Abstract
Osteoarthritis (OA) is the most common and debilitating joint disease of advanced age and has no universally effective therapy. Here, we demonstrate that systemic transplantation of adult multipotent muscle-derived stem/progenitor cells (MDSPCs)—isolated from young mice—rejuvenates the knee articular cartilage (AC) of naturally aged mice. This intervention reduced expression of pro-inflammatory cytokines (Tnf and Il1a) and catabolic matrix-degrading proteinases (Mmp3 and Mmp13) in aged cartilage. Treatment with young MDSPCs also increased expression of pro-regenerative (Col2a1 and Acan) and prolongevity genes (Pot1b), including those associated with chondrocyte proliferation and differentiation, cartilage growth, and telomere protection. Indeed, the AC of MDSPC-treated mice exhibited reduced age-related histological pathologies. Importantly, the reduced mobility and arthritis-related gait dysfunctions of aged mice were also ameliorated by this treatment. Together, our findings demonstrate the rejuvenating effects of systemic transplantation of young MDSPCs on aging AC—at the molecular, tissue, and functional levels. This suggests that MDSPCs, or their secreted factors, may represent a novel therapy that can increase mobility and function in aged or OA patients.
Highlights
Aging is the primary risk factor and predictor of articular cartilage (AC) degeneration, which leads to osteoarthritis (OA)
Expression of pro-inflammatory cytokine and senescence-associated secretory phenotype (SASP) genes, Il1a and Tnf—which promote age-related pathologies associated with OA and enhance extracellular matrix (ECM) proteinases [6]—was significantly upregulated in naturally aged (NA)-C mice compared to young mice (Fig. 1A)
We examined whether systemic transplantation of young muscle-derived stem/progenitor cells (MDSPCs)—isolated from 3-week-old mice— ameliorates these OA-like changes
Summary
Aging is the primary risk factor and predictor of articular cartilage (AC) degeneration, which leads to osteoarthritis (OA). The declining ability of aging AC to repair and regenerate is manifested by an increase in inflammatory mediators, matrix degradation, and chondrocyte alterations [1]. Autologous cell therapies based on chondrocyte implantation, matrix-induced chondrogenesis, and transplantation of mesenchymal stem cells have not been successful in older adults [2]. We previously discovered that multipotent adult stem cells—muscle-derived stem/progenitor cells (MDSPCs)—isolated from young mice and injected intraperitoneally into mouse models of progeria, delayed the onset of aging-related diseases, doubled lifespan, and improved tissue regeneration [3]. These results strongly suggest that MDSPCs exert therapeutic effects on the aged microenvironment. We report molecular, tissue, and functional outcomes of systemic MDSPC transplantation on aged AC
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