B1: Regenerative Medicine I

MESENCHYMAL STEM CELL-DERIVED EXTRACELLULAR VESICLES: AN OFF-THESHELF AND CELL-FREE THERAPEUTIC FOR CARTILAGE REPAIR


Shipin Zhang, Wern Cui Chu1, Ruenn Chai Lai2, Sai Kiang Lim1,3, James Hoi Po Hui1,4,5, Eng Hin Lee1,5, Wei Seong Toh1,5


1National University of Singapore, Singapore;
2Institute of Medical Biology, A*STAR, Singapore;
3Institute of Medical Biology, A*STAR, Singapore;

4National University Health System, Singapore;
5Life Sciences Institute, National University of Singapore, Singapore


Articular cartilage injuries as a result of excessive sports activities are very common Mesenchymal stem cell (MSC) therapy has demonstrated clinical efficacy for cartilage repair However, the mechanisms underlying the biological effects of MSCs in cartilage repair remain unclear Also, as with all cellular therapies, there exist logistic and operational challenges in maintaining cell viability and vitality Increasingly, the therapeutic efficacy of MSCs has been attributed to the secretion of paracrine factors Notably, exosomes are cell-secreted, nano-sized, bi-lipid membrane vesicles present in the MSC secretome found to possess potent immunomodulatory and regenerative properties Here, we hypothesized that MSC exosomes could promote orderly cartilage and subchondral bone regeneration in a critical-sized osteochondral defect model in immunocompetent rats The purified MSC exosomes were purified from conditioned medium of human embryonic MSCs and possessed all the defining characteristics of exosomes including a modal size of 100nm and presence of exosome-associated markers including CD81, TSG101 and ALIX In vivo, weekly intraarticular injections of MSC exosomes demonstrated potent ability in promoting orderly cartilage and subchondral bone regeneration By the end of 12 weeks, exosome treatment resulted in formation of a smooth continuous layer of hyaline cartilage and complete regeneration of the underlying subchondral bone On contrary, the contralateral control knees treated with saline showed poor repair with fibrous tissue and minimal matrix deposition Immunohistochemistry further revealed early cell proliferation at 2 weeks denoted by increased proliferative cell nuclear antigen (PCNA) immunoreactivity in synovium and reparative tissues of animals treated with MSC exosomes (P<0 001)  In vitro, MSC exosomes induced proliferation of rat chondrocytes and suppressed the expression of genes associated with matrix degradation Our results show that MSC exosomes likely mediate cartilage regeneration through mechanisms of active cell proliferation and attenuated matrix degradation In summary, MSC exosomes are promising off-the-shelf and cell-free therapeutic for cartilage repair

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