Transcriptional Reversion of Cardiac Myocyte Fate During Mammalian Cardiac Regeneration

Abstract

Rationale Neonatal mice have the capacity to regenerate their hearts in response to injury, but this potential is lost after the first week of life. The transcriptional changes that underpin mammalian cardiac regeneration have not been fully characterized at the molecular level. Objective The objectives of our study were to determine if myocytes revert the transcriptional phenotype to a less differentiated state during regeneration and to systematically interrogate the transcriptional data to identify and validate potential regulators of this process. Methods and Results We derived a core transcriptional signature of injury-induced cardiac myocyte regeneration in mouse by comparing global transcriptional programs in a dynamic model of in vitro and in vivo cardiac myocyte differentiation, in vitro cardiac myocyte explant model, as well as a neonatal heart resection model. The regenerating mouse heart revealed a transcriptional reversion of cardiac myocyte differentiation processes including reactivation of latent developmental programs similar to those observed during de-stabilization of a mature cardiac myocyte phenotype in the explant model. We identified potential upstream regulators of the core network, including interleukin 13 (IL13), which induced cardiac myocyte cell cycle entry and STAT6/STAT3 signaling in vitro. We demonstrate that STAT3/periostin and STAT6 signaling are critical mediators of IL13 signaling in cardiac myocytes. These downstream signaling molecules are also modulated in the regenerating mouse heart. Conclusions Our work reveals new insights into the transcriptional regulation of mammalian cardiac regeneration and provides the founding circuitry for identifying potential regulators for stimulating heart regeneration.

Notch signalling restricts inflammation and serpine1 expression in the dynamic endocardium of the regenerating zebrafish heart

“…6H). During regeneration, dedifferentiating zebrafish and mouse cardiomyocytes disassemble the sarcomere for cell division to proceed (Jopling et al, 2010;Porrello et al, 2011), and high levels of sarcomeric proteins are characteristic of differentiated cardiomyocytes (O'Meara et al, 2015). Confirming the RNA-seq data, we detected fewer woundadjacent cardiomyocytes showing decreased levels of myosin light chain kinase 3 (mylk3), which regulates sarcomere assembly (Seguchi et al, 2007), in hearts after RO treatment than in DMSO-treated hearts (Fig.…”

Cardiac cytoarchitecture — why the “hardware” is important for heart function!

“…Elegant studies by Porrello and colleagues have shown that neonatal mouse hearts still possess the ability to regenerate by reactivation of cell division in cardiomyocytes and that this ability gets lost within the first week after birth [39]. Recent studies have correlated a regenerative capacity with a specific transcriptional signature, which resembles a more immature phenotype [40]. It was postulated that the trigger for the switch may be the oxygen-rich environment after birth and a residual population of smaller cardiomyocytes with hypoxic characteristics and increased proliferative potential was identified [41].…”

The Transcriptional Landscape of Regenerating Newborn Mouse Hearts

“…In the current issue of Circulation Research, O'Meara et al 6 analyzed the transcriptional signature of mouse hearts at different stages of postnatal development (p0, p4, p7, and 8-to 10-week-old mice) and of embryonic stem cells undergoing cardiac differentiation. RNA-sequencing analysis revealed increased expression of multiple genes, which function in mitochondrial, sarcoplasm, and sarcomere-specific processes whereas genes primarily involved in RNA processing (RNA transport, RNA splicing, and RNA capping) and cell cycle were downregulated.…”