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Updated: Sep 14, 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, Angela Paul1,2, Wei Feng1,2
1Department of Cell Biology, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15213, USA.
Insights
Suppressing cited4a in zebrafish hearts promotes cardiac regeneration by increasing cardiomyocyte proliferation. This finding offers a potential therapeutic strategy for heart repair after injury.
Area of Science:
- Cardiovascular Biology
- Regenerative Medicine
- Molecular Cardiology
Background:
- Cardiac regeneration is crucial for heart repair but the underlying mechanisms are not fully understood.
- Cardiomyocytes dedifferentiate and proliferate to replace cells lost after cardiac injury.
- Distinct cardiomyocyte populations with varied functions exist in the heart.
Purpose of the Study:
- To investigate the role of cited4a in cardiomyocyte function and cardiac regeneration.
- To identify molecular regulators of cardiomyocyte proliferation during heart repair.
- To explore potential therapeutic targets for promoting heart regeneration.
Main Methods:
- Single nucleus RNA-sequencing of injured zebrafish hearts.
- Generation and analysis of cited4a loss-of-function zebrafish mutants.
- Assessment of cardiomyocyte dedifferentiation and proliferation after ventricular resection.
Main Results:
- Identified distinct cardiomyocyte populations with diverse functions including stress response, myofibril assembly, proliferation, and contraction.
- Found increased expression of cited4a in mature contracting cardiomyocytes, but not in proliferating ones.
- Observed increased cardiomyocyte dedifferentiation and proliferation in cited4a mutants after injury.
Conclusions:
- Cited4a may maintain contractile function by restricting mature cardiomyocytes from re-entering the cell cycle.
- Suppressing cited4a activity in the injured heart can expand the cardiomyocyte pool for myocardial repair.
- Targeting cited4a presents a potential strategy to enhance cardiac regeneration.
Abstract:
Cardiac regeneration involves the interplay of complex interactions between many different cell types, including cardiomyocytes. In regeneration, cardiomyocytes undergo dedifferentiation and proliferation to replace lost cells at the injury border. The exact mechanism regulating this process is not completely understood. Here, we report a single nucleus RNA-sequencing profile of the injured zebrafish heart revealing distinct cardiomyocyte populations. These cardiomyocyte populations have diverse functions, including stress response, myofibril assembly, proliferation and contraction. Notably, increased expression of cited4a, a p300/CBP transcriptional coactivator, was detected in the mature contracting cardiomyocytes, but absent from proliferating cardiomyocytes, suggesting it may play a role in maintaining contractile function in a subset of cardiomyocytes. We reasoned that cited4a is induced in heart injury to maintain cardiomyocyte function and therefore cited4a+ populations are restricted from entering the cell cycle. Loss-of-function cited4a mutants were generated and, following ventricular resection, increased cardiomyocyte dedifferentiation and proliferation was observed. Our findings indicate that suppressing cited4a activity in the injured heart expands the pool of cardiomyocytes available for replacing damaged and lost myocardium and could be an approach to promote heart regeneration.
