were termed by Gabbiani (82, 83) who pioneered this field, take part in the growth, development, and repair of normal tissue as well as the diseases affecting many different organs. These cells belong to a unique class, and, even allowing for specific functions for those cells in a given organ or tissue, there is an amazing similarity in their morphology, function, and biochemical repertoire regardless of their location. Nonetheless, in a given tissue, they may express some specific appearances and functions, i.e., phenotypic and functional heterogeneity. Because of this propensity and their location next to epithelial or parenchymal cells, we have suggested they might be termed “juxtaparenchymal cells” (247).
In this review, we give an overview of myofibroblasts, illustrating similarities and differences in their biochemical/physiological/immunologic properties, and we indicate the role that these cells play in specific disease states. The major soluble factors secreted by these cells are discussed, and important receptors on myofibroblasts are listed. We have slanted the discussion toward the intestinal myofibroblasts (247): the interstitial cells of Cajal (ICC) and the subepithelial intestinal myofibroblast. This review is not meant to be entirely comprehensive of the field of myofibroblasts. It focuses on recently discovered information about the interactions of myofibroblasts with epithelial and parenchymal cells and the molecules that mediate these interactions. Furthermore, we have purposely referenced review articles when possible to amplify the reference base.
ROLES IN HEALTH AND DISEASE
Table 1 lists various tissue myofibroblasts and what is thought to be their normal function. Some of these functions are well proven, and others can be inferred from the known properties of myofibroblasts in other tissues. In general, there are several common normal activities of myofibroblasts. First, through mesenchymal-epithelial interactions, myofibroblasts are key components of organogenesis or morphogenesis, i.e., the growth and differentiation of the tissue or organ (227). They do so through the secretion of soluble mediators of inflammation and growth factors (Table 2) and expression of their receptors (Table 3) and through secretion and formation of interstitial matrix and/or basement membrane molecules (Table 4) (20, 73, 82, 247). Myofibroblasts also play a fundamental role in many disease states, either through activation and proliferation or through deletion (Table5) (51, 214, 216). They play a central role in wound healing, presumably as an extension or accentuation of their role in normal growth and differentiation (82, 83, 99, 120, 136). They appear to be involved in the formation and repair of the extracellular matrix (ECM) and proliferation and differentiation of epithelial (or parenchymal), vascular and neurogenic elements (50, 215, 250, 262).
| Tissue or Organ | Function |
|---|---|
| Skin | |
| Granulation tissue | Epithelial growth and differentiation; wound repair (41, 51, 81,99) |
| Pericyte* | Angiogenesis; regulation of local blood flow (216) |
| Mouth | |
| Periodontal ligament | Attachment of teeth (136, 214, 216) |
| Gingival myofibroblasts | Structure of gum (136, 214, 216) |
| Palatal mucosa | Structure of palate (27) |
| Eye | |
| Orbital fibroblast | Glycosaminoglycan secretion for cushioning eye in orbit (9, 221, 254) |
| Retinal myofibroblast | Angiogenesis and wound healing; connective tissue matrix formation (253) |
| Anterior capsule of lens | Lens formation (172, 217) |
| Corneal myofibroblast | Wound healing (184) |
| Heart and pericardium | Structure of cardiac valve; repair after myocardial infarction (258) |
| Kidney | |
| Mesangial cell | Glomerular growth and differentiation; regulation of glomerular blood flow (185, 239) |
| Interstitial cell | Tubule growth and differentiation (136, 177, 239) |
| Liver | |
| Perisinusoidal stellate cell (Ito cell) | Endothelial and sinusoid structure and function; regulation of blood flow; vitamin A storage (72, 88, 150) |
| Pancreas | |
| Periacinar stellate cell | Growth and development of the acinus (4, 8) |
| Lung | |
| Interstitial contractile cell | Alveolus formation (26,105) |
| Stomach and intestine | |
| Interstitial cell of Cajal | Regulation of motility, “pacemaker” activity (212,243) |
| Subepithelial myofibroblast | Epithelial growth and differentiation; contraction of gastric glands and intestinal villi; regulation of intestinal absorption and secretion (120, 152, 153, 180,247) |
| Brain | |
| Astrocyte | Substrate pathways for neural growth; formation of blood-brain barrier; secrete mitogens and growth factor for neurons (166) |
| Breast | |
| Stromal myofibroblast | Epithelial growth and differentiation; possibly contraction and expulsion of milk (204) |
| Bone marrow | |
| Stromal cell | Nurture stem cells and promote hematopoiesis (182, 218) |
| Joint | |
| Synoviocyte | Lines joint space (11) |
| Uterus | |
| Endometrial myofibroblasts | Regeneration of endometrium after menses (40, 76) |
| Placental myofibroblasts | Structure of placental stem villus (134) |
| Ovary | |
| Theca cells | Meiosis and ovulation (49, 136) |
| Prostate | |
| Stromal cells | Growth and differentiation of prostate gland (98, 125, 181) |
| Testicular | |
| Peritubular myoid cells | Growth and differentiation of seminiferous tubules; ? contraction and expulsion of sperm (104, 106) |
| Leydig cells | Androgen secretion (136) |
| Capsule cells | Contraction of capsule (85) |
| Cytokines | Growth Factors | Chemokines | Inflammatory Mediators |
|---|---|---|---|
| IL-1 (178, 185, 240, 246) IL-6 (178,179, 185) TNF-α (185) IL-10 (178) | TGF-β (17, 25) CSF-1 (185) GM-CSF (178, 185) PDGF-AA (26,185) PDGF-BB (141, 142) bFGF (17) IGF-I (144, 162, 185) IGF-II (144, 226) NGF (185) KGF (37,207) HGF (28, 84) SCF (132) | IL-8 (36, 178, 185) MCP-1 (36, 185,236) GRO-1α (36) MIP-1α (36) MIP-2 (235) RANTES (36) ENA-78 (5, 36) | Phospholipase A2activating protein (185) PGE2(19) Prostacyclin (262) HETEs (185) PAF (247) NO (39, 69, 151,167, 185, 202) CO (1, 14, 162) H2O2, O− (19,185) |
| Cytokines | Growth Factors | Inflammatory Mediators | Neurotransmitters and Paracrine Mediators | Adhesion Proteins |
|---|---|---|---|---|
| IL-1 (139, 178) IL-1Ra (102) TNF-α (100,101) IL-6 R (179) IL-8 R (31) IL-4 R (128, 156) IL-11 R (143) | TGF-α/EGFR (138, 214) TGF-β RI and RII (25, 58, 159, 203) PDGF-α (26, 111, 263) PDGF-β (111, 141, 234) c-kit(18, 109, 174) aFGF and bFGF R (111) IGF-IR (144) Thrombin receptor (15,151) FGFR-II | Prostaglandins (19) HETEs (210) | Acetylcholine (102) Histamine (19) Serotonin (19) Bradykinin (19) Endothelin (80, 142, 246) Atrial natriuretic factor (246) Aldosterone or ANG II (34,258) | ICAM-1 (100, 178) VCAM-1 (178) NCAM (133) MCP-1 (151, 235) α1β1 integrin (192) CD18 (31) |
| Collagens (20, 96, 138, 154, 168, 220, 227, 268) |
| Types I–VI, XVIII4-150 |
| Glycoproteins (20, 96, 138, 154, 220, 227, 251) |
| Laminins |
| Entactin/nidogen |
| Fibronectin |
| Tenascin |
| Sparc/BM40 |
| Thrombospondin |
| Proteoglycans (20, 96, 138, 154, 220, 227) |
| Glycosaminoglycans (GAGS) |
| Hyaluronic acid (HA-type) |
| Heparan sulfate (HS-type) |
| Chondroitin sulfate (CS-type) |
| Perlecan4-151 |
| Matrix modifying proteins (16, 146) |
| Matrix metalloproteinases (MAPs) |
| Tissue inhibitor of metalloproteinases (TIMPs) |
| Tissue or Organ | Activation/ Proliferation | Deletion or Damage |
|---|---|---|
| Skin | ||
| Granulation tissue | Scleroderma; keloid; Dupuytren’s contracture (73, 213, 224); ? psoriasis (63) | |
| Pericyte | Atherosclerosis and restenosis (149, 159); hypertension (208) | Microaneurysms, edema, and hemorrhage (26,239) |
| Mouth | ||
| Periodontal ligament | Periodontal disease (136, 214) | |
| Gingival myofibroblasts | Gingival hypertrophy secondary to drugs (cyclosporin and Dilantin) (135, 136,212, 214, 216) | |
| Eye | ||
| Orbital fibroblast | Exophthalmos (proptosis) of Grave’s disease (9, 221, 254) | |
| Retinal myofibroblast | Proliferative vitreoretinopathy (253) | Diabetic microaneurysm (26, 142, 239) |
| Anterior capsule of lens | Anterior capsular cataract (172, 217) | |
| Corneal myofibroblast | Corneal scarring (184) | |
| Heart and pericardium | Myocardial fibrosis, atherosclerosis, and coronary artery restenosis (35, 149, 159, 258) | |
| Kidney | ||
| Mesangial cell | Proliferative and sclerosing glomerulonephritis (108, 184,239) | Absence of glomerular structure (141, 234) |
| Interstitial cell | Renal tubulointerstitial fibrosis (171,177, 198, 239) | |
| Liver | ||
| Perisinusoidal stellate (Ito cell) | Fibrosis and cirrhosis (72, 88, 150) | |
| Ischemia-reperfusion injury of hepatic transplantation (206) | ||
| Necrotizing hepatitis (62) | ||
| Pancreas | ||
| Periacinal stellate cell | Pancreatic fibrosis (4, 8) | |
| Lung | ||
| Interstitial contractile cell | Pulmonary interstitial fibrosis, idiopathic and drug-induced; sarcoidosis (105,209, 214) | Emphysema (25) |
| Diffuse alveolar damage disease (176) | ||
| Pulmonary hypertension (123) | ||
| Stomach and intestine | ||
| Interstitial cell of Cajal | ? | Abnormal intestinal motility; hypertrophic pyloric stenosis; Hirschsprung’s disease; megacolon of piebaldism; idiopathic pseudoobstruction (33, 52, 115, 183, 212, 243, 248, 249) |
| Subepithelial myofibroblast | Collagenous colitis; villous atrophy and crypt hyperplasia; polyp formation; ? fibrosis of Crohn’s disease (2, 86, 114, 131, 153) | |
| Healing gastric ulcer (170) | ||
| Brain | ||
| Astrocyte | Produce glial scar tissue (166) | Human immunodeficiency virus-associated cognitive motor disease; spongiform encephalopathy (166) |
| Breast | ||
| Stromal myofibroblast | Fibrocystic disease; desmoplastic reaction to breast cancer (73, 214) | |
| Bone marrow | ||
| Stromal cell | Fibrosis in myelodysplasia and neoplastic diseases (182, 218) | Aplastic anemia (182, 218) |
| Joint | ||
| Synoviocyte | Rheumatoid pannus formation (11) |
Healing is facilitated by the fact that the myofibroblasts are contractile, which aids in reducing the amount of denuded surface area of wounded tissue (163, 192, 242). An extension of this contractile capability allows these cells to participate in the ejection of fluid from the gastric glands (237) and in the motility of intestinal villi (120). Their relationship to myoepithelial cells, which have this function in the breast lobule (204) and the seminiferous tubules of the testis (106), is unclear. The contractile property of pericytes and specialized pericytes such as the hepatic stellate (Ito) cell, the mesangial cell of the kidney, and the glomus cell of peripheral vessels gives these myofibroblasts the ability to locally autoregulate blood flow (122, 124, 160, 177, 216, 247). The ability to accumulate and extrude calcium causes cyclic increases and decreases in calcium concentration in these cells, permitting actin-myosin contraction (77). This process is probably the same as or similar to the one responsible for the ability of the ICC to perform a pacemaker function in the intestine (212). Because myofibroblasts are interconnected through gap junctions (120, 212, 246), the electrical signals created by cyclic ion movements can be transmitted through the syncytium and thus through the length of the resident organ.
