Heart Regeneration in Zebrafish
Abstract
Cardiac injury in mammals and amphibians typically leads to scarring, with minimal regeneration of heart muscle. Here, we demonstrate histologically that zebrafish fully regenerate hearts within 2 months of 20% ventricular resection. Regeneration occurs through robust proliferation of cardiomyocytes localized at the leading epicardial edge of the new myocardium. The hearts of zebrafish with mutations in the Mps1 mitotic checkpoint kinase, a critical cell cycle regulator, failed to regenerate and formed scars. Thus, injury-induced cardiomyocyte proliferation in zebrafish can overcome scar formation, allowing cardiac muscle regeneration. These findings indicate that zebrafish will be useful for genetically dissecting the molecular mechanisms of cardiac regeneration.
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The mps1 mutants and wild-type controls were maintained at 25°C before and for 24 hours after surgery and then shifted to 32° to 33°C–recirculating aquarium water for 7 to 25 days. Pulse-chase studies with BrdU showed no evidence of myocyte proliferation in mps1 mutants during this period. Animals of the WIK or (WIK × *AB) strains, closest in genetic background to the mps1 mutant strain, were used as wild-type controls. The WIK strain had more difficulty surviving surgery than other strains. So, in these experiments, we removed only 10 to 15% of the ventricle. Regeneration appears to occur less effectively at 32° to 33°C than at 25°C in wild-type fish, with less myocyte proliferation (6).
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We thank A. Hillam for help with histology; A. Nechiporuk and S. Johnson for helping to generate and analyze mps1 mutants; H. Stern and R. Bronson for help with histopathology; D. Clapham for confocal imaging equipment; A. Nechiporuk, S. Odelberg, A. Limbourg, E. Lien, and L. Zon for critique of the manuscript; A. Sanchez and S. Kimfor animal care; and Keating laboratory members for helpful discussions. Supported by the Helen Hay Whitney Foundation (K.D.P.) and grants from the National Heart, Lung, and Blood Institute. All animal procedures were performed in accordance with Children's Hospital guidelines.
Materials and Methods
Figs. S1 to S4
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Science
Volume 298 | Issue 5601
13 December 2002
13 December 2002
Submission history
Received: 28 August 2002
Accepted: 23 October 2002
Published in print: 13 December 2002
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- Kenneth D. Poss et al.
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