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Updated: Jun 4, 2025
Intrathoracic Injection for the Study of Adult Zebrafish Heart
Published on: May 14, 2019
Cited4a limits cardiomyocyte dedifferentiation and proliferation during zebrafish heart regeneration
Rachel Forman-Rubinsky1,2, Wei Feng1,2, Brent T Schlegel3
1Department of Cell Biology, University of Pittsburgh, School of Medicine, Pittsburgh, PA.
Insights
Suppression of cardiomyocyte maturation pathways, like those involving cited4a, can promote heart regeneration by enhancing cell dedifferentiation and proliferation after injury.
Area of Science:
- Cardiovascular Biology
- Regenerative Medicine
- Molecular Cardiology
Background:
- Cardiac regeneration is a complex process involving cardiomyocyte dedifferentiation and proliferation.
- Understanding the molecular mechanisms governing cardiomyocyte response to injury is crucial for therapeutic development.
Purpose of the Study:
- To identify distinct cardiomyocyte populations and their functions in the injured zebrafish heart.
- To investigate the role of cited4a in cardiomyocyte maturation and its impact on cardiac regeneration.
Main Methods:
- Single nuclear RNA sequencing of injured zebrafish hearts.
- Analysis of cardiomyocyte populations and gene expression profiles.
- Utilizing loss-of-cited4a zebrafish mutants to assess regeneration capacity.
Main Results:
- Identified diverse cardiomyocyte populations with functions in stress response, myofibril assembly, proliferation, and contraction.
- Observed activation of maturation pathways in contracting cardiomyocytes post-injury.
- Found that cited4a is induced in mature cardiomyocytes after injury.
- Loss-of-cited4a mutants exhibited enhanced cardiomyocyte dedifferentiation, proliferation, and accelerated heart regeneration.
Conclusions:
- Maintaining a terminally differentiated cardiomyocyte population is vital for cardiac function during regeneration.
- Suppressing cardiomyocyte maturation pathways, potentially by targeting cited4a, can promote heart regeneration.
- Targeting cardiomyocyte maturation pathways offers a novel therapeutic strategy for cardiac repair.
Abstract:
Cardiac regeneration involves the interplay of complex interactions between many different cell types, including cardiomyocytes. The exact mechanism that enables cardiomyocytes to undergo dedifferentiation and proliferation to replace lost cells has been intensely studied. Here we report a single nuclear RNA sequencing profile of the injured zebrafish heart and identify distinct cardiomyocyte populations in the injured heart. These cardiomyocyte populations have diverse functions, including stress response, myofibril assembly, proliferation and contraction. The contracting cardiomyocyte population also involves the activation of maturation pathways as an early response to injury. This intriguing finding suggests that constant maintenance of a distinctive terminally differentiated cardiomyocyte population is important for cardiac function during regeneration. To test this hypothesis, we determined that cited4a, a p300/CBP transcriptional coactivator, is induced after injury in the mature cardiomyocyte population. Moreover, loss-of-cited4a mutants presented increased dedifferentiation, proliferation and accelerated heart regeneration. Thus, suppressing cardiomyocyte maturation pathway activity in injured hearts could be an approach to promote heart regeneration.