Myofibroblasts play a major role in the inflammatory response. These cells are avid producers of both chemokines and cytokines (105, 178,179, 227, 235, 267) and are capable of augmenting or downregulating the inflammatory response by the secretion of these soluble mediators of inflammation (Table 2). They also synthesize prostaglandins, expressing both the constitutive cyclooxygenase-1 (COX-1 or PHS-1) gene product and the inducible COX-2 (PHS-2) protein (19, 69, 102, 105, 167, 240,241, 259). In some tissues they make both nitric oxide and carbon monoxide, gases known or proposed to be important neurotransmitters and regulators of motility and inflammation (1, 14, 39, 69, 162, 167, 202,240, 241). When activated, myofibroblasts also express adhesion molecules such as intracellular adhesion molecule-1, vascular cell adhesion molecule, and neural cell adhesion molecule (100, 133, 151,178, 192). Thus lymphocytes, mast cells, and neutrophils may dock on the myofibroblasts and participate in organized immunological and inflammatory reactions (31, 48, 67, 105, 201, 236). Myofibroblasts also express α and β integrins that are part of the adhesion mechanism of myofibroblasts to matrix proteins (192). Through these or other properties, myofibroblasts participate in the formation of tissue granulomas (208, 247). Granulomas themselves are impressive factories of cytokines and other inflammatory mediators (87, 114).
Last, production of matrix molecules such as collagen, glycosaminoglycans, tenascin, and fibronectin in the interstitial space or basement membrane (Table 4) is part of the structure, growth, differentiation, and wound healing function of myofibroblasts (20,227). These processes, when unchecked, deranged, or repeated, can result in tissue fibrosis (4, 25, 71, 72, 88, 138, 150). Therefore, fibrotic disease is a major pathological end point of activated and proliferating myofibroblasts in most, if not all, tissues.
Disease states not mentioned in Table 3 are inflammatory pseudotumors of the lung, liver, or stomach (64) and neoplastic transformation of the myofibroblasts themselves. Recent evidence indicates that stromal tumors of the gastrointestinal tract are derived from c-kit mutations in gastrointestinal myofibroblasts (103). Another benign neoplasm of myofibroblasts is the desmoid tumor, which can occur in any tissue but develops most commonly in the mesentery of the gut (92). Although desmoids can and do occur sporadically, they are particularly common (increased 850 times) in the familial adenomatous polyposis (FAP) syndrome. FAP is a hereditary malignancy presenting as colonic polyps and colorectal carcinoma (233) that is due to mutations in the adenomatous polyposis coli gene (92). Malignant myofibroblasts are also observed in clearly aggressive tumors such as angiosarcomas, fibrosarcomas, histiocytomas, and mesotheliomas (46, 216). Myofibroblasts are also responsible for the desmoplastic reaction seen in many cancers, i.e., the proliferation of fibrotic tissue within or adjacent to the tumor itself. This is most often observed in breast carcinoma, carcinoid tumors, Hodgkin’s disease, and malignant melanomas (70, 153, 204, 218, 264). The role of myofibroblasts in both hereditary and nonhereditary colon cancer is discussed in more detail later in part II of this review [which will appear in the August issue (191)] (see also Ref. 131).
DEFINITION OF A MYOFIBROBLAST
Myofibroblasts may be defined morphologically and immunologically through identification of expressed cytoskeletal proteins (214, 216). The simplest definition of a myofibroblast is that they are smooth-muscle-like fibroblasts. Some investigators choose to call them smooth-muscle-like cells or activated smooth muscle cells (159, 163,237). Others refer to them as lipocytes because of their propensity to store retinoids (vitamin A) or as stellate cells, because of a shape change of transiently differentiated myofibroblasts (see below). Myofibroblasts may well represent an intermediate state between fibroblasts and smooth muscle cells. This is best demonstrated in the prostate (98, 125, 181), in the pericytes surrounding the fetal vessels of the placental stem villus (134), and in the stromal myofibroblasts of the breast (204).
In both cell culture in vitro and native tissues in situ, myofibroblasts possess several distinguishing morphological characteristics, some of which are present in fibroblasts or smooth muscle cells (Fig. 1). They display prominent cytoplasmic actin microfilaments (stress fibers), and they are connected to each other by adherens and gap junctions (51,239). These cells are also in contact with the ECM by focal contacts once known as the fibronexus, a transmembrane complex made up of intracellular contractile microfilaments and the ECM protein fibronectin (65). Both fibronexus formation and stress fiber assembly are regulated by Rho, a newly described member of the RAS superfamily of small guanosine triphosphatases (GTPases) (94), specifically in mammalian cells by Rho A. These small, monomeric GTP-binding proteins also regulate myofibroblast morphology (191, 265). Often, an incomplete basal lamina surrounds the myofibroblasts. Gap junctions couple some myofibroblasts to the tissue smooth muscle, and the cells are commonly in close apposition to varicosities of nerve fibers (134, 212, 243).
Fig. 1. A: transmission electron micrograph of a cultured lumen intestinal subepithelial myofibroblast (18Co). The cell membrane displays numerous caveolae. Stress fibers (bundles of actin microfilaments) are prominent. The cytoplasm is rich in rough endoplasmic reticulum, Golgi apparatus, and mitochondria.B: nucleus of an activated myofibroblast shows multiple indentations. Adherens (C) and gap junctions (D) are present between myofibroblasts. [From Valentich et al. (246).]
In some tissues, e.g., the liver (Ito cells) (88), intestine [both the ICC (243) and the subepithelial myofibroblasts] (78, 246), the orbital myofibroblast (195, 254), the synoviocyte of the joint space (11), and brain (astrocyte) (15, 166, 193), the myofibroblasts exist in two distinct morphological states (Fig.2): 1) the “activated” myofibroblast, as described above, and2) the stellate-transformed myofibroblast, which is considered to be a transiently differentiated myofibroblast. This generalization, correlating appearance and function, has not been verified in every tissue where such morphological heterogeneity has been seen. Agents (e.g., prostaglandins, cholera toxin, vasoactive intestinal polypeptide) that increase the cAMP content of activated myofibroblasts and cell-soluble cAMP analogs themselves induce stellate transformation in vitro within 24 h (78) and stop myofibroblast proliferation (5, 119).
Fig. 2.Phase-contrast micrographs (A andB) and scanning electron micrographs (C andD) of stellate 18Co cells. The stellate myofibroblast displays a highly refractile cell body on phase-contrast microscopy and possesses a highly arborized array of cell processes with several orders of bifurcation. The cell processes are devoid of microvilli, whereas the cell body shows a dense array of long microvilli, giving it a shaggy appearance. [From Valentich et al. (246).]
Immunohistochemical characterization of myofibroblasts is based on antibody reactions to two of the three filament systems of eukaryotic cells (75, 116). These three systems are composed of1) actin, a component of the microfilaments; 2) vimentin, desmin, lamin, or glial fibrillary acidic protein (GFAP), members of the intermediate filament system; and 3) the tubulins of the microtubules. Myofibroblasts have not been characterized with regard to tubulins. The β and γ actins are expressed by all cells, including myofibroblasts, which may also express α-smooth muscle (α-SM) actin (214, 216). Myofibroblasts stain negatively for α-cardiac and α-skeletal actin (216). Myofibroblasts are not well characterized with regard to the newly defined myosin isoforms (75, 161, 217). In some tissues, such as the intestine and reticular cells of lymph nodes and spleen, myofibroblasts stain positive for smooth muscle heavy chain myosin or tropomyosin (old terminology) (216, 243).
Vimentin, desmin, and α-SM actin are the three filaments most often used to classify myofibroblasts (161). Expression of these proteins may vary with the tissue studied within species and is subject to environmental factors, e.g., whether the cells are studied in situ or in culture and, even within a given tissue, whether the cells are activated by hormonal or cytokine treatment or by disease (191). Based on immunohistochemical staining of these filaments in a given tissue, a classification system has been proposed (134, 216). Myofibroblasts that express only vimentin are termed V-type myofibroblasts, those that express vimentin and desmin are called VD-type, those that express vimentin, α-SM actin, and desmin are called VAD-type, those that express vimentin and α-SM actin are called VA-type, and those that express vimentin and myosin are called VM-type.
In the intestine, the ICC express immunoreactive vimentin, γ-SM actin, and smooth muscle tropomyosin, suggesting that they are members of the V or VM (243) class of myofibroblasts. However, we have not been able to find references indicating that ICC have been explored with antibodies to α-SM actin. The intestinal subepithelial myofibroblasts (ISEMFs) stain positive for vimentin and α-SM actin and negative (or weakly) for desmin (VA-type). They also express smooth muscle myosin (thus may be called VAM-type myofibroblasts), although expression of myosin is less than that seen in corresponding smooth muscle cells in the same tissue (120, 153, 246). It is possible that both intestinal myofibroblasts, the ICC and ISEMF, could be the VA(M)-type.
Specific monoclonal antibodies have been developed to identify myofibroblasts in certain tissues. For example, the monoclonal antibody Gb42 recognizes placental myofibroblasts (134). The 8E1 monoclonal antibody reacts with many of the stellate-shaped myofibroblasts, such as GFAP-positive astrocytes, and both intestinal myofibroblasts, the ICC and ISEMF (79). Anti-GFAP serum stains astrocytes, pancreatic periacinar stellate cells, and hepatic stellate (Ito) cells (30). The PR2D3 antibody stains subepithelial myofibroblasts in the stomach and intestine, lung myofibroblasts, periductular myofibroblasts of the kidney, testes, and breast, Ito cells of the liver, umbilical cord stellate myofibroblasts, and both vascular and tissue smooth muscle of most organs (199). Antibodies against the protooncogene c-kit, the receptor for stem cell factor (SCF or steel factor), react with ICC (109, 132, 244) and possibly with pulmonary alveolar myofibroblasts (61). No systematic studies have been reported concerning the reactivity of all the other myofibroblasts to c-kit antibodies.
In many of the studies quoted above, only a subset of the (myo)fibroblasts stain with α-SM actin antibodies in vivo or in vitro (culture). In vivo, not all fibroblastic-appearing cells are myofibroblasts. In culture, treatment with transforming growth factor-β (TGF-β) may induce uniform α-SM actin staining of all the cells, providing the cells are of a single clone (226). Furthermore, activation to an α-SM actin-expressing phenotype may require both TGF-β and a specific cell-matrix interaction (118, 222) (see activation, proliferation, and migration of myofibroblasts).
ORIGIN OF MYOFIBROBLASTS AND ROLE IN GROWTH AND DEVELOPMENT
It is unclear whether myofibroblasts originate from progenitor stem cells (possibly neuroepithelial stem cells) (24, 157) from the neural crest (117) or simply transdifferentiate from resident tissue fibroblasts (81) or from tissue (e.g., vascular, intestinal, or uterine) smooth muscle cells (204). The close anatomic relationship of pericytes to vascular smooth muscle and of intestinal myofibroblasts to intestinal smooth muscle suggests a bidirectional route of transdifferentiation. These various possibilities are depicted in Fig.3. It has recently been suggested that renal tubular cells (a cell of endoderm origin) might differentiate into myofibroblasts (mesenchymal cells) under noxious stimuli (171,177, 198). However, it is equally likely that the peritubular interstitial myofibroblasts are proliferating under these circumstances and simply replacing apoptotic tubular cells in these disease states.
Fig. 3.Proposed scheme depicting the origin, transdifferentiation, activation, and stellate transformation of myofibroblasts. PDGF, platelet-derived growth factor; TLP, tethered ligand protein; TGF-β, transforming growth factor-β; IL-1, interleukin-1; EGF, epidermal growth factor; bFGF, basic fibroblast growth factor; IGFI, insulin-like growth factor I; CTGF, connective tissue growth factor.
Two soluble factors have been shown to promote differentiation from embryonic stem cells: PDGF and SCF. PDGF has two chains, A and B, and exists as a homodimer (PDGF-AA or PDGF-BB) or as a heterodimer (PDGF-AB). Each form acts on separate receptors: α receptors that are nondiscriminatory and can bind AA, BB, and AB dimers or β receptors that are specific for the B chain (126). After ligand binding, there are two separate intercellular signaling pathways for the PDGF receptor: a mitogen-activated protein kinase (MAPK) path and one involving phosphatidylinositol 3-kinase (PI3K). Depending on the cell types, one pathway may be required for cell activation and/or proliferation and the other pathway for cell motility (migration) (3,72, 150). For example, smooth muscle cells proliferate in response to the MAPK cascade and migrate in response to the PI3K path, whereas hepatic stellate cells and endothelial cells respond with both proliferation and migration via the PI3K (72).
