Indian Hedgehog regulates senescence in bone marrow-derived mesenchymal stem cell through modulation of ROS/mTOR/4EBP1, p70S6K1/2 pathway

被引:43
作者
Al-Azab, Mahmoud [1 ,2 ]
Wang, Bing [1 ]
Elkhider, Abdalkhalig [1 ]
Walana, Williams [1 ,6 ]
Li, Weiping [1 ]
Yuan, Bo [1 ]
Ye, Yunshan [1 ]
Tang, Yawei [1 ]
Almoiliqy, Marwan [4 ]
Adlat, Salah [5 ]
Wei, Jing [1 ]
Zhang, Yan [3 ]
Li, Xia [1 ]
机构
[1] Dalian Med Univ, Coll Basic Med Sci, Dept Immunol, Dalian, Liaoning, Peoples R China
[2] Guangzhou Med Univ, Guangzhou Women & Childrens Med Ctr, Guangzhou Inst Pediat, Dept Immunol, Guangzhou, Peoples R China
[3] Dalian Med Univ, Affiliated Hosp 2, Dept Rheumatol & Immunol, Dalian, Liaoning, Peoples R China
[4] Dalian Med Univ, Coll Pharm, Dept Pharmacol, Dalian, Liaoning, Peoples R China
[5] Northeast Normal Univ, Sch Life Sci, Key Lab Mol Epigenet MOE, Changchun, Jilin, Peoples R China
[6] Univ Dev Studies, Dept Clin Microbiol, Tamale, Ghana
来源
AGING-US | 2020年 / 12卷 / 07期
基金
中国国家自然科学基金;
关键词
Indian hedgehog; aging; differentiation; mesenchymal stem cell; mammalian target of rapamycin; SIGNALING PATHWAY; STROMAL CELLS; MTOR; AGE; DIFFERENTIATION; OSTEOPOROSIS; ACTIVATION; MIGRATION; DELAYS;
D O I
10.18632/aging.102958
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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.
引用
收藏
页码:5693 / 5715
页数:23
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