Mesenchymal Progenitor Cell Resilience Counteracts Tissue Aging
DOI:
https://doi.org/10.65649/c833dn40Keywords:
Cellular Senescence, Mesenchymal Stromal Cells, Aging, Osteoporosis, Regenerative Medicine, Stem Cell Heterogeneity, DNA Repair, EpigeneticsAbstract
The age-related functional decline of mesenchymal stromal/progenitor cells (MSCs) is a central driver of skeletal aging, leading to osteoporosis and impaired tissue regeneration (Li, Wu, & Tuan, 2019). Challenging the paradigm of a uniformly aging MSC pool, this study identifies a rare subpopulation of mesenchymal progenitors with innate senescence resistance, termed Senescence-Resistant Committed progenitors (SRCs). Isolated from aged murine and human tissues via a unique immunophenotype (CD45⁻CD31⁻CD34⁻CD73⁺CD90⁺CD105⁺CD200⁺ITGA10⁺), SRCs demonstrated remarkable numerical preservation compared to severely depleted classical MSCs. Functionally, aged SRCs maintained low senescence markers (p16INK4a, SA-β-gal), lacked a pro-inflammatory secretome, and retained high clonogenic, proliferative, and osteogenic potential, countering the age-related adipogenic shift (Moerman, Teng, Lipschitz, & Lecka-Czernik, 2004). Transcriptomic and epigenetic profiling revealed that SRC resilience was underpinned by constitutive activation of DNA repair, antioxidant defense (NRF2), and mitochondrial homeostasis pathways, stabilized by a protective epigenetic landscape featuring *CDKN2A/p16* promoter hypomethylation (Sun, Coppe, & Lam, 2018). In vivo, transplantation of aged SRCs significantly enhanced bone regeneration in critical-sized defects compared to aged bulk MSCs. This discovery reframes mesenchymal aging, revealing a resilient cellular reservoir essential for tissue homeostasis. Targeting the SRC pool or mimicking its molecular signature represents a novel therapeutic frontier for age-related skeletal disorders.
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