Disruption of the PDGF-AA gene in mice is lethal in 50% of affected animals (26). The surviving animals are almost completely devoid of lung alveolar myofibroblasts (also called pulmonary contractile interstitial cells) and develop emphysema due to failure of lung septation. In contrast, animals born with disruption of the PDGF-BB gene have a virtual absence of renal mesangial cells and failure of the formation of the complex structure of the glomerulus (141, 234). The PDGF-BB-deficient animals also lack pericytes and thus develop microaneurysms, reminiscent of those seen in the diabetic retina, and leaky vessels that cause tissue edema and hemorrhage (142). Intestinal subepithelial myofibroblasts (119) and hepatic stellate cells (147) proliferate in response to low concentrations of PDGF-BB, suggesting that this growth factor is important in the growth and development of these cells.
The protooncogene c-kit is the transmembrane glycoprotein tyrosine kinase (III) receptor (160 kDa molecular mass) for SCF, a growth factor secreted by epithelial cells, white blood cells, and (myo)fibroblasts. SCF is also a member of the PDGF family, and the tyrosine kinase type III family also includes receptors for granulocyte/macrophage colony-stimulating factor (GM-CSF). Intestinal ICC (in situ and in culture) express c-kit as detected by rat anti-kit (ACK2) monoclonal antibodies (18, 109, 132, 174, 244). Mutations in the c-kit locus, the W mutants, result in abnormalities in the number, structure, and function of the ICC (18,52, 174, 212, 249). Furthermore, mutants of the ligand SCF, steel (Sl) mutants, also show morphological and functional abnormalities of the ICC (257). Thus the PDGF family of growth factors seems crucial for the embryological development of myofibroblasts. Unfortunately, no systematic study of the various different tissue myofibroblasts has been reported in PDGF or SCF knockout mice or in mutants of their respective receptors.
TGF-β, PDGF, insulin-like growth factor II (IGF-II), and interleukin-4 (IL-4) appear to be the most important growth factors for the transdifferentiation of fibroblasts to myofibroblasts or of stellate-transformed myofibroblasts into activated myofibroblasts (45,61, 145, 211, 239). When myofibroblasts from the intestine (74), breast (203), skin (17, 111, 263), liver (88), lung (214), prostate (181), nose (256), and joint synovium (214) are treated with TGF-β in serum-containing media, they express α-SM actin, reduce the number of vitamin A lipid droplets, and expand the rough endoplasmic reticulum, i.e., they take on the morphology of an activated myofibroblast. Conversely, interferon (IFN)-α and IFN-γ (56, 90) decrease the expression of α-SM actin in myofibroblasts. It is not clear whether they do so by transdifferentiating myofibroblasts back to the fibroblast state, inducing them to undergo stellate transformation, or simply downregulating the amount of α-SM actin in the cell.
ACTIVATION, PROLIFERATION, AND MIGRATION OF MYOFIBROBLASTS
Fibroblasts or stellate-transformed myofibroblasts become activated and proliferate when cultured on plastic in serum-containing growth culture media, especially when seeded at low cell density (74, 155). In vivo activation, as signified by the development of α-SM actin positivity, may be separable from proliferation. Whereas many fibrogenic cytokines [IL-1, tumor necrosis factor (TNF)-α, PDGF, fibroblast growth factor (FGF), and TGF-β] have been incriminated in this process (138), TGF-β appears to be the most important cytokine causing the development of α-SM actin staining and an activated phenotype (25,45, 88, 97, 155, 165, 223, 238) capable of collagen secretion (25, 45,165). The source of TGF-β in damaged tissue may be from white blood cells, parenchymal or epithelial cells, or from the myofibroblast itself in an autocrine fashion (22, 25, 45, 88). Recently, it has been determined that the activation of the myofibroblast requires the presence of matrix molecules, specifically, the ED-A (EIIIA) domain of fibronectin (118, 222). Tissue injury gives rise to this specific ED-A domain splice variant of fibronectin. ED-A is the binding site for cell membranes and for other matrix molecules. It has been shown in both skin granulation tissue (222) and hepatic (118) models that this fibronectin ED-A domain is necessary for TGF-β to trigger α-SM actin expression and collagen secretion by myofibroblasts. Following activation of the myofibroblast, PDGF or connective tissue growth factor (CTGF), a member of the PDGF family (29), appears to be the factor primarily responsible for myofibroblast proliferation (71, 72,89, 119, 147). TGF-β was once considered the prime factor (88, 214,216), but it is now thought that TGF-β acts predominantly through the induction of PDGF receptors on or synthesis of CTGF by the myofibroblasts (72, 89, 111, 112, 263). Thus TGF-β is predominantly a cytodifferentiating rather than a proliferating growth factor.
The TGF-βs are a large superfamily of soluble factors important in growth, development, and fibrogenesis (149). TGF-β1, TGF-β2, and TGF-β3 are encoded from three separate genes. TGF-β1 is the isoform usually upregulated in the presence of tissue injury. It is secreted in a latent form after cleavage from a large promolecule and then noncovalently binds to another peptide on the cell membrane called the latency-associated peptide, which, in turn, is formed from the cleavage fragments of the TGF-β precursor. This latent TGF-β is stored on the surface of the cell or on the extracellular matrix, awaiting conversion by unknown mechanisms to active TGF-β. In contrast to their apparent (but probably indirect) proliferative effect on myofibroblasts (see above), TGF-βs cause G1 phase cell cycle arrest of epithelial and smooth muscle cells and may even induce apoptosis (25). TGF-β acts through a superfamily of serine-threonine kinase cell surface receptors. All three TGF-βs bind first to the type II (RII) receptor that assembles and phosphorylates the type I (RI) receptor, activating this serine-threonine kinase and transducing the signal (25). Microsatellite (genomic) instability due to defects in DNA mismatch repair systems of the TGF-β receptors has been incriminated in the unregulated growth of cancer and in vascular atherosclerosis/restenosis (159). This raises the question of a role for myofibroblasts in these two diseases [see part II of this review (191)].
TGF-α (138), a member of the epidermal growth factor (EGF) family, as well as EGF itself (138, 214, 216, 226), GM-CSF (25), both acidic and basic FGF (aFGF and bFGF, respectively) (25, 119, 185, 214, 216, 226), and IGF-I and IGF-II (25, 226) are candidate growth factors promoting myofibroblast proliferation (see more details in Growth Factors). Proinflammatory cytokines such as TNF-α, IL-1, IL-6, and IL-8 may also cause activation and proliferation (119,138, 177, 185, 246) as does IL-4, a protein generally thought of as an anti-inflammatory cytokine (61, 156, 211).
ANG II or aldosterone, thrombin, and endothelin are also important soluble factors reported to promote myofibroblast activation (15, 34,35, 77, 246, 258). Endothelin is capable of rapidly transdifferentiating the stellate morphology of intestinal myofibroblasts to the activated phenotype within 30 min of addition to cell culture media (78, 80, 246). After it activates the myofibroblasts, endothelin may subsequently inhibit their proliferation (147, 148).
Cocultures of fibroblasts and myofibroblasts with cancer cells of several different types induce transdifferentiation of fibroblasts to myofibroblasts and activation and proliferation of myofibroblasts (13,19, 46, 70, 136, 149, 153, 204, 246, 264). This property of neoplastic cells, perhaps via secretion of growth hormones such as TGF-β, may well be responsible for the desmoplastic reaction (excessive fibrosis) seen in many cancers.
ROLE IN WOUND REPAIR
The process of wound healing is a highly orchestrated event that entails the release of proinflammatory cytokines, eicosanoids of the cyclooxygenase, lipoxygenase, and cytochromeP-450 family, nitric oxide, and a host of growth factors; the secretion of collagen and other matrix proteins; the elaboration of angiogenic, angiostatic, and nerve growth factors; and, finally, if it is a deep or open wound, the formation of granulation tissue that then becomes a scar (fibrosis) (20, 57, 187,208, 214, 247, 252). Myofibroblasts appear to be key cells in these various events. They become activated and proliferate in the early stages of wounding. They respond to proinflammatory cytokines with elaboration of matrix proteins and additional growth factors and then disappear by apoptosis following repair or scar formation (51, 54, 55,113, 164, 266).
Repair Processes
Epithelial tissues such as the intestine or stomach, in contrast to organs such as the liver, kidney, or lung, do not commonly sustain widespread injury that leads to uniform fibrosis. However, gastrointestinal epithelial tissues are often superficially injured. In fact, exfoliation of the epithelium is viewed as a defense response to certain noxious insults such as toxins, microbiological invasion, or gut anaphylaxis (163). The process of repair of the epithelium occurs through two separate mechanisms (252). If the basement membrane underlying the sloughed epithelium is intact, residual epithelial cells at the edges of the wound become motile and move along the basement membrane until they meet advancing epithelial cells from the other side of the wound and form new tight junctions. This process is called restitution (189, 225). Prostaglandins from COX-1 or COX-2 activation are key factors promoting restitution (23) and preserving the epithelial cells from damage (47). Myofibroblast-secreted growth factors such as TGF-β, TGF-α, EGF, aFGF, and bFGF and inflammatory cytokines such as IL-1β and IFN-γ also promote restitution (58, 59, 189, 190, 200).
Conversely, if the wound is deep, the subepithelial tissues that contain interstitial substance, blood vessels, nerves, and fibroblasts must be reconstituted. If the basement membrane has been destroyed by the noxious stimulus, epithelial cells and mesenchymal elements form a new basement membrane (252). Epithelial stem cells then undergo mitosis and proliferate and migrate along the newly formed basement membrane. This latter process is a coordinated event involving secretion of matrix proteins and growth factors. Thus myofibroblasts appear to play roles both in the restitution and repair processes.
A key event in the process of wound repair by either restitution or proliferation is contraction of the underlying granulation tissue or gastrointestinal lamina propria to limit the exposed surface area of the wound (51, 120, 163, 192, 208, 242). Myofibroblasts contain smooth muscle myosin isoforms in addition to α-SM actin, the requisite machinery for contraction and/or motility. The ability of myofibroblasts to carry out these processes depends on changes in the cellular cytoskeleton as well as in the Rho-regulated fibronexus and on the expression of integrins that allow attachment of the myofibroblasts to the extracellular matrix (192, 242).
The fibronexus, discovered and characterized by Eyden (65) and Singer and colleagues (228-232) connects the myofibroblast to the extracellular matrix through a transmembrane αβ integrin complex that joins the actin stress fiber of the myofibroblast to ECM fibronectin (32, 192). The Rho family of small GTPases includes Rac 1–3, Cdc 42, and Rho A–H, which respond to PDGF, TNF-α or bradykinin, or lipopolysaccharide A, respectively. In mammals, Rho A acts on the actin cytoskeleton to cause myofibroblast shape change or motility (6, 265).
ECM
The ECM is a complex mixture of collagen, other glycoproteins, and proteoglycans distributed in each organ or tissue in unique proportions (220, 227). These matrix proteins have several general functions: they are the scaffold for tissue formation and growth; through binding to cell receptors (integrins), they initiate intercellular signaling events; and they bind to growth factors and thus supply sustained concentration of these factors for epithelial or parenchymal cell migration, proliferation, and differentiation (20, 219, 227). There are at least 19 different collagens in the collagen superfamily, with types I, III, IV, and VIII being secreted by myofibroblasts (154, 168). Proteoglycans are proteins with large sulfated polysaccharide side chains of several types (Table 4). The major glycoproteins secreted by the myofibroblasts are the various laminins, which include fibronectin (see activation, proliferation, and migration of myofibroblasts) and tenascin. Laminin is a constituent of the basement membrane along with type IV collagen, entactin, and chondroitin sulfate (all of mesenchymal origin) and perlecan, a large, low-density proteoglycan composed of heparan sulfate side chains of epithelial cell origin (20, 227). Basement membranes and matrix are degraded by a family of Zn2+-dependent matrix metalloproteinases (MMPs 1–3) also secreted by myofibroblasts (146, 251). They are classified by the substrates they degrade: MMP 1 digests types I, II, and III collagen; MMP 2 (gelatinase A) digests denatured collagens I and III and native collagen IV; and MMP 3 (stromelysin) degrades laminin, fibronectin, proteoglycans, type IV collagen, and casein (16, 251). These MMPs are inhibited by tissue inhibitors of metalloproteinases (TIMPs) (16). Growth factors may bind to heparan sulfate proteoglycans or collagen, thus controlling their availability both temporally and spatially, and so modify their biological activity (20, 219, 227, 242).
Growth Factors
The growth factors secreted by myofibroblasts have three general functions as follows: 1) they initiate or increase cell mobility,2) they induce proliferation, i.e., they are paracrine mitogens for epithelial or parenchymal cells and perhaps autocrine mitogens for themselves, or3) they induce terminal differentiation of these cells, even driving the cells to apoptosis. Some growth factors seem to have all three effects.
