Mesenchymal stem cells (MSCs) have been investigated as a potential injectable therapy for the treatment of knee osteoarthritis, with some evidence of success in preliminary human trials. However, optimisation and scale-up of this therapeutic approach depends on the identification of functional markers that are linked to their mechanism of action. One possible mechanism is through their chondrogenic differentiation and direct role in neo-cartilage synthesis. Alternatively, they could remain undifferentiated and act through the release of trophic factors that stimulate endogenous repair processes within the joint. Here, we show that extensive in vitro ageing of bone-marrow-derived human MSCs leads to loss of chondrogenesis but no reduction in trophic repair, thereby separating out the two