Transcriptional Landscape of Cardiomyocyte Maturation
Hideki Uosaki,
Patrick Cahan,
Dong I. Lee,
Songnan Wang,
Matthew Miyamoto,
Laviel Fernandez,
David A. Kass,
Chulan Kwon
Affiliations
Hideki Uosaki
Division of Cardiology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Patrick Cahan
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
Dong I. Lee
Division of Cardiology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Songnan Wang
Division of Cardiology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Matthew Miyamoto
Division of Cardiology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Laviel Fernandez
Division of Cardiology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
David A. Kass
Division of Cardiology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Chulan Kwon
Division of Cardiology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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 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.