Individual growth factors may be produced by the epithelial cells alone (trefoil proteins), by mesenchymal cells such as myofibroblasts or inflammatory cells, particularly macrophages and lymphocytes, and some by both cell types (67). Furthermore, the various inflammatory cytokines, eicosanoids, and growth factors released during tissue damage may directly affect the epithelium or parenchymal cell of the injured tissue, or these agents may act more proximally on myofibroblasts to induce these cells to secrete additional cytokines, eicosanoids, or growth factors (67). Thus an in vivo epithelial proliferative response could be the result of a cytodifferentiating effect of mediators on the myofibroblasts, inducing them to express receptors for other factors or to secrete specific epithelial proliferating growth factors. Examples of this are TGF-β1, which induces the expression of PDGF receptors on or CTGF secretion by the myofibroblasts, causing them to proliferate in response to PDGF (137), or the secretion of hepatocyte growth factor (HGF) or keratinocyte growth factor (KGF) by myofibroblasts in response to IL-1 (37) or immune stimulation (10, 66).
IL-1 (60), IL-6 (261), IL-15 (196), and TNF-α (121, 139) have also been identified as being involved in tissue repair and have been shown to be mitogenic for several mesenchymal and epithelial cell lines. Furthermore, combinations of cytokines and growth factors may have offsetting effects on epithelial proliferation, so the ultimate consequence of these various factors in vivo can be quite complicated.
Factors secreted by myofibroblasts such as EGF and TGF-α (12, 188), IGF-I and IGF-II (144, 145), HGF (28, 84, 173), and members of the FGF family, including aFGF, bFGF (also known as FGF-2) (110), KGF (also known as FGF-7) (107, 207), and IL-11 (38, 175, 194), have been demonstrated to be the major paracrine growth factors for epithelial and parenchymal cells. The trefoil peptides, secreted by the epithelial cells themselves, have similar effects through autocrine stimulation (186). These factors may also have nonmitogenic effects on intestinal cells as well, e.g., they may regulate secretory and contractile processes as well as regulate blood flow (245).
The trefoil peptides are so named because of a distinctive pairing of six cysteine residues that results in three interchained loops, thus giving a “three leaf” trefoil shape (38, 186). There are three such trefoil proteins that are small, highly stable molecules secreted principally by the goblet (mucus)-secreting cells of the epithelium and not by myofibroblasts. The stomach secretes peptide pS2 in the fundus and spasmolytic polypeptide (SP) in the antrum, whereas the breast epithelium secretes only pS2 and the pancreas secretes only pancreatic SP (pSP) (129). In contrast, the intestinal epithelium secretes only intestinal trefoil factor (ITF). Targeted gene disruption of ITF causes abnormal epithelial cells and increased susceptibility to various models of injury, resulting in a colitis-like picture (7, 130). Exogenous administration of ITF repairs the damage susceptibility in this knockout model and also protects the gastric mucosa against other injuries such as those induced by ethanol or chronic indomethacin administration (7). PS2 gene knockout mice have a different disease phenotype; they develop extensive neoplastic adenomas in the antrum of the stomach, which then progress to carcinoma in situ (140).
TGF-α, EGF, and the EGF human homologue urogastrone (EGF/URO) are members of the same family of polypeptides and act on a common cell membrane receptor (12, 188). The TGF-α/EGF receptor appears to be upregulated in the mucosa of injured intestine and other organs. TGF-α is expressed in epithelial cells, myofibroblasts, and monocytes/macrophages, whereas EGF seems to be produced primarily by the epithelial cells of the salivary gland and Brunner’s glands of the duodenum. TGF-α is synthesized as a 160-amino acid precursor molecule that spans the cell membrane. Proteases release the soluble 50-amino acid form. It is unclear whether the membrane-bound form is active as a growth factor for adjacent cells. The soluble factor is trophic (mitogenic) for a number of cell lines in vitro and intestinal epithelial cells in vivo. It may well have differentiating functions as well. Ulceration of the human gastrointestinal mucosa causes the development of a specific cell lineage from epithelial stem cells that bud from the crypts next to an ulcer and then ramify to form a small gland. These budding glands secrete EGF/URO, which stimulates epithelial proliferation and promotes ulcer healing (260).
The FGF family (aFGF and bFGF) are important mitogens for myofibroblasts and have powerful neurotrophic and angiogenic properties that are important for tissue healing (68, 110). Other angiogenic factors secreted by myofibroblasts include the CXC family of cytokines such as IL-8 and epithelial neutrophil-activating peptide (ENA-78) (5, 127, 178). Cell-to-cell contact such as that occurring in restitution or wound healing has its antiapoptotic action via the adhesion molecule N-cadherin. When the adjacent cells touch, there is homophilic binding of N-cadherin molecules, which activate the FGF family of receptors. In this way, cell contact mimics the antiapoptotic effect of bFGF (91).
IGF-I and IGF-II are structurally related polypeptides that have various metabolic, proliferative, and differentiating effects through endocrine, autocrine, and paracrine mechanisms (144, 145). The effects are mediated by IGF-I receptors and insulin receptors. There is an IGF-II receptor, but its role in signal transduction is unclear. IGF is present in the circulation (from liver) and is also secreted in a paracrine fashion by myofibroblasts adjacent to epithelial and parenchymal cells (144). The IGF actions are determined by the availability of free IGF, the form that interacts with its receptors. In turn, the amount of free IGF is modulated by the level of high-affinity IGF-binding proteins (IGFBPs), of which six have been identified (42-44). These IGFBPs not only regulate the bioavailability of IGF but also inhibit or enhance its action on target tissues. Although the IGFs are weakly mitogenic for epithelial and parenchymal cells, they seem to be powerfully mitogenic for myofibroblasts (226) and other smooth muscle cells (255).
A new member of the family of factors stimulating epithelial growth is IL-11, a multifunctional cytokine originally derived from bone marrow stromal cells (175, 194). It regulates the growth of hematopoietic and lymphoid cells by acting on the IL-6 family of cytokine receptors. It stimulates proliferation of small intestinal crypts and accelerates recovery of the intestinal mucosa from models of damage (143). It also has trophic effects on neurons, preadipocytes, and myofibroblasts of the lung (175). TGF-β and IL-1 are potent stimulants of IL-11 production. Paradoxically, IL-11 has been shown to inhibit epithelial cell proliferation in the lung by altering phosphorylation of the retinoblastoma protein (194). Thus it is possible that the proliferative effect of IL-11 on epithelia occurs via activation of myofibroblasts, with subsequent secretion of epithelial proliferating factors by these cells, rather than being a direct effect of IL-11 on the epithelium itself.
KGF is a member of the FGF family (FGF-7) (107, 207). This factor is unique because, unlike other members of the FGF family, it does not appear to have activity on fibroblasts, endothelial cells, or other nonepithelial targets. This is a consequence of the epithelial cell expression of the KGF receptor (KGFR), a transmembrane tyrosine kinase that binds KGF and aFGF with high affinity and binds bFGF much more poorly. The KGFR is nearly identical to the FGF receptor type II, except for alterations in a 49-amino acid residue in one of its extracellular loops. FGFR-II does not bind KGF but shows a high affinity for both aFGF and bFGF. KGFR expression is limited to epithelial cells, whereas FGFR-II is present in a variety of tissues including fibroblasts. KGF, initially isolated from lung fibroblasts, appears to be a myofibroblast-secreted epithelial growth factor with specific roles in epithelial growth and differentiation. The KGFR is expressed on the epithelial cells, and KGF has been shown to induce proliferation and differentiation of a host of epithelial and parenchymal cells, including intestinal epithelial cells, type II pneumocytes, hepatocytes, and keratinocytes of the skin. Its expression and secretion are regulated by IL-1 (37). Its synthesis is significantly upregulated in the lamina propria of inflamed intestine (66). Thus KGF represents a prime example of a mediator causing a specific mesenchymal-epithelial interaction.
HGF, also known as scatter factor because it induces cell migration as well as proliferation, is synthesized and secreted by fibroblasts and myofibroblasts (28, 84). HGF is a glycoprotein heparin-binding heterodimer related to plasminogen, consisting of a heavy α chain and a light β chain held together by disulfide bonds (84). It is produced as a single-chain precursor protein and proteolytically cleaved to form HGF. The HGF receptor, prominently expressed by epithelial cells, is encoded by the protooncogene c-met. This receptor is a heterodimeric glycoprotein of 190 kDa linked with two disulfide bonds; the α chain is extracellular, while the membrane-spanning β chain has the cytoplasmic domain of a tyrosine kinase. C-met also is regulated by proteases that cleave both chains from a 178-kDa common precursor. Thus HGF is only active if the correct proteases are present. Like TGF-β, HGF has effects on cell division, motility, and apoptosis and appears to have angiogenic activity (28). Its synthesis is stimulated by IL-1 (28). Not only does it cause proliferation of epithelial cells but it also affects parenchymal cells such as liver and bone (28). Thus HGF, like KGF, is a major mediator of epithelial-mesenchymal interactions and epithelial morphogenesis (207).
The process of repair is completed by the terminal differentiation of epithelial and parenchymal cells and by apoptosis of the α-SM actin myofibroblasts (51, 81, 216). The factors that terminate the repair process are poorly understood. The role of IL-10, INF-γ, and INF-α in either the downregulation (90, 197) of myofibroblasts or induction of their apoptosis (95, 128) needs further investigation.
ROLE IN FIBROSIS
With repeated cycles of injury and repair or if, for unclear reasons, there is loss of the signals that discontinue the healing process, organ fibrosis occurs. The important functions of the myofibroblasts in the fibrosis of tissues such as the skin, lung, pancreas, and kidney are well described (see references in Table 4). The effects of PDGF, TGF-β, and other growth factors in the fibrotic process have been studied in detail (72, 93, 167, 214, 239) and are beyond the scope of this review (see Refs. 20 and 96 for detailed reviews of fibrosis).
Factors that act on myofibroblasts are important in tissue fibrosis. Recently, the key role of TGF-β in fibrosis has been accentuated by the finding of fibrosis of multiple organs, including the liver, kidney (both renal interstitium and glomerulus), and adipose tissue in a transgenic mouse overexpressing TGF-β (45). PDGF-BB causes fibrosis in the kidney (239), and, given the propensity of TGF-β to upregulate PDGF receptors, an equally important role for PDGF cannot be ruled out. IGF-I has been shown also to induce collagen mRNA and IGF binding protein-5 mRNA in rat intestinal smooth muscle (269), raising the question of an important role for this growth factor in organ fibrogenesis (268). IL-1, IL-6, INF-γ, TNF-α, and bFGF have also been incriminated as fibrogenic cytokines (101, 205). Potential abnormalities in matrix secretion, degradation of matrix by MMPs, and inhibition of MMPs by TIMPs (see above) that might result in fibrosis are under investigation (21, 96, 154). An understanding of these processes and the development of effective pharmacological or biological inhibitors would be important advances in the treatment of disease.
CONCLUSIONS AND SPECULATION
Myofibroblasts are ubiquitous cells with similar properties and functions that play important roles in growth and development, wound repair, and disease. Either their absence or their activation and proliferation in a given tissue or organ can lead to specific diseases as outlined in Table 3. However, because they are present in virtually every tissue, it is possible that they may play a role in multisystem diseases as well. For example, do abnormalities in pericytes account for some of the multifocal effects of chronic hypertension (208)? Are the multiple abnormalities of diabetes mellitus due to stimulation of or damage to vascular, renal, intestinal, and skin myofibroblasts? It is intriguing that high glucose concentrations induce TGF-β1 production by the glomerular mesangial cell (135), and PDGF and bFGF improve wound healing in genetically diabetic animals (87). What is the role of myofibroblasts in aging, a condition in which myofibroblasts are reported to be morphologically abnormal (169)? These are but a few of the intriguing questions raised by this unique family of pleiotropic cells.
We thank Terri Kirschner for excellent editorial expertise.
FOOTNOTES
We acknowledge the support of National Institute of Diabetes and Digestive and Kidney Diseases Grant 2 R37 DK-15350, a grant from the Crohn’s and Colitis Foundation of America, and support from The Keating Fund for Research Prevention of Cancer, administered by the University of Texas Medical Branch (UTMB) Small Grants Program, UTMB at Galveston.
