Cardiac neural crest contributes to cardiomyocytes in amniotes and heart regeneration in zebrafish

Abstract

Cardiac neural crest cells contribute to important portions of the cardiovascular system including the aorticopulmonary septum and cardiac ganglion. Using replication incompetent avian retroviruses for precise high-resolution lineage analysis, we uncover a previously undescribed neural crest contribution to cardiomyocytes of the ventricles in Gallus gallus, supported by Wnt1-Cre lineage analysis in Mus musculus. To test the intriguing possibility that neural crest cells contribute to heart repair, we examined Danio rerio adult heart regeneration in the neural crest transgenic line, Tg(−4.9sox10:eGFP). Whereas the adult heart has few sox10+ cells in the apex, sox10 and other neural crest regulatory network genes are upregulated in the regenerating myocardium after resection. The results suggest that neural crest cells contribute to many cardiovascular structures including cardiomyocytes across vertebrates and to the regenerating heart of teleost fish. Thus, understanding molecular mechanisms that control the normal development of the neural crest into cardiomyocytes and reactivation of the neural crest program upon regeneration may open potential therapeutic approaches to repair heart damage in amniotes.

Fate of developmental mechanisms of myocardial plasticity in the postnatal heart

“…Differentiation of CNCs to CMs has been previously shown in zebrafish (Abdul-Wajid et al, 2018;Li et al, 2003;Sande-Melón et al, 2019;Sato and Yost, 2003;Tang et al, 2019) and mice (Hatzistergos et al, 2015;Tamura et al, 2011;Tang et al, 2019;Tomita et al, 2005). Developmentally, CNCs primarily contribute trabecular CMs in both species; whereas in mice, they further contribute IVS CMs, a structure that has not evolved in the univentricular zebrafish heart (Abdul-Wajid et al, 2018;Hatzistergos et al, 2015;Tang et al, 2019). Consistently, we show that migration and CM differentiation are compromised in Isl1-cKO CNCs and that these mice die at midgestation with abnormalities in AV cushions, IVS and trabecular myocardium.…”

“…Of note, the grossly normal cardiovascular phenotype of Wnt1-GOF mice suggests that CNC-CMs are not essential for the development of trabeculated and IVS myocardium since it appears to be compensated through other CM sources. Interestingly, loss of CNC-CMs does not affect heart development in zebrafish either, but leads to adult onset hypertrophic cardiomyopathy(Abdul-Wajid et al, 2018) and impaired postnatal cardiac regenerative capacity(Sande-Melón et al, 2019;Tang et al, 2019). We have also observed signs of LV and IVS hypertrophy in Wnt1-GOF mice [e.g.Fig.…”

“…Following this approach, we ], led us to challenge the existing interpretations (Laugwitz et al, 2005) and hypothesized that that the Isl1-MCM -derived CMs reflect CNC-rather than aSHF-Isl1-CPC-GRN activity. Contributions of CNCs to the myocardial lineage have been previously shown in fish (Abdul-Wajid et al, 2018;Li et al, 2003;Tang et al, 2019) but remains a topic of debate in mice (Hatzistergos et al, 2018;Hatzistergos et al, 2016;Hatzistergos et al, 2015;Tang et al, 2019;Tomita et al, 2005). Accordingly, to test this possibility, we first conducted clonal analysis of Isl1 + cardiac cells and their derivatives by crossing the Isl1-Cre (Yang et al, 2006) to the multicolor Cre-reporter mouse line Confetti (Snippert et al, 2010) [ Fig.…”

This preprint has been taken down.

“…In urodele amphibians, NCdC release trophic factors that promote blastemal cell proliferation and epimorphic regeneration 18 . In zebrafish, NCdC contribute to cardiac development and regeneration 20,21 , but their role in appendage regeneration is not known. To determine whether the foxd3 + cell population in the blastema was involved in caudal fin fold regeneration in zebrafish larvae, we first analysed foxd3 + NCdC presence and behaviour by confocal microscopy.…”

“…These cells release trophic factors that promote blastemal cell proliferation and epimorphic regeneration 18,19 . In zebrafish, NCdC contribution has recently been demonstrated during cardiac development and regeneration 20,21 , but has never been investigated in appendage regeneration. Interestingly, after nerve injury, SC release factors that will promote pro-inflammatory macrophage recruitment and macrophage polarization towards an antiinflammatory phenotype 22,23 .…”