Transcriptional Landscape of Cardiomyocyte Maturation

Abstract

SUMMARY Decades of progress in developmental cardiology has advanced our understanding of the early aspects of heart development, including cardiomyocyte (CM) differentiation. However, control of CM maturation which is subsequently required to generate adult myocytes, remains elusive. Here, we analyzed over 200 microarray datasets from early embryonic to adult hearts and identified a large number of genes whose expression shifts gradually and continuously during maturation. We generated an atlas of integrated gene expression, biological pathways, transcriptional regulators, and gene regulatory networks (GRNs), which show discrete sets of key transcriptional regulators and pathways activated or suppressed during CM maturation. We developed a GRN-based program named MatStatCM that indexes CM maturation status. MatStatCM reveals that pluripotent stem cell-derived CMs mature early in culture, but are arrested at the late embryonic stage with aberrant regulation of key transcription factors. Our study provides a foundation for understanding CM maturation.

Ectopic expression of Cdk8 induces eccentric hypertrophy and heart failure

“…The heart uses highly coordinated waves of transcription that begin during embryogenesis and propagate through postnatal development (1). Prolonged exposure to any number of pathological stressors in the adult myocardium triggers adaptive responses, including disruption of transcriptional homeostasis.…”

Sall1 transiently marks undifferentiated heart precursors and regulates their fate

“…The GFP + cells were efficiently differentiated into cardiomyocytes (Figure S1B, C) with increased levels of contractile genes (Figure S1E). Isl1 levels were maintained even after 8 days of culture, but this is likely due to an ESC culture effect [14]. Through bioinformatics analyses, we identified putative Sall1-binding sites near loci of Isl1 and Flk1 (Figure S1F).…”

Comparative Gene Expression Analysis of Mouse and Human Cardiac Maturation

“…However, PSC-derived cardiomyocytes barely mature [9]. More importantly, there are no established readouts to define maturation status of cardiomyocytes.…”