REFERENCES
- 1 Hemeoxygenase-1 inhibits human myometrial contractility via carbon monoxide and is upregulated by progesterone during pregnancy.J. Clin. Invest.1011998949955
Crossref | PubMed | ISI | Google Scholar - 2 Extracellular matrix composition and gene expression in collagenous colitis.Gastroenterology1131997136143
Crossref | PubMed | ISI | Google Scholar - 3 Platelet-derived growth factor and fibronectin-stimulated migration are differentially regulated by the Rac and extracellular signal-regulated kinase pathways.J. Biol. Chem.27219973068830692
Crossref | PubMed | ISI | Google Scholar - 4 Periacinar stellate shaped cells in rat pancreas: identification, isolation and culture.Gut431998128133
Crossref | PubMed | ISI | Google Scholar - 5 Epithelial neutrophil-activating peptide (ENA-78) is an important angiogenic factor in non-small cell lung cancer.J. Clin. Invest.1021998465472
Crossref | PubMed | ISI | Google Scholar - 6 The Rho GTPases have multiple effects on the actin cytoskeleton.Exp. Cell Res.24619992025
Crossref | PubMed | ISI | Google Scholar - 7 Oral trefoil peptides protect against ethanol- and indomethacin-induced gastric injury in rats.Gastroenterology1101996489497
Crossref | PubMed | ISI | Google Scholar - 8 Identification, culture, and characterization of pancreatic stellate cells in rats and humans.Gastroenterology1151998421432
Crossref | PubMed | ISI | Google Scholar - 9 The fibroblast is the target cell in the connective tissue manifestations of Graves’ disease.Int. Arch. Allergy Immunol.1061998213218
Crossref | ISI | Google Scholar - 10 Interactions between stromal cell-derived keratinocyte growth factor and epithelial transforming growth factor in immune-mediated crypt cell hyperplasia.J. Clin. Invest.102199814731480
Crossref | PubMed | ISI | Google Scholar - 11 Rheumatoid synovial cell morphologic changes induced by a mononuclear cell factor in culture.Arthritis Rheum.261983814
Crossref | PubMed | Google Scholar - 12 Epidermal growth factor-related peptides and their relevance to gastrointestinal pathophysiology.Gastroenterology1081995564580
Crossref | PubMed | ISI | Google Scholar - 13 Desmoplastic breast carcinoma as a source of human myofibroblasts.Am. J. Pathol.1151984329333
PubMed | ISI | Google Scholar - 14 Expression pattern of heme oxygenase isoenzymes 1 and 2 in normal and stress-exposed rat liver.Hepatology271998829838
Crossref | PubMed | ISI | Google Scholar - 15 Thrombin receptor peptides induce shape change in neonatal murine astrocytes in culture.J. Neurosci. Res.371994108115
Crossref | PubMed | ISI | Google Scholar - 16 Expression of tissue inhibitor of metalloproteinases 1 and 2 is increased in fibrotic human liver.Gastroenterology1101996821831
Crossref | PubMed | ISI | Google Scholar - 17 TGF beta and bFGF synthesis and localization in Dupuytren’s disease (nodular palmar fibromatosis) relative to cellular activity, myofibroblast phenotype and oncofetal variants of fibronectin.Histochem. J.27199510141020
Crossref | PubMed | Google Scholar - 18 Spatial and temporal patterns of c-kit-expressing cells in WlacZ/+ and WlacZ/WlacZ mouse embryos.Development122199630233033
Crossref | PubMed | ISI | Google Scholar - 19 Fibroblasts modulate intestinal secretory responses to inflammatory mediators.J. Clin. Invest.891992484489
Crossref | PubMed | ISI | Google Scholar - 20 Molecular aspects of mesenchymal-epithelial interactions.Annu. Rev. Cell Biol.91993511540
Crossref | PubMed | Google Scholar - 21 Hepatic fibrosis and cirrhosis.Hepatology: A Textbook of Liver Disease, Zakim D., Boyer T. D.1996506525SaundersPhiladelphia, PA
Google Scholar - 22 Cell-specific expression of transforming growth factor-β in rat liver. Evidence for autocrine regulation of hepatocyte proliferation.J. Clin. Invest.961995447455
Crossref | PubMed | ISI | Google Scholar - 23 Prostaglandins I2 and E2 have a synergistic role in rescuing epithelial barrier function in porcine ileum.J. Clin. Invest.100199719281933
Crossref | PubMed | ISI | Google Scholar - 24 A new source of cells contributing to the developing gastrointestinal tract demonstrated in chick embryos.Gastroenterology1141998878882
Crossref | PubMed | ISI | Google Scholar - 25 Transforming growth factor β in tissue fibrosis.N. Engl. J. Med.331199412861292
Crossref | PubMed | ISI | Google Scholar - 26 PDGF-A signaling is a critical event in lung alveolar myofibroblast development and alveogenesis.Cell851996863873
Crossref | PubMed | ISI | Google Scholar - 27 Myofibroblasts in human palatal mucosa.Acta Anat. (Basel)1311988161165
Crossref | PubMed | Google Scholar - 28 A two-pronged approach to the clinical use of HGF.Lancet3511998272
Crossref | PubMed | ISI | Google Scholar - 29 Connective tissue growth factor: a cysteine-rich mitogen secreted by human vascular endothelial cells is related to the SRC-induced immediate early gene product CEF-10.J. Cell Biol.114199112851294
Crossref | PubMed | ISI | Google Scholar - 30 Glial fibrillary acidic protein as a marker of perisinusoidal stellate cells that can distinguish between the normal and myofibroblast-like phenotypes.Biol. Cell8719966573
Crossref | PubMed | ISI | Google Scholar - 31 Chemotactic factors stimulate CD18-dependent canine neutrophil adherence and motility on lung fibroblasts.J. Immunol.156199633893401
PubMed | ISI | Google Scholar - 32 Cell shape determination: a pivotal role for Rho.Science2721996224225
Crossref | PubMed | ISI | Google Scholar - 33 Interstitial cells of Cajal (ICC) are absent or deranged in intestinal pseudo-obstruction (Abstract).Lab. Invest.78199861A
Google Scholar - 34 Temporal differences in fibroblast proliferation and phenotype expression in response to chronic administration of angiotensin II or aldosterone.J. Mol. Cell. Cardiol.27199515451560
Crossref | PubMed | ISI | Google Scholar - 35 Angiotensin II stimulated expression of transforming growth factor-β1 in cardiac fibroblasts and myofibroblasts.J. Mol. Cell. Cardiol.29199719471958
Crossref | PubMed | ISI | Google Scholar - 36 Chemokine expression by intestinal myofibroblasts (Abstract).Gastroenterology1121997A944
Google Scholar - 37 Regulation of keratinocyte growth factor gene expression by interleukin 1.J. Biol. Chem.26919941075310757
Crossref | PubMed | ISI | Google Scholar - 38 Trefoil peptides: less clandestine in the intestine.Science2741996204
Crossref | PubMed | ISI | Google Scholar - 39 Nitric oxide in excitable tissues: physiological roles and disease.J. Clin. Invest.100199724242429
Crossref | PubMed | ISI | Google Scholar - 40 Expression of α-smooth-muscle actin in stromal cells of the uterine cervix during epithelial neoplastic changes.Int. J. Cancer471991843846
Crossref | PubMed | ISI | Google Scholar - 41 Regulation of fibroplasia in cutaneous wound repair.Am. J. Med. Sci.30619934248
Crossref | PubMed | ISI | Google Scholar - 42 Insulin-like growth factor binding proteins and their role in controlling IGF actions.Cytokine Growth Factor Rev.819974562
Crossref | PubMed | Google Scholar - 43 Role of insulin-like growth factor binding proteins in controlling IGF actions.Mol. Cell. Endocrinol.14019981924
Crossref | PubMed | ISI | Google Scholar - 44 Modifications of insulin-like growth factor binding proteins and their role in controlling IGF actions.Endocr. J.45, Suppl.1998S1S8
Crossref | PubMed | ISI | Google Scholar - 45 Hepatic fibrosis, glomerulosclerosis, and a lipodystrophy-like syndrome in PEPCK-TGF-β1 transgenic mice.J. Clin. Invest.100199726972713
Crossref | PubMed | ISI | Google Scholar - 46 Characterisation of a myofibroblast-like cell line from an angiosarcoma.Int. J. Oncol.91996411418
PubMed | ISI | Google Scholar - 47 Crypt stem cell survival in the mouse intestinal epithelium is regulated by prostaglandins synthesized through cyclooxygenase-1.J. Clin. Invest.99199713671379
Crossref | PubMed | ISI | Google Scholar - 48 T-lymphocyte-fibroblast interactions.Biochem. Soc. Trans.251997529531
Crossref | PubMed | ISI | Google Scholar - 49 Alpha smooth muscle actin (alpha-SM actin) in normal human ovaries, in ovarian stromal hyperplasia and in ovarian neoplasms.Virchows Arch. B Cell Pathol. Incl. Mol. Pathol.5719895561
Crossref | PubMed | Google Scholar - 50 Capillary growth: a two-cell system.Semin. Cancer Biol.319924956
PubMed | Google Scholar - 51 Alpha-smooth muscle actin is transiently expressed by myofibroblasts during experimental wound healing.Lab. Invest.6319902129
PubMed | ISI | Google Scholar - 52 Interstitial cells of Cajal direct normal propulsive contractile activity in the mouse small intestine.Gastroenterology1141998724736
Crossref | PubMed | ISI | Google Scholar - 53 A cellular reticulum of fibroblast-like cells in the rat intestine: scanning and transmission electron microscopy.Arch. Histol. Jpn.471984179186
Crossref | PubMed | Google Scholar - 54 Myofibroblast differentiation during fibrosis.Exp. Nephrol.31995134139
PubMed | Google Scholar - 55 Apoptosis mediates the decrease in cellularity during the transition between granulation tissue and scar.Am. J. Pathol.14619955666
PubMed | ISI | Google Scholar - 56 Alpha-smooth muscle actin is expressed in a subpopulation of cultured and cloned fibroblasts and is modulated by gamma-interferon.Exp. Cell Res.20119926473
Crossref | PubMed | ISI | Google Scholar - 57 Liver regeneration 3: regulation of signal transduction during liver regeneration.FASEB J.101996215227
Crossref | PubMed | ISI | Google Scholar - 58 Cytokine modulation of intestinal epithelial cell restitution: central role of transforming growth factor β.Gastroenterology105199313231332
Crossref | PubMed | ISI | Google Scholar - 59 Fibroblast growth factors modulate intestinal epithelial cell growth and migration.Gastroenterology106199412541262
Crossref | PubMed | ISI | Google Scholar - 60 Biologic basis for interleukin-1 in disease.Blood87199620952147
Crossref | PubMed | ISI | Google Scholar - 61 Interleukin (IL) 4 and IL-13 act on human lung fibroblasts. Implication in asthma.J. Clin. Invest.101199821292139
Crossref | PubMed | ISI | Google Scholar - 62 Sequential changes in human Ito cells and their relation to postnecrotic liver fibrosis in massive and submassive hepatic necrosis.Virchows Arch.426199595101
Crossref | PubMed | ISI | Google Scholar - 63 Insights into the pathogenesis of psoriasis and psoriatic arthritis.Am. J. Med. Sci.3161998271276
Crossref | PubMed | ISI | Google Scholar - 64 Gastric inflammatory myofibroblastic proliferation in children.Pediatr. Surg. Int.1319989599
Crossref | PubMed | ISI | Google Scholar - 65 Brief review of the fibronexus and its significance for myofibroblastic differentiation and tumor diagnosis.Ultrastruct. Pathol.171993611622
Crossref | PubMed | ISI | Google Scholar - 66 Increased expression of keratinocyte growth factor messenger RNA associated with inflammatory bowel disease.Gastroenterology1101996441451
