Hypoxic preconditioning rejuvenates mesenchymal stem cells and enhances neuroprotection following intracerebral hemorrhage via the miR-326-mediated autophagy

Stem Cell Research & Therapy

Han Xiao¹  Jianyang Liu¹  Lite Ge¹  Jialin He¹  Zheng Jiang¹  Zhiping Hu¹  Liuwang Zeng¹  Ming Lu²  Yan Huang³ 

[1] Department of Neurology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China;Developmental Biology of Ministry of Education, College of Life Sciences, Hunan Normal University, Changsha, Hunan, China;Hunan Provincial Key Laboratory of Neurorestoratology, Second Affiliated Hospital of Hunan Normal University, Changsha, Hunan, China;National Health Commission Key Laboratory of Birth Defects Research, Prevention, and Treatment, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, Hunan, China;

关键词: Mesenchymal stem cells;    Intracerebral hemorrhage;    Hypoxic preconditioning;    Cellular senescence;    Autophagy;    miRNAs;   

DOI  :  10.1186/s13287-021-02480-w

来源: Springer

【 摘 要 】

BackgroundIntracerebral hemorrhage (ICH) is a major public health concern, and mesenchymal stem cells (MSCs) hold great potential for treating ICH. However, the quantity and quality of MSCs decline in the cerebral niche, limiting the potential efficacy of MSCs. Hypoxic preconditioning is suggested to enhance the survival of MSCs and augment the therapeutic efficacy of MSCs in ICH. MicroRNAs (miRNAs) are known to mediate cellular senescence. However, the precise mechanism by which miRNAs regulate the senescence of hypoxic MSCs remains to be further studied. In the present study, we evaluated whether hypoxic preconditioning enhances the survival and therapeutic effects of olfactory mucosa MSC (OM-MSC) survival and therapeutic effects in ICH and investigated the mechanisms by which miRNA ameliorates hypoxic OM-MSC senescence.MethodsIn the in vivo model, ICH was induced in mice by administration of collagenase IV. At 24 h post-ICH, 5 × 105 normoxia or hypoxia OM-MSCs or saline was administered intracerebrally. The behavioral outcome, neuronal apoptosis, and OM-MSC survival were evaluated. In the in vitro model, OM-MSCs were exposed to hemin. Cellular senescence was examined by evaluating the expressions of P16INK4A, P21, P53, and by β-galactosidase staining. Microarray and bioinformatic analyses were performed to investigate the differences in the miRNA expression profiles between the normoxia and hypoxia OM-MSCs. Autophagy was confirmed using the protein expression levels of LC3, P62, and Beclin-1.ResultsIn the in vivo model, transplanted OM-MSCs with hypoxic preconditioning exhibited increased survival and tissue-protective capability. In the in vitro model, hypoxia preconditioning decreased the senescence of OM-MSCs exposed to hemin. Bioinformatic analysis identified that microRNA-326 (miR-326) expression was significantly increased in the hypoxia OM-MSCs compared with that of normoxia OM-MSCs. Upregulation of miR-326 alleviated normoxia OM-MSC senescence, whereas miR-326 downregulation increased hypoxia OM-MSC senescence. Furthermore, we showed that miR-326 alleviated cellular senescence by upregulating autophagy. Mechanistically, miR-326 promoted the autophagy of OM-MSCs via the PI3K signaling pathway by targeting polypyrimidine tract-binding protein 1 (PTBP1).ConclusionsOur study shows that hypoxic preconditioning delays OM-MSC senescence and augments the therapeutic efficacy of OM-MSCs in ICH by upregulating the miR-326/PTBP1/PI3K-mediated autophagy.

【 授权许可】

CC BY