PgmNr Z535: Zebrafish heart regeneration requires alleviation of cardiomyocyte genomic stress by BMP signaling.

Authors:
Gilbert Weidinger; Mohan Dalvoy; Chi-Chung Wu


Institutes
Ulm University, Ulm, Germany.


Abstract:

In contrast to adult mammals, zebrafish can regenerate heart injuries via dedifferentiation and proliferation of differentiated cardiomyocytes in the wound border zone. Cell cycle re-entry of non-cycling cells can result in replication stress and thus DNA damage, a phenomenon that has been linked to failed homeostasis and regeneration of organ systems in aged mammals. Surprisingly, we found that a large fraction of cardiomyocytes in the regenerating heart of young zebrafish experience DNA damage, as indicated by accumulation of the phosphorylated histone variant H2a.x (gammaH2a.x). DNA damage is likely the result of replication stress caused by injury-induced cardiomyocyte cell cycle re-entry since no gammaH2a.x is detected in proliferating cardiomyocytes during physiological heart growth but occurs in the same temporal and spatial profile as cardiomyocyte cell cycle re-entry during heart regeneration. Importantly, inhibition of DNA damage response pathways results in blockage of regenerative cardiomyocyte proliferation, indicating that replication stress needs to be resolved for heart regeneration to occur.

We have recently shown that BMP signaling is activated in cardiomyocytes at the wound border and that BMP signaling is required for heart regeneration by promoting cardiomyocyte proliferation (Wu et al, Dev. Cell 2016). Since BMP signaling is not required for cardiomyocyte proliferation during physiological heart growth, it might regulate regeneration-specific cellular processes in cardiomyocytes, which are prerequisites for proliferation. Intriguingly, we found that inhibition of BMP signaling increases the number of gammaH2a.x positive cardiomyocytes, while pathway overactivation alleviates DNA damage, suggesting that BMP signaling is required for protection from replication stress or repair of DNA damage.

Our results surprisingly indicate that the elevated heart regenerative capacity of zebrafish might depend on efficient means to deal with replication stress and DNA damage, which are thought to impair organ regeneration in aged mammals. We propose that BMP signaling promotes heart regeneration by protecting cells from genomic stress or by augmenting DNA damage repair, a novel function of the pathway that could be conserved in other systems.



ZFIN Genetics Index
1. bmp2b