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Acute severe hypoxia induces apoptosis of human pluripotent stem cells by a HIF-1α and P53 independent mechanism.

ABSTRACT: Human embryonic and induced pluripotent stem cells are self-renewing pluripotent stem cells (hPSCs) that can differentiate into a wide range of specialized cells. Although moderate hypoxia (5% O₂) improves hPSC self-renewal, pluripotency, and cell survival, the effect of acute severe hypoxia (1% O₂) on hPSC viability is still not fully elucidated. In this sense, we explore the consequences of acute hypoxia on hPSC survival by culturing them under acute (maximum of 24 h) physical severe hypoxia (1% O₂). After 24 h of hypoxia, we observed HIF-1α stabilization concomitant with a decrease in cell viability. We also observed an increase in the apoptotic rate (western blot analysis revealed activation of CASPASE-9, CASPASE-3, and PARP cleavage after hypoxia induction). Besides, siRNA-mediated downregulation of HIF-1α and P53 did not significantly alter hPSC apoptosis induced by hypoxia. Finally, the analysis of BCL-2 family protein expression levels disclosed a shift in the balance between pro- and anti-apoptotic proteins (evidenced by an increase in BAX/MCL-1 ratio) caused by hypoxia. We demonstrated that acute physical hypoxia reduced hPSC survival and triggered apoptosis by a HIF-1α and P53 independent mechanism.

SUBMITTER: Mucci S

PROVIDER: S-EPMC9637190 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Acute severe hypoxia induces apoptosis of human pluripotent stem cells by a HIF-1α and P53 independent mechanism.

Mucci Sofía S Isaja Luciana L Rodríguez-Varela María Soledad MS Ferriol-Laffouillere Sofía Luján SL Marazita Mariela M Videla-Richardson Guillermo Agustín GA Sevlever Gustavo Emilio GE Scassa María Elida ME Romorini Leonardo L

Scientific reports 20221105 1

Human embryonic and induced pluripotent stem cells are self-renewing pluripotent stem cells (hPSCs) that can differentiate into a wide range of specialized cells. Although moderate hypoxia (5% O<sub>2</sub>) improves hPSC self-renewal, pluripotency, and cell survival, the effect of acute severe hypoxia (1% O<sub>2</sub>) on hPSC viability is still not fully elucidated. In this sense, we explore the consequences of acute hypoxia on hPSC survival by culturing them under acute (maximum of 24 h) phy ...[more]

PMID: 36335243

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Project description:Background Few reports have addressed the mechanism by which microRNA miR-10b-5p regulates post-myocardial infarction (post-MI) cardiomyocyte apoptosis under hypoxic conditions. Methods and Results C57BL/6 mice underwent surgical ligation of the left anterior descending artery to create an MI or ischemia/reperfusion animal model. The expression of miR-10b-5p, PTEN (phosphatase and tensin homolog), and HIF-1α (hypoxia-inducible factor 1α) was detected in infarct border zone tissues at various time points. After precordial injections of the negative control or miR-10b-5p, overexpression lentiviruses were made in the areas surrounding the MI sites at 1 week, and myocardial infarct size, cardiac function, and cardiomyocyte apoptosis were examined. A miR-10b-5p mimic was transfected into primary mouse cardiomyocytes to analyze its effects on cardiomyocyte apoptosis and PTEN expression. Meanwhile, PTEN as a target of miR-10b-5p was verified via luciferase reporter gene assays. Cotransfection of miR-10b-5 and PTEN verified the relationship between miR-10b-5 and PTEN. Under hypoxic stress, the expression of HIF-1α and miR-10b-5p was examined. The results showed that miR-10b-5p expression was markedly reduced in the infarct border zone. Overexpression of miR-10b-5p in the murine model of MI significantly reduced MI size, improved cardiac function, and inhibited apoptosis. Overexpression of miR-10b-5p in vitro antagonized hypoxia-induced cardiomyocyte apoptosis and specifically inhibited the expression of the apoptosis-related gene PTEN, but overexpression of PTEN weakened these effects. We also found that hypoxia-induced accumulation of HIF-1α resulted in decreased expression of miR-10b-5p. Interfering with the activation of the HIF-1α signaling pathway promoted Pri-miR-10b and miR-10b-5p expression and inhibited PTEN expression. Conclusions MicroRNA miR-10b-5p antagonizes hypoxia-induced cardiomyocyte apoptosis, indicating that miR-10b-5p may serve as a potential future clinical target for the treatment of MI.

Dataset Information

Acute severe hypoxia induces apoptosis of human pluripotent stem cells by a HIF-1α and P53 independent mechanism.

Publications

Acute severe hypoxia induces apoptosis of human pluripotent stem cells by a HIF-1α and P53 independent mechanism.

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