The early embryonic heart regenerates by compensation of proliferating residual cardiomyocytes after cryoinjury

• Published in: Cell and tissue research Vol. 384; no. 3; pp. 757 - 769
• Main Authors: Narematsu, Mayu, Nakajima, Yuji
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.06.2021; Springer; Springer Nature B.V
• Subjects: Biomedical and Life Sciences; Biomedicine; Cardiomyocytes; Cell cycle; Compensation; Cryoinjury; Cyclin-dependent kinase inhibitor p27; Ethylenediaminetetraacetic acid; G1 phase; Heart; Heart cells; Human Genetics; Immunohistochemistry; Islet-1 protein; Mesenchyme; Molecular Medicine; Myocytes; Proteomics; Regular Article; S phase; Ventricle; Heart regeneration; Early embryo; Cryoinjury; p27 (Kip1); Cell cycle length
• ISSN: 0302-766X; 1432-0878
• DOI: 10.1007/s00441-021-03431-w

The adult mammalian heart is non-regenerative because cardiomyocytes withdraw from the cell cycle shortly after birth. Embryonic mammalian hearts, in which cardiomyocytes are genetically ablated in a salt-and-pepper–like pattern, regenerate due to compensation by residual cardiomyocytes. To date, it remains unknown whether or how transmural ventricular defects at the looped heart stage regenerate after cryoinjury. We established a cryoablation model in stage 16 chick embryonic hearts. In hearts at 5 h post cryoinjury (hpc), cryoinjury-induced defects were approximately 200 µm in width in the primitive ventricle; thereafter, the defect was filled with mesenchymal cells accumulating between the epicardium and endocardium. The defect began to regress at 4 days post cryoinjury (dpc) and disappeared around 9 dpc. Immunohistochemistry showed that there were no isl1-positive cells in either the scar tissue or residual cardiomyocytes. BrdU incorporation into residual cardiomyocytes was transiently downregulated in association with upregulation of p27 (Kip1), suggesting that cell cycle arrest occurred at G1-to-S transition immediately after cryoinjury. Estimated cell cycle length was examined, and the results showed that the shortest cell cycle length was 18 h at stages 19–23; it increased with development due to elongation of the G2-M-G1 phase and 30 h at stages 27–29. The S phase length was constant at 6–8 h. The cell cycle length was elongated immediately after cryoinjury, and it reversed at 1–2 dpc. Cryoablated transmural defects in the early embryonic heart were restored by compensation by residual myocytes.