Crossref | PubMed | ISI | Google Scholar - 67 Intestinal inflammation: a complex interplay of immune and nonimmune cell interactions.Am. J. Physiol.273Gastrointest. Liver Physiol. 361997G769G775
Abstract | ISI | Google Scholar - 68 Basic fibroblast growth factor-induced activation of latent transforming growth factor in endothelial cells: regulation of plasminogen activator activity.J. Cell Biol.1181992901909
Crossref | PubMed | ISI | Google Scholar - 69 Expressional control of the ”constitutive“ isoforms of nitric oxide synthase (NOS I and NOS III).FASEB J.121998773790
Crossref | PubMed | ISI | Google Scholar - 70 Expression of connective tissue growth factor mRNA in the fibrous stroma of mammary tumors.Int. J. Biochem. Cell Biol.291997153161
Crossref | PubMed | ISI | Google Scholar - 71 The cellular basis of hepatic fibrosis.N. Engl. J. Med.328199318281835
Crossref | PubMed | ISI | Google Scholar - 72 Closing in on the signals of hepatic fibrosis.Gastroenterology112199714061409
Crossref | PubMed | ISI | Google Scholar - 73 Evidence of fibroblast heterogeneity and the role of fibroblast subpopulations in fibrosis.Clin. Immunol. Immunopathol.721994283292
Crossref | PubMed | Google Scholar - 74 Cytokines modulate fibroblast phenotype and epithelial-stroma interactions in rat intestine.Gastroenterology1121997826838
Crossref | PubMed | ISI | Google Scholar - 75 A structural scaffolding of intermediate filaments in health and disease.Science2791998514519
Crossref | PubMed | ISI | Google Scholar - 76 Ovarian steroids regulate the expression of basic fibroblast growth factor and its mRNA in fibroblasts derived from uterine endometrium.Ann. Clin. Biochem.3419979196
Crossref | PubMed | ISI | Google Scholar - 77 Intracellular calcium responses and shape conversions induced by endothelin in cultured subepithelial fibroblasts of rat duodenal villi.Pflügers Arch.428199497104
Crossref | PubMed | ISI | Google Scholar - 78 Characteristics of cultured subepithelial fibroblasts of rat duodenal villi.Anat. Embryol.1871993529538
Crossref | PubMed | Google Scholar - 79 A monoclonal antibody to astrocytes, subepithelial fibroblasts of small intestinal villi and interstitial cells of the myenteric plexus layer.Anat. Embryol.1951997113126
Crossref | PubMed | Google Scholar - 80 125I-endothelin binds to fibroblasts beneath the epithelium of rat small intestine.J. Electron Microsc.391990264268
PubMed | Google Scholar - 81 The cellular derivation and the life span of the myofibroblast.Pathol. Res. Pract.1921996708711
Crossref | PubMed | ISI | Google Scholar - 82 The fibroblast.Handbook of Inflammation. Tissue Repair and Regeneration, Glynn L. E.1981150Elsevier/North-Holland BiomedicalAmsterdam
Google Scholar - 83 Presence of modified fibroblasts in granulation tissue and their possible role in wound contraction.Experientia271971549550
Crossref | PubMed | Google Scholar - 84 Intestinal fibroblasts regulate intestinal epithelial cell proliferation via hepatocyte growth factor.Am. J. Physiol.274Gastrointest. Liver Physiol. 371998G809G818
Abstract | ISI | Google Scholar - 85 Myofibroblasts in the rat testicular capsule.Cell Tissue Res.1541974533541
Crossref | PubMed | ISI | Google Scholar - 86 Pathogenesis of intestinal strictures in Crohn’s disease—an update.Inflamm. Bowel Dis.11995220227
Crossref | PubMed | Google Scholar - 87 PDGF and FGF stimulate wound healing in the genetically diabetic mouse.Am. J. Pathol.136199012351246
PubMed | ISI | Google Scholar - 88 Transdifferentiation of hepatic stellate cells (Ito cells) to myofibroblasts: a key event in hepatic fibrogenesis.Kidney Int. Suppl.541996S39S45
PubMed | Google Scholar - 89 Connective tissue growth factor: a mediator of TGF-β action on fibroblasts.Cytokine Growth Factor Rev.81997171179
Crossref | PubMed | Google Scholar - 90 Liver stellate cells in chronic viral hepatitis: the effect of interferon therapy.J. Hepatol.241996301307
Crossref | PubMed | ISI | Google Scholar - 91 Opposing actions of hepatocyte growth factor and basic fibroblast growth factor on cell contact, intracellular free calcium levels, and rat ovarian surface epithelial cell viability.Endocrinology138199718471856
Crossref | PubMed | ISI | Google Scholar - 92 Desmoid tumours in familial adenomatous polyposis.Gut351994377381
Crossref | PubMed | ISI | Google Scholar - 93 The origin of Ia antigen-expressing cells in the rat kidney.Am. J. Pathol.1271987342348
PubMed | ISI | Google Scholar - 94 Rho GTPases and the actin cytoskeleton.Science2791998509514
Crossref | PubMed | ISI | Google Scholar - 95 Regulation of cell number in the mammalian gastrointestinal tract: the importance of apoptosis.J. Cell Sci.107199435693577
Crossref | PubMed | ISI | Google Scholar - 96 Fibrosis: representative molecular elements, a basic concept, and emerging targets for suppressive treatment.Hepatology: A Textbook of Liver Disease, Zakim D., Boyer T. D.1996465506SaundersPhiladelphia, PA
Google Scholar - 97 A transforming growth factor β (TGFβ) control element drives TGFβ-induced stimulation of smooth muscle α-actin gene expression in concert with two CArG elements.J. Biol. Chem.27219971094810956
Crossref | PubMed | ISI | Google Scholar - 98 Stromal-epithelial interactions in the normal and neoplastic prostate.Br. J. Urol.79, Suppl. 219971826
Crossref | PubMed | Google Scholar - 99 Mast cell and myofibroblast in wound healing.Dermatol. Clin.111993685696
Crossref | PubMed | ISI | Google Scholar - 100 Expression of intracellular adhesion molecule 1 by activated hepatic stellate cells.Hepatology241996670676
Crossref | PubMed | ISI | Google Scholar - 101 Tumor necrosis factor α inhibits collagen α 1(I) gene expression in rat hepatic stellate cells through a G protein.Gastroenterology1131997625640
Crossref | PubMed | ISI | Google Scholar - 102 IL-1 stimulates intestinal myofibroblast COX gene expression and augments activation of Cl− secretion in T84 cells.Am. J. Physiol.271Cell Physiol. 401996C1262C1268
Link | ISI | Google Scholar - 103 Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors.Science2791998577580
Crossref | PubMed | ISI | Google Scholar - 104 Characterization of newly established testicular peritubular and prostatic stromal cell lines: potential use in the study of mesenchymal-epithelial interactions.Endocrinology136199528622873
Crossref | PubMed | ISI | Google Scholar - 105 Dynamic interactions between lung fibroblasts and leukocytes: implications for fibrotic lung disease.Proc. Assoc. Am. Physicians1101998313320
PubMed | Google Scholar - 106 Myofibroblasts in the lamina propria of human seminiferous tubules are dynamic structures of heterogeneous phenotype.Arch. Histol. Cytol.591996109125
Crossref | PubMed | Google Scholar - 107 Keratinocyte growth factor induces proliferation of hepatocytes and epithelial cells throughout the rat gastrointestinal tract.J. Clin. Invest.94199417641777
Crossref | PubMed | ISI | Google Scholar - 108 Glomerulonephritis.N. Engl. J. Med.3391998888899
Crossref | PubMed | ISI | Google Scholar - 109 W/kit gene required for interstitial cells of Cajal and for intestinal pacemaker activity.Nature3731995347349
Crossref | PubMed | ISI | Google Scholar - 110 Basic fibroblast growth factor treatment for non-steroidal anti-inflammatory drug associated gastric ulceration.Gut371995610612
Crossref | PubMed | ISI | Google Scholar - 111 Different effects of basic fibroblast growth factor and transforming growth factor-β on the two platelet-derived growth factor receptors’ expression in scleroderma and healthy human dermal fibroblasts.J. Invest. Dermatol.1041995124127
Crossref | PubMed | ISI | Google Scholar - 112 Regulation of connective tissue growth factor gene expression in human skin fibroblasts and during wound repair.Mol. Biol. Cell41993637645
Crossref | PubMed | ISI | Google Scholar - 113 Mechanisms of spontaneous resolution of rat liver fibrosis. Hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors.J. Clin. Invest.1021998538549
Crossref | PubMed | ISI | Google Scholar - 114 Modulation of morphology, proliferation and collagen synthesis in fibroblasts by the exudate from hypersensitive granulomatous inflammation in rats.Int. Arch. Allergy Immunol.1041994340347
Crossref | PubMed | ISI | Google Scholar - 115 Deficiency of c-kit+ cells in patients with a myopathic form of chronic idiopathic intestinal pseudo-obstruction.Am. J. Gastroenterol.921997332334
PubMed | ISI | Google Scholar - 116 Intermediate filaments of myofibroblasts. Immunochemical and immunocytochemical analyses.Pathol. Res. Pract.1821987248254
Crossref | PubMed | ISI | Google Scholar - 117 In vitro system for differentiating pluripotent neural crest cells into smooth muscle cells.J. Biol. Chem.273199859935996
Crossref | PubMed | ISI | Google Scholar - 118 Expression of variant fibronectins in wound healing: cellular source and biological activity of the EIIIA segment in rat hepatic fibrogenesis.J. Cell Biol.127199420372048
Crossref | PubMed | ISI | Google Scholar - 119 Regulation of proliferation of human colonic subepithelial myofibroblasts by mediators important in intestinal inflammation.J. Clin. Invest.101199826502657
Crossref | PubMed | ISI | Google Scholar - 120 Morphologic and biochemical evidence for a contractile cell network within the rat intestinal mucosa.Gastroenterology9219876881
Crossref | PubMed | ISI | Google Scholar - 121 Tumor necrosis factor α regulates proliferation in a mouse intestinal cell line.Gastroenterology112199712311240
Crossref | PubMed | ISI | Google Scholar - 122 Endothelin-1-induced vasoconstriction causes a significant increase in portal pressure of rat liver: localized constrictive effect on the distal segment of preterminal portal venules as revealed by light and electron microscopy and serial reconstruction.Hepatology271998735747
Crossref | PubMed | ISI | Google Scholar - 123 Modulation of actin isoform expression in alveolar myofibroblasts (contractile interstitial cells) during pulmonary hypertension.Am. J. Pathol.1361990881889
PubMed | ISI | Google Scholar - 124 Immunoelectron microscopical characterization of the epithelioid type of smooth muscle cells in human glomus organs.Ultrastruct. Pathol.211997425430
Crossref | PubMed | ISI | Google Scholar - 125 Stromal cells of the human prostate: initial isolation and characterization.Prostate2819968997
Crossref | PubMed | ISI | Google Scholar - 126 The colonic pericryptal fibroblast sheath: replication, migration, and cytodifferentiation of a mesenchymal cell system in adult tissue. 3. Replication and differentiation in human hyperplastic and adenomatous polyps.Gastroenterology601971515536
Crossref | PubMed | ISI | Google Scholar - 127 CXC chemokines and angiogenesis/angiostasis.Proc. Assoc. Am. Physicians1101998288296
PubMed | Google Scholar - 128 IL-4 regulates growth and differentiation by distinct mechanisms.Immunologist41996194198
