Abstract
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.
Highlights
Eukaryotic cell aging is an irreversible loss of growth and proliferation which is maintained by intrinsic and extrinsic factors after unceasing cellular replication or surrounding stress
We amplified the gene expression of cells using RT-PCR and the results revealed a significant decrease in Indian Hedgehog (IHH) gene expression in senescent bone marrow-derived mesenchymal stem cells (MSC) (BMSC) compared to non-senescent cells (Figure 1C)
These results suggested that BMSC lost their ability to synthesize IHH as they aged, and IHH could have an essential task in the regulation of BMSC senescence and differentiation
Summary
Eukaryotic cell aging is an irreversible loss of growth and proliferation which is maintained by intrinsic and extrinsic factors after unceasing cellular replication or surrounding stress. MSC’s early aging in vitro remains a challenge which seems to restrain the efforts of scientists and physicians in MSC research and clinical applications. One of the In vivo signs of cell aging is skewed differentiation of MSC to adipocyte at the cost of osteoblast, which is considered a core effector in osteoporosis [6]. Keeping BMSC young, preventing aging, and maintaining physiologically balanced differentiation during in vitro or in vivo proliferation are important fundamental requirements in the clinical applications of BMSC and management of aging-related diseases
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