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Updated: Aug 23, 2025
Induction and Validation of Cellular Senescence in Primary Human Cells
Published on: June 20, 2018
Nr1d1 Mediated Cell Senescence in Mouse Heart-Derived Sca-1+CD31- Cells
Shiming Pu1,2,3,4, Qian Wang1,4, Qin Liu1,4
1Guangxi Universities Key Laboratory of Stem Cell and Biopharmaceutical Technology, Guangxi Normal University, Guilin 541004, China.
Insights
Nuclear Receptor 1D1 (Nr1d1) influences cardiac progenitor cell aging. Upregulating Nr1d1 promotes senescence, while depleting it in aged cells enhances proliferation and reduces apoptosis, suggesting Nr1d1 as an anti-aging target.
Area of Science:
- Cardiovascular Biology
- Cellular Senescence
- Molecular Endocrinology
Background:
- Sca-1+CD31- cells are identified as resident cardiac progenitor cells with differentiation potential.
- Aging cardiac progenitor cells exhibit increased Nuclear Receptor 1D1 (Nr1d1) mRNA levels.
- The precise role of Nr1d1 in the senescence of cardiac progenitor cells remains unclear.
Purpose of the Study:
- To investigate the impact of Nuclear Receptor 1D1 (Nr1d1) on the senescence of Sca-1+CD31- cardiac progenitor cells.
- To elucidate the molecular mechanisms by which Nr1d1 affects cardiac cell proliferation, apoptosis, and senescence.
Main Methods:
- Lentiviral transduction was used for Nr1d1 overexpression and knockdown in Sca-1+CD31- cells and mouse cardiac myocytes (MCMs).
- Assessed effects of Nr1d1 levels on cell differentiation, proliferation, apoptosis, cell cycle, and transcriptomic profiles.
- Luciferase reporter assays were employed to examine Nr1d1 binding to the promoter regions of Nr4a3 and Serpina3.
Main Results:
- Overexpression of Nr1d1 in young cells inhibited proliferation and promoted apoptosis.
- Depletion of Nr1d1 in aged cells enhanced proliferation and reduced apoptosis.
- Nr1d1 negatively correlated with proliferation, promoted apoptosis, and increased senescence-associated beta-galactosidase production in MCMs.
Conclusions:
- Nr1d1 plays a critical role in regulating cardiac progenitor cell senescence.
- Nr1d1 stimulates Serpina3 expression via interaction with Nr4a3.
- Nr1d1 emerges as a potential anti-aging therapeutic target for age-related cardiovascular diseases.
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.
