Research Paper Volume 12, Issue 7 pp 5693—5715

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

Mahmoud Al-Azab1,2, *, , Bing Wang1, *, , Abdalkhalig Elkhider1, , Williams Walana1,6, , Weiping Li1, , Bo Yuan1, , Yunshan Ye1, , Yawei Tang1, , Marwan Almoiliqy4, , Salah Adlat5, , Jing Wei1, , Yan Zhang3, , Xia Li1, ,

  • 1 Department of Immunology, College of Basic Medical Science, Dalian Medical University, Liaoning, China
  • 2 Department of Immunology, Guangzhou Institute of Pediatrics, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China
  • 3 Department of Rheumatology and Immunology, The Second Affiliated Hospital of Dalian Medical University, Liaoning, China
  • 4 Department of Pharmacology, College of Pharmacy, Dalian Medical University, Liaoning, China
  • 5 Key Laboratory of Molecular Epigenetics of MOE, School of Life Science, Northeast Normal University, Changchun, Jilin Province, China
  • 6 Department of Clinical Microbiology, University for Development Studies, Tamale, Ghana
* Equal contribution

Received: April 4, 2019       Accepted: February 19, 2020       Published: April 1, 2020
How to Cite

Copyright © 2020 Al-Azab et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


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 β-galactosidase activity (SA-β-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.


IHH: Indian Hedgehog; 4EBP1: 4E-binding protein 1; p70S6K1/2: Phosphorylated ribosomal S6 kinase.