Google Scholar - 129 Expression of trefoil peptides pS2 and human spasmolytic polypeptide in gastric metaplasia at the margin of duodenal ulcers.Gut371995205209
Crossref | PubMed | ISI | Google Scholar - 130 Trefoil peptide protection of intestinal epithelial barrier function: cooperative interaction with mucin glycoprotein.Gastroenterology1091995516523
Crossref | PubMed | ISI | Google Scholar - 131 Landscaping the cancer terrain.Science280199810361037
Crossref | PubMed | ISI | Google Scholar - 132 A role for stem cell factor (SCF): c-kit interaction(s) in the intestinal tract response to Salmonella typhimurium infection.J. Exp. Med.1841996271276
Crossref | PubMed | ISI | Google Scholar - 133 Cell-type-specific expression of neural cell adhesion molecule (N-CAM) in Ito cells of rat liver. Up-regulation during in vitro activation and in hepatic tissue repair.Am. J. Pathol.1491996449462
PubMed | ISI | Google Scholar - 134 Placental villous stroma as a model system for myofibroblast differentiation.Histochem. Cell Biol.1051996415429
Crossref | PubMed | ISI | Google Scholar - 135 High glucose-induced transforming growth factor β1 production is mediated by the hexosamine pathway in porcine glomerular mesangial cells.J. Clin. Invest.1011998160169
Crossref | PubMed | ISI | Google Scholar - 136 Re-evaluation of fibroblasts and fibroblast-like cells.Anat. Embryol.1821990103112
Crossref | PubMed | Google Scholar - 137 Inhibition of TGF-β-stimulated CTGF gene expression and anchorage-independent growth by cAMP identifies a CTGF-dependent restriction point in the cell cycle.FASEB J.12199811511161
Crossref | PubMed | ISI | Google Scholar - 138 Fibrogenic cytokines and connective tissue production.FASEB J.81994854861
Crossref | PubMed | ISI | Google Scholar - 139 TR1, a new member of the tumor necrosis factor receptor superfamily, induces fibroblast proliferation and inhibits osteoclastogenesis and bone resorption.FASEB J.121998845854
Crossref | PubMed | ISI | Google Scholar - 140 Gastric mucosa abnormalities and tumorigenesis in mice lacking the pS2 trefoil protein.Science2741996259262
Crossref | PubMed | ISI | Google Scholar - 141 Mice deficient for PDGF B show renal, cardiovascular, and hematological abnormalities.Genes Dev.8199418751887
Crossref | PubMed | ISI | Google Scholar - 142 Pericyte loss and microaneurysm formation in PDGF-B-deficient mice.Science2771997242245
Crossref | PubMed | ISI | Google Scholar - 143 Trophic effects of interleukin-11 in rats with experimental short bowel syndrome.J. Pediatr. Surg.31199610471050
Crossref | PubMed | ISI | Google Scholar - 144 Insulin-like growth factors.Gut Peptides: Biochemistry and Physiology, Dockray G., Walsh J. H.1994587613RavenNew York
Google Scholar - 145 Insulin-like growth factors and inflammatory bowel disease.Cytokines and Growth Factors in Gastroenterology, Goodlad R., Wright N.19968396Ballière, Tindal, & CoxLondon
Google Scholar - 146 Proteolytic enzymes in inflammatory bowel disease.Inflamm. Bowel Dis.41998157164
Crossref | PubMed | ISI | Google Scholar - 147 Platelet-derived growth factor-BB and thrombin generate positive and negative signals for human hepatic stellate cell proliferation. Role of a prostaglandin/cyclic AMP pathway and cross-talk with endothelin receptors.J. Biol. Chem.27319982730027305
Crossref | PubMed | ISI | Google Scholar - 148 Growth inhibitory properties of endothelin-1 in activated human hepatic stellate cells: a cyclic adenosine monophosphate-mediated pathway. Inhibition of both extracellular signal-regulated kinase and c-Jun kinase and upregulation of endothelin B receptors.J. Clin. Invest.98199627712778
Crossref | PubMed | ISI | Google Scholar - 149 Atherosclerosis, just another cancer?J. Clin. Invest.100199721432145
Crossref | PubMed | ISI | Google Scholar - 150 Phosphatidylinositol 3-kinase is required for platelet-derived growth factor’s actions on hepatic stellate cells.Gastroenterology112199712971306
Crossref | PubMed | ISI | Google Scholar - 151 Thrombin stimulates proliferation of liver fat-storing cells and expression of monocyte chemotactic protein-1: potential role in liver injury.Hepatology221995780787
Crossref | PubMed | ISI | Google Scholar - 152 Morphology and cell proliferation of subepithelial fibroblasts in adult mouse jejunum. II. Radioautographic studies.Gastroenterology671974636645
Crossref | PubMed | ISI | Google Scholar - 153 Role of stromal myofibroblasts infiltrating colon cancer in tumor invasion.Pathol. Res. Pract.1921996712717
Crossref | PubMed | ISI | Google Scholar - 154 The extracellular matrix in hepatic regeneration.FASEB J.9199514011410
Crossref | PubMed | ISI | Google Scholar - 155 Myofibroblasts differentiate from fibroblasts when plated at low density.Proc. Natl. Acad. Sci. USA93199642194223
Crossref | PubMed | ISI | Google Scholar - 156 Interleukin-4 induces myofibroblast differentiation in synovial fibroblasts.Biochem. Soc. Trans.251997290S
Crossref | PubMed | ISI | Google Scholar - 157 Progenitor cells of the central nervous system: a boon for clinical neuroscience.J. NIH Res.919973136
Google Scholar - 158 Inducible nitric oxide synthase plays a critical role in resolving intestinal inflammation.Gastroenterology112199710221027
Crossref | PubMed | ISI | Google Scholar - 159 Genomic instability in the type II TGF-β1 receptor gene in atherosclerotic and restenotic vascular cells.J. Clin. Invest.100199721822188
Crossref | PubMed | ISI | Google Scholar - 160 Eicosanoids, mesangial contraction, and intracellular signal transduction.Tohoku J. Exp. Med.16619925773
Crossref | PubMed | ISI | Google Scholar - 161 Unconventional myosins in cell movement, membrane traffic, and signal transduction.Science2791998527533
Crossref | PubMed | ISI | Google Scholar - 162 Heme oxygenase 2 is present in interstitial cell networks of the mouse small intestine.Gastroenterology1141998239244
Crossref | PubMed | ISI | Google Scholar - 163 Villus contraction aids repair of intestinal epithelium after injury.Am. J. Physiol.257Gastrointest. Liver Physiol. 201989G274G283
Abstract | ISI | Google Scholar - 164 Role of multipotent fibroblasts in the healing colonic mucosa of rabbits. Ultrastructural and immunocytochemical study.Histol. Histopathol.71992583590
PubMed | ISI | Google Scholar - 165 Myofibroblast phenotypes expression in experimental renal scarring.Nephrol. Dial. Transplant.121997904915
Crossref | PubMed | ISI | Google Scholar - 166 Astrocytes in infectious and immune-mediated diseases of the central nervous system.FASEB J.7199312261232
Crossref | PubMed | ISI | Google Scholar - 167 Amplification of nitric oxide synthase expression by nitric oxide in interleukin 1β-stimulated rat mesangial cells.J. Clin. Invest.95199519411946
Crossref | PubMed | ISI | Google Scholar - 168 Collagen XVIII is localized in sinusoids and basement membrane zones and expressed by hepatocytes and activated stellate cells in fibrotic human liver.Hepatology28199898107
Crossref | PubMed | ISI | Google Scholar - 169 Myofibroblasts and ECL cells are altered in the aged rat stomach (Abstract).Gastroenterology1141998A240
ISI | Google Scholar - 170 Fluorescent histochemical study on the localization of myofibroblasts in the healing of acetic acid-induced gastric ulcers in the rat.Scand. J. Gastroenterol. Suppl.1621989150153
Crossref | PubMed | Google Scholar - 171 Tubular epithelial-myofibroblast transdifferentiation in progressive tubulointerstitial fibrosis in 5/6 nephrectomized rats.Kidney Int.541998864876
Crossref | PubMed | ISI | Google Scholar - 172 Myofibroblast-like cells in human anterior capsular cataract.Virchows Arch. A Pathol. Anat. Histopathol.4041984393401
Crossref | PubMed | Google Scholar - 173 Hepatocyte growth factor/scatter factor effects on epithelia. Regulation of intercellular junctions in transformed and nontransformed cell lines, basolateral polarization of c-met receptor in transformed and natural intestinal epithelia, and induction of rapid wound repair in a transformed model epithelium.J. Clin. Invest.93199420562065
Crossref | PubMed | ISI | Google Scholar - 174 Expression and function of c-kit in hemopoietic progenitor cells.J. Exp. Med.17419916371
Crossref | PubMed | ISI | Google Scholar - 175 Interleukin-11 prevents apoptosis and accelerates recovery of small intestinal mucosa in mice treated with combined chemotherapy and radiation.Lab. Invest.7519963342
PubMed | ISI | Google Scholar - 176 Myofibroblasts in diffuse alveolar damage of the lung.Mod. Pathol.11199810641070
PubMed | ISI | Google Scholar - 177 The renal tubule in the progression of chronic renal failure.J. Investig. Med.451997346361
PubMed | ISI | Google Scholar - 178 GM-CSF, IL-1α, IL-1β, IL-6, IL-8, IL-10, ICAM-1 and VCAM-1 gene expression and cytokine production in human duodenal fibroblasts stimulated with lipopolysaccharide, IL-1α and TNFα.Clin. Exp. Immunol.961994437443
Crossref | PubMed | ISI | Google Scholar - 179 The pathophysiologic roles of interleukin-6 in human disease.Ann. Intern. Med.1281998127137
Crossref | PubMed | ISI | Google Scholar - 180 Colonic pericryptal fibroblast sheath: replication, migration, and cytodifferentiation of a mesenchymal cell system in adult tissue. I. Autoradiographic studies of normal rabbit colon.Gastroenterology541968835851
Crossref | PubMed | ISI | Google Scholar - 181 Induction of smooth muscle cell phenotype in cultured human prostatic stromal cells.Exp. Cell Res.2321997208215
Crossref | PubMed | ISI | Google Scholar - 182 Expression of α-smooth muscle actin in murine bone marrow stromal cells.Blood781991304309
Crossref | PubMed | ISI | Google Scholar - 183 Various mechanisms cause RET-mediated signaling defects in Hirschsprung’s disease.J. Clin. Invest.101199814151423
Crossref | PubMed | ISI | Google Scholar - 184 Immunodetection of connexins and cadherins in corneal fibroblasts and myofibroblasts.Invest. Ophthalmol. Vis. Sci.37199617401748
PubMed | ISI | Google Scholar - 185 Mesangial cells orchestrate inflammation in the renal glomerulus.News Physiol. Sci.91994271276
Abstract | Google Scholar - 186 Trefoil peptides in the defense of the gastrointestinal tract.N. Engl. J. Med.3361997506507
Crossref | PubMed | ISI | Google Scholar - 187 Peptides and gastrointestinal mucosal integrity.Gut371995595597
Crossref | PubMed | ISI | Google Scholar - 188 Why is epidermal growth factor present in the gut lumen?Gut381996303305
Crossref | PubMed | ISI | Google Scholar - 189 Healing the epithelium: solving the problem from two sides.J. Gastroenterol.321997122126
Crossref | PubMed | ISI | Google Scholar - 190 Epidermal growth factor receptor-stimulated intestinal epithelial cell migration requires phospholipase C activity.Gastroenterology1141998493502
Crossref | PubMed | ISI | Google Scholar - 191 Powell, D. W., R. C. Mifflin, J. D. Valentich, S. E. Crowe, J. I. Saada, and A. B. West. Myofibroblasts. II. Intestinal subepithelial myofibroblasts. Am. J. Physiol. 277 (Cell Physiol. 46). In press.
