期刊
AGING-US
卷 12, 期 7, 页码 5693-5715出版社
IMPACT JOURNALS LLC
DOI: 10.18632/aging.102958
关键词
Indian hedgehog; aging; differentiation; mesenchymal stem cell; mammalian target of rapamycin
资金
- Liaoning Provincial Program for Top Discipline of Basic Medical Sciences
- Dalian key laboratory of human homeostasis microbiology and disease immunology
- National Natural Science Foundation of China [81671606, 81801609]
- Natural Science Foundation of Liaoning Province of China [20180550662]
- Special Grant for Translational Medicine, Dalian Medical University [2015010]
- College Scientific Research Project of Education Department of Liaoning Province [LQ2017004]
- Liaoning Distinguished Professor (Liao taught (2018-2020))
Premature senescence of bone marrow-derived mesenchymal stem cells (BMSC) remains a major concern for their application clinically. Hedgehog signaling has been reported to regulate aging-associated markers and MSC skewed differentiation. Indian Hedgehog (IHH) is a ligand of Hedgehog intracellular pathway considered as an inducer in chondrogenesis of human BMSC. However, the role of IHH in the aging of BMSC is still unclear. This study explored the role IHH in the senescence of BMSC obtained from human samples and senescent mice. Isolated BMSC were transfected with IHH siRNA or incubated with exogenous IHH protein and the mechanisms of aging and differentiation investigated. Moreover, the interactions between IHH, and mammalian target of rapamycin (mTOR) and reactive oxygen species (ROS) were evaluated using the corresponding inhibitors and antioxidants. BMSC transfected with IHH siRNA showed characteristics of senescence-associated features including increased senescence-associated beta-galactosidase activity (SA-beta-gal), induction of cell cycle inhibitors (p53/p16), development of senescence-associated secretory phenotype (SASP), activation of ROS and mTOR pathways as well as the promotion of skewed differentiation. Interestingly, BMSC treatment with IHH protein reversed the senescence markers and corrected biased differentiation. Moreover, IHH shortage-induced senescence signs were compromised after mTOR and ROS inhibition. Our findings presented anti-aging activity for IHH in BMSC through down-regulation of ROS/mTOR pathways. This discovery might contribute to increasing the therapeutic, immunomodulatory and regenerative potency of BMSC and introduce a novel remedy in the management of aging-related diseases.
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