Nr1d1 Mediated Cell Senescence in Mouse Heart-Derived Sca-1+CD31− Cells

Abstract

Aim: Sca-1+CD31− cells are resident cardiac progenitor cells, found in many mammalian tissues including the heart, and able to differentiate into cardiomyocytes in vitro and in vivo. Our previous work indicated that heart-derived Sca-1+CD31− cells increased the Nr1d1 mRNA level of Nr1d1 with aging. However, how Nr1d1 affects the senescence of Sca-1+CD31− cells. Methods: Overexpression and knockdown of Nr1d1 in Sca-1+CD31− cells and mouse cardiac myocyte (MCM) cell lines were performed by lentiviral transduction. The effects of Nr1d1 abundance on cell differentiation, proliferation, apoptosis, cell cycle, and transcriptomics were evaluated. Moreover, binding of Nr1d1 to the promoter region of Nr4a3 and Serpina3 was examined by a luciferase reporter assay. Results and Conclusions: Upregulation Nr1d1 in young Sca-1+CD31− cells inhibited cell proliferation and promoted apoptosis. However, depletion of Nr1d1 in aged Sca-1+CD31− cells promoted cell proliferation and inhibited apoptosis. Furthermore, Nr1d1 was negatively associated with cell proliferation, promoting apoptosis and senescence-associated beta-galactosidase production in MCMs. Our findings show that Nr1d1 stimulates Serpina3 expression through its interaction with Nr4a3. Nr1d1 may therefore act as a potent anti-aging receptor that can be a therapeutic target for aging-related diseases.