Google Scholar - 192 The role of alpha1beta1 integrin in wound contraction. A quantitative analysis of liver myofibroblasts in vivo and in primary culture.J. Biol. Chem.27219973091130917
Crossref | PubMed | ISI | Google Scholar - 193 Regulation of astrocyte morphology by RhoA and lysophosphatidic acid.Exp. Cell Res.2451998252262
Crossref | PubMed | ISI | Google Scholar - 194 Regulated overexpression of interleukin 11 in the lung. Use to dissociate development-dependent and -independent phenotypes.J. Clin. Invest.100199725012511
Crossref | PubMed | ISI | Google Scholar - 195 Assessment of rapid morphological changes associated with elevated cAMP levels in human orbital fibroblasts.Exp. Cell Res.2451998360367
Crossref | PubMed | ISI | Google Scholar - 196 Intestinal epithelial cells both express and respond to interleukin 15.Gastroenterology111199617061713
Crossref | PubMed | ISI | Google Scholar - 197 Interleukin-10 modulates type I collagen and matrix metalloprotease gene expression in cultured human skin fibroblasts.J. Clin. Invest.6199424892492
Crossref | ISI | Google Scholar - 198 Pathophysiology of progressive nephropathies.N. Engl. J. Med.339199814481456
Crossref | PubMed | ISI | Google Scholar - 199 Colonic pericrypt sheath cells: characterisation of cell type with new monoclonal antibody.J. Clin. Pathol.401987593600
Crossref | PubMed | ISI | Google Scholar - 200 Epidermal growth factor promotes rapid response to epithelial injury in rabbit duodenum in vitro.Gastroenterology11119962836
Crossref | PubMed | ISI | Google Scholar - 201 Mesenchymal cells stimulate human intestinal intraepithelial lymphocytes.Gastroenterology1131997144150
Crossref | PubMed | ISI | Google Scholar - 202 Inducible nitric oxide synthase in rat hepatic lipocytes and the effect of nitric oxide on lipocyte contractility.J. Clin. Invest.95199511991206
Crossref | PubMed | ISI | Google Scholar - 203 Induction of α-smooth muscle actin by transforming growth factor-β1 in quiescent human breast gland fibroblasts. Implications for myofibroblast generation in breast neoplasia.Lab. Invest.681993696707
PubMed | ISI | Google Scholar - 204 The origin of the myofibroblasts in breast cancer: recapitulation of tumor environment in culture unravels diversity and implicates converted fibroblasts and recruited smooth muscle cells.J. Clin. Invest.951995859873
Crossref | PubMed | ISI | Google Scholar - 205 Fibroblast growth factor 2 and transforming growth factor β1 interactions in human liver myofibroblasts.Gastroenterology109199519861996
Crossref | PubMed | ISI | Google Scholar - 206 Hepatic stellate cells reversibly express α-smooth muscle actin during acute hepatic ischemia.Transplant. Proc.29199723902395
Crossref | PubMed | ISI | Google Scholar - 207 Keratinocyte growth factor.Cell Biol. Int.191995399411
Crossref | PubMed | ISI | Google Scholar - 208 The role of cytoskeletal and cytocontractile elements in pathologic processes.Top. Clin. Nurs.81986361392
Google Scholar - 209 Idiopathic pulmonary fibrosis: current concepts.Mayo Clin. Proc.73199810851101
Crossref | PubMed | ISI | Google Scholar - 210 Nonsteroidal anti-inflammatory drugs (NSAIDs) induce cyclooxygenase-2 (COX-2) expression via delayed activation of ERK and P38 MAPK pathways in human intestinal subepithelial myofibroblasts synergistic interaction with interleukin-1 induced signaling (Abstract).Gastroenterology1161999A297
ISI | Google Scholar - 211 Expression of interleukin-4 in scleroderma skin specimens and scleroderma fibroblast cultures. Potential role in fibrosis.Arch. Dermatol.1321996802806
Crossref | PubMed | Google Scholar - 212 A case for interstitial cells of Cajal as pacemakers and mediators of neurotransmission in the gastrointestinal tract.Gastroenterology1111996492515
Crossref | PubMed | ISI | Google Scholar - 213 Smooth muscle differentiation in scleroderma fibroblastic cells.Am. J. Pathol.1371990585591
PubMed | ISI | Google Scholar - 214 Differentiation repertoire of fibroblastic cells: expression of cytoskeletal proteins as marker of phenotypic modulations.Lab. Invest.631990144161
PubMed | ISI | Google Scholar - 215 An in vitro model for cell-cell interactions.In Vitro Cell. Dev. Biol.28A1992521528
Crossref | PubMed | ISI | Google Scholar - 216 Heterogeneity of myofibroblast phenotypic features: an example of fibroblastic cell plasticity.Virchows Arch.4251994324
Crossref | PubMed | ISI | Google Scholar - 217 Appearance of α-smooth muscle actin in human eye lens cells of anterior capsular cataract and in cultured bovine lens-forming cells.Differentiation431990115122
Crossref | PubMed | ISI | Google Scholar - 218 Alpha-smooth muscle actin is expressed in a subset of bone marrow stromal cells in normal and pathological conditions.Virchows Arch. B Cell Pathol. Incl. Mol. Pathol.571989291302
Crossref | PubMed | Google Scholar - 219 Collagens in the liver extracellular matrix bind hepatocyte growth factor.Gastroenterology1141998139152
Crossref | PubMed | ISI | Google Scholar - 220 Extracellular matrix: the cellular environment.News Physiol. Sci.91994110115
Abstract | Google Scholar - 221 Human orbital fibroblasts are activated through CD40 to induce proinflammatory cytokine production.Am. J. Physiol.274Cell Physiol. 431998C707C714
Link | ISI | Google Scholar - 222 The fibronectin domain ED-A is crucial for myofibroblastic phenotype induction by transforming growth factor-β1.J. Cell Biol.1421998873881
Crossref | PubMed | ISI | Google Scholar - 223 Transforming growth factor-β1 expression and myofibroblast formation during arterial repair.Arterioscler. Thromb. Vasc. Biol.16199612981305
Crossref | PubMed | ISI | Google Scholar - 224 Histogenesis of Dupuytren’s disease: an immunohistochemical study of 30 cases.J. Hand Surg. [Am.]1319886167
Crossref | PubMed | ISI | Google Scholar - 225 Mechanisms for rapid re-epithelialization of the gastric mucosal surface.Annu. Rev. Physiol.471985217229
Crossref | PubMed | ISI | Google Scholar - 226 Autocrine and paracrine actions of intestinal fibroblast-derived insulin-like growth factors.Am. J. Physiol.276Gastrointest. Liver Physiol. 391999G817G827
Abstract | ISI | Google Scholar - 227 Extracellular matrix components in intestinal development.Experientia511995883900
Crossref | PubMed | Google Scholar - 228 The fibronexus: a transmembrane association of fibronectin-containing fibers and bundles of 5 nm microfilaments in hamster and human fibroblasts.Cell161979675685
Crossref | PubMed | ISI | Google Scholar - 229 Fibronexus formation is an early event during fibronectin-induced restoration of more normal morphology and substrate adhesion patterns in transformed hamster fibroblasts.J. Cell Sci.561982120
PubMed | ISI | Google Scholar - 230 Localization of the fibronexus at the surface of granulation tissue myofibroblasts using double-label immunogold electron microscopy on ultrathin frozen sections.Eur. J. Cell Biol.38198594101
PubMed | ISI | Google Scholar - 231 Extracellular matrix-cytoskeletal interactions in rheumatoid arthritis. I. Immunoelectron microscopic analysis of the fibronexus at the adhesive surface of normal porcine type B synoviocytes in vitro.Arthritis Rheum.28198511051116
Crossref | PubMed | Google Scholar - 232 A transmembrane relationship between fibronectin and vinculin (130 kd protein): serum modulation in normal and transformed hamster fibroblasts.Cell241981481492
Crossref | PubMed | ISI | Google Scholar - 233 Apc1638N: a mouse model for familial adenomatous polyposis-associated desmoid tumors and cutaneous cysts.Gastroenterology1141998275283
Crossref | PubMed | ISI | Google Scholar - 234 Abnormal kidney development and hematological disorders in PDGF β-receptor mutant mice.Genes Dev.8199418881896
Crossref | PubMed | ISI | Google Scholar - 235 Induction of neutrophil-attracting chemokines in transforming rat hepatic stellate cells.Gastroenterology1131997277285
Crossref | PubMed | ISI | Google Scholar - 236 Proinflammatory cytokines differentially modulate their own expression in human intestinal mucosal mesenchymal cells.Gastroenterology114199812441256
Crossref | PubMed | ISI | Google Scholar - 237 Gastric mucosal smooth muscles may explain oscillations in glandular pressure: role of vasoactive intestinal peptide.Gastroenterology1141998284294
Crossref | PubMed | ISI | Google Scholar - 238 Transforming growth factor-β1 induces α-smooth muscle-actin expression in cultured human and monkey trabecular meshwork.Exp. Eye Res.621996389397
Crossref | PubMed | ISI | Google Scholar - 239 Platelet-derived growth factor-BB induces renal tubulointerstitial myofibroblast formation and tubulointerstitial fibrosis.Am. J. Pathol.148199611691180
PubMed | ISI | Google Scholar - 240 Antioxidants inhibit interleukin-1-induced cyclooxygenase and nitric-oxide synthase expression in rat mesangial cells. Evidence for post-transcriptional regulation.J. Biol. Chem.27119961168911693
Crossref | PubMed | ISI | Google Scholar - 241 Cross-talk between cyclooxygenase and nitric oxide pathways: prostaglandin E2 negatively modulates induction of nitric oxide synthase by interleukin 1.Proc. Natl. Acad. Sci. USA9119941216812172
Crossref | PubMed | ISI | Google Scholar - 242 Fibroblast contraction occurs on release of tension in attached collagen lattices: dependency on an organized actin cytoskeleton and serum.Anat. Rec.2321992359368
Crossref | PubMed | Google Scholar - 243 Identification and classification of interstitial cells in the canine proximal colon by ultrastructure and immunocytochemistry.Histochemistry1011994169183
Crossref | PubMed | Google Scholar - 244 Development of c-Kit-positive cells and the onset of electrical rhythmicity in murine small intestine.Gastroenterology1121997144155
Crossref | PubMed | ISI | Google Scholar - 245 Nonmitogenic actions of growth factors: an integrated view of their role in intestinal physiology and pathophysiology.Gastroenterology1121997255268
PubMed | ISI | Google Scholar - 246 Phenotypic characterization of an intestinal subepithelial myofibroblast cell line.Am. J. Physiol.272Cell Physiol. 411997C1513C1524
Link | ISI | Google Scholar - 247 Intestinal subepithelial myofibroblasts and mucosal immunophysiology.Curr. Opin. Gastroenterol.101994645651
Crossref | ISI | Google Scholar - 248 Study of the interstitial cells of Cajal in infantile hypertrophic pyloric stenosis.Gastroenterology1111996279288
Crossref | PubMed | ISI | Google Scholar - 249 Interstitial cells of Cajal in human colon and in Hirschsprung’s disease.Gastroenterology1111996901910
Crossref | PubMed | ISI | Google Scholar - 250 Paracrine interactions between fibroblasts and endothelial cells in a serum-free coculture model. Modulation of angiogenesis and collagen gel contraction.Lab. Invest.711994291299
PubMed | ISI | Google Scholar - 251 Rat hepatic lipocytes synthesize and secrete transin (stromelysin) in early primary culture.Gastroenterology1091995889898
Crossref | PubMed | ISI | Google Scholar - 252 The cellular and molecular basis of gastric mucosal defense.FASEB J.101996731740
Crossref | PubMed | ISI | Google Scholar - 253 Proliferative retinal diseases: myofibroblasts cause chronic vitreoretinal traction.Br. J. Ophthalmol.761992550552
Crossref | PubMed | ISI | Google Scholar - 254 Prostaglandin E2 alters human orbital fibroblast shape through a mechanism involving the generation of cyclic adenosine monophosphate.J. Clin. Endocrinol. Metab.80199535533560
PubMed | ISI | Google Scholar - 255 Targeted overexpression of IGF-I evokes distinct patterns of organ remodeling in smooth muscle cell tissue beds of transgenic mice.J. Clin. Invest.100199714251439
Crossref | PubMed | ISI | Google Scholar - 256 Myofibroblast accumulation induced by transforming growth factor-β is involved in the pathogenesis of nasal polyps.Laryngoscope1071997926931
Crossref | PubMed | ISI | Google Scholar - 257 Impaired development of interstitial cells and intestinal electrical rhythmicity in steel mutants.Am. J. Physiol.269Cell Physiol. 381995C1577C1585
Link | ISI | Google Scholar - 258 Myofibroblasts and local angiotensin II in rat cardiac tissue repair.Int. J. Biochem. Cell Biol.2919973142
Crossref | PubMed | ISI | Google Scholar - 259 Cultured lung fibroblasts isolated from patients with idiopathic pulmonary fibrosis have a diminished capacity to synthesize prostaglandin E2 and to express cyclooxygenase-2.J. Clin. Invest.95199518611868
Crossref | PubMed | ISI | Google Scholar - 260 Induction of a novel epidermal growth factor-secreting cell lineage by mucosal ulceration in human gastrointestinal stem cells.Nature34319908285
Crossref | PubMed | ISI | Google Scholar - 261 IL-6 is an antiinflammatory cytokine required for controlling local or systemic acute inflammatory responses.J. Clin. Invest.1011998311320
Crossref | PubMed | ISI | Google Scholar - 262 Vascular pericytes not only regulate growth, but also preserve prostacyclin-producing ability and protect against lipid peroxide-induced injury of co-cultured endothelial cells.Biochem. Biophys. Res. Commun.1901993418425
Crossref | PubMed | ISI | Google Scholar - 263 Selective upregulation of platelet-derived growth factor α receptors by transforming growth factor β in scleroderma fibroblasts.J. Exp. Med.175199212271234
Crossref | PubMed | ISI | Google Scholar - 264 Differential responses of scirrhous and well-differentiated gastric cancer cells to orthotopic fibroblasts.Br. J. Cancer74199610961103
Crossref | PubMed | ISI | Google Scholar - 265 Rho directs activation-associated changes in rat hepatic stellate cell morphology via regulation of the actin cytoskeleton.Hepatology281998843850
Crossref | PubMed | ISI | Google Scholar - 266 Immunohistochemical localization of the actin in the healing stage of gastric ulcers.J. Exp. Pathol.31987271280
PubMed | Google Scholar - 267 Localization of intestinal interleukin 1 activity and protein and gene expression to lamina propria cells.Gastroenterology1041993749758
Crossref | PubMed | ISI | Google Scholar - 268 Intestinal fibrosis in inflammatory bowel disease.Regul. Pept. Lett.VII19976063
Google Scholar - 269 IGF-I induces collagen and IGFBP-5 mRNA in rat intestinal smooth muscle.Am. J. Physiol.273Gastrointest. Liver Physiol. 361997G875G882
Abstract | ISI | Google Scholar
