Hey2 enhancer activity defines unipotent progenitors for left ventricular cardiomyocytes in juxta-cardiac field of early mouse embryo

Author:

Watanabe Yusuke1ORCID,Wang Yunce12,Tanaka Yuki12,Iwase Akiyasu3ORCID,Kawamura Teruhisa2,Saga Yumiko4ORCID,Yashiro Kenta5,Kurihara Hiroki3,Nakagawa Osamu1ORCID

Affiliation:

1. Department of Molecular Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka 564-8565, Japan

2. Laboratory of Stem Cell & Regenerative Medicine, Department of Biomedical Sciences, College of Life Sciences, Ritsumeikan University, Kusatsu, Shiga 525-8577, Japan

3. Department of Physiological Chemistry and Metabolism, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan

4. Mammalian Development Laboratory, Department of Gene Function and Phenomics, National Institute of Genetics, Mishima, Shizuoka 411-8582, Japan

5. Division of Anatomy and Developmental Biology, Department of Anatomy, Kyoto Prefectural University of Medicine, Kamigyo, Kyoto 602-8566, Japan

Abstract

The cardiac crescent is the first structure of the heart and contains progenitor cells of the first heart field, which primarily differentiate into left ventricular cardiomyocytes. The interface between the forming cardiac crescent and extraembryonic tissue is known as the juxta-cardiac field (JCF), and progenitor cells in this heart field contribute to the myocardium of the left ventricle and atrioventricular canal as well as the epicardium. However, it is unclear whether there are progenitor cells that differentiate specifically into left ventricular cardiomyocytes. We have previously demonstrated that an enhancer of the gene encoding the Hey2 bHLH transcriptional repressor is activated in the ventricular myocardium during mouse embryonic development. In this study, we aimed to investigate the characteristics of cardiomyocyte progenitor cells and their cell lineages by analyzing Hey2 enhancer activity at the earliest stages of heart formation. We found that the Hey2 enhancer initiated its activity prior to cardiomyocyte differentiation within the JCF. Hey2 enhancer-active cells were present rostrally to the Tbx5 -expressing region at the early phase of cardiac crescent formation and differentiated exclusively into left ventricular cardiomyocytes in a lineage distinct from the Tbx5 -positive lineage. By the late phase of cardiac crescent formation, Hey2 enhancer activity became significantly overlapped with Tbx5 expression in cells that contribute to the left ventricular myocardium. Our study reveals that a population of unipotent progenitor cells for left ventricular cardiomyocytes emerge in the JCF, providing further insight into the mode of cell type diversification during early cardiac development.

Funder

MEXT | Japan Society for the Promotion of Science

Mochida Memorial Foundation for Medical and Pharmaceutical Research

Mother and Child Health Foundation

Smoking Research Foundation

Intramural Research Fund for Cardiovascular Diseases of the National Cerebral and Cardiovascular Center

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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