Activation of Nkx2.5 transcriptional program is required for adult myocardial repair

Abstract

The cardiac developmental network has been associated with myocardial regenerative potential. However, the embryonic signals triggered following injury have yet to be fully elucidated. Nkx2.5 is a key causative transcription factor associated with human congenital heart disease and one of the earliest markers of cardiac progenitors, thus it serves as a promising candidate. Here, we show that cardiac-specific RNA-sequencing studies reveal a disrupted embryonic transcriptional profile in the adult Nkx2.5 loss-of-function myocardium. nkx2.5−/− fish exhibit an impaired ability to recover following ventricular apex amputation with diminished dedifferentiation and proliferation. Complex network analyses illuminate that Nkx2.5 is required to provoke proteolytic pathways necessary for sarcomere disassembly and to mount a proliferative response for cardiomyocyte renewal. Moreover, Nkx2.5 targets embedded in these distinct gene regulatory modules coordinate appropriate, multi-faceted injury responses. Altogether, our findings support a previously unrecognized, Nkx2.5-dependent regenerative circuit that invokes myocardial cell cycle re-entry, proteolysis, and mitochondrial metabolism to ensure effective regeneration in the teleost heart.

Cardiomyocyte maturation and its reversal during cardiac regeneration

“…Mutations in NKX2‐5 are commonly found in human congenital heart disease, 125 and NKX2‐5 has been shown in multiple model systems to regulate gene expression programs that promote cardiac specification and morphogenesis 126‐128 . nkx2.5 is re‐expressed by border zone CMs following apical resection in zebrafish, 114 and an essential function of Nkx2.5 in regenerating zebrafish CMs has recently been shown 129 . nkx2.5 mutation in zebrafish is embryonic lethal, but can be rescued by transgenic nkx2.5 expression during early stages of heart development.…”

“…This phenotype was suggested to be due to a decrease in CM proliferation and dedifferentiation (re‐expression of an embryonic form of myosin as discussed below). Putative Nkx2.5 target genes that were decreased in nkx2.5 mutant hearts and may mediate these effects were ect2 , whose protein product is essential for cytokinesis, and psmb3 (proteasome subunit beta type‐3) and psmd7 (proteasome 26 S subunit, non‐ATPase 7), whose protein products are drivers of proteolysis 129 …”

“…[126][127][128] nkx2.5 is re-expressed by border zone CMs following apical resection in zebrafish, 114 and an essential function of Nkx2.5 in regenerating zebrafish CMs has recently been shown. 129 nkx2.5 mutation in zebrafish is embryonic lethal, but can be rescued by transgenic nkx2.5 expression during early stages of heart development. Using nkx2.5 mutant zebrafish, it was shown that Nkx2.5 is essential for adult cardiac regeneration.…”

Optimal transplantation strategy using human induced pluripotent stem cell‐derived cardiomyocytes for acute myocardial infarction in nonhuman primates

“…Compared to the model group, the intramyocardial Tx decreased Bax expression and increased Bcl‐2 expression, while the intravenous Tx decreased Bax expression but did not significantly affect Bcl‐2 expression (Figure 4C,D). Notably, injured cardiomyocytes expressing Nkx2.5 were found in the infarcted area of the macaque heart after intramyocardial Tx (Figure 4E), which has been shown to play a critical role in repairing the adult heart 15 . No significant positive expression of Nkx2.5 in the infarcted area of the macaque heart was found in the model and intravenous groups.…”

“…We hypothesize that mitochondrial transfer is one of the reasons for the improved heart function, even in the absence of hiPSC‐CMs at weeks 8 or 10. Besides, we discovered that the intramyocardial Tx of hiPSC‐CMs attenuated apoptosis and increases the expression of Nkx2.5 and GATA4 in host cardiomyocytes, both of which are known to protect cardiomyocytes from oxidative damage 15,16 . Furthermore, we detected the key proteins that affect electrical remodeling, including SERCA2α, PLB, CAMK II, and Kv1.5.…”