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Cell Rep. 2015 Nov 24;13(8):1705-16. doi: 10.1016/j.celrep.2015.10.032. Epub 2015 Nov 12.

Transcriptional Landscape of Cardiomyocyte Maturation.

Author information

1
Division of Cardiology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Johns Hopkins Institute for Cell Engineering, Baltimore, MD 21205, USA.
2
Stem Cell Transplantation Program, Division of Pediatric Hematology and Oncology, Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Boston Children's Hospital and Dana Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
3
Division of Cardiology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
4
Division of Cardiology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Johns Hopkins Institute for Cell Engineering, Baltimore, MD 21205, USA. Electronic address: ckwon13@jhmi.edu.

Abstract

Decades of progress in developmental cardiology has advanced our understanding of the early aspects of heart development, including cardiomyocyte (CM) differentiation. However, control of the CM maturation that 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 MatStat(CM) that indexes CM maturation status. MatStat(CM) 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.

PMID:
26586429
PMCID:
PMC4662925
DOI:
10.1016/j.celrep.2015.10.032
[Indexed for MEDLINE]
Free PMC Article

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