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Fetal Mammalian Heart Generates a Robust Compensatory Response to Cell Loss
Anthony C Sturzu1, Kuppusamy Rajarajan1, Derek Passer1
1From Stanford Cardiovascular Institute (A.C.S., K.R., K.P., A.S., A.F.X., G.L., S.M.W.), Division of Cardiovascular Medicine, Department of Medicine (A.C.S., S.M.W.), Department of Pathology (R.G.), Institute for Stem Cell Biology and Regenerative Medicine (S.M.W.), and Child Health Research Institute (S.M.W.), Stanford University School of Medicine, CA; and Division of Cardiology, Department of Medicine (A.C.S., K.R., D.P., A.R., T.C.T., M.C.E., R.F., K.D.R., M.S.-C., I.J.D.) and Department of Pathology (M.K.S.), Massachusetts General Hospital, Boston.
Background:
Heart development is tightly regulated by signaling events acting on a defined number of progenitor and differentiated cardiac cells. Although loss of function of these signaling pathways leads to congenital malformation, the consequences of cardiac progenitor cell or embryonic cardiomyocyte loss are less clear. In this study, we tested the hypothesis that embryonic mouse hearts exhibit a robust mechanism for regeneration after extensive cell loss.
Methods And Results:
By combining a conditional cell ablation approach with a novel blastocyst complementation strategy, we generated murine embryos that exhibit a full spectrum of cardiac progenitor cell or cardiomyocyte ablation. Remarkably, ablation of up to 60% of cardiac progenitor cells at embryonic day 7.5 was well tolerated and permitted embryo survival. Ablation of embryonic cardiomyocytes to a similar degree (50% to 60%) at embryonic day 9.0 could be fully rescued by residual myocytes with no obvious adult cardiac functional deficit. In both ablation models, an increase in cardiomyocyte proliferation rate was detected and accounted for at least some of the rapid recovery of myocardial cellularity and heart size.
Conclusion:
Our study defines the threshold for cell loss in the embryonic mammalian heart and reveals a robust cardiomyocyte compensatory response that sustains normal fetal development.
Insights
Embryonic mouse hearts can regenerate after significant cell loss. Even with up to 60% of cardiac progenitor cells or cardiomyocytes ablated, the heart compensates, ensuring normal fetal development.
Area of Science:
- Developmental biology
- Cardiovascular research
- Regenerative medicine
Background:
- Heart development relies on precise signaling pathways.
- Consequences of embryonic cardiac cell loss were previously unclear.
- Investigated regenerative capacity of embryonic hearts post-cell loss.
Purpose of the Study:
- To test if embryonic mouse hearts regenerate after extensive cell loss.
- To define the threshold for cell loss in embryonic mammalian hearts.
- To understand compensatory mechanisms in embryonic cardiac development.
Main Methods:
- Conditional cell ablation in murine embryos.
- Novel blastocyst complementation strategy.
- Analysis of cardiac progenitor cell and cardiomyocyte ablation.
Main Results:
- Up to 60% ablation of cardiac progenitor cells at E7.5 was tolerated.
- 50%-60% embryonic cardiomyocyte ablation at E9.0 was rescued by residual myocytes.
- Increased cardiomyocyte proliferation contributed to recovery of heart size and cellularity.
- No obvious adult cardiac functional deficit observed post-ablation.
Conclusions:
- Embryonic mammalian heart has a defined threshold for cell loss.
- A robust cardiomyocyte compensatory response sustains fetal development.
- Identified significant regenerative potential in the developing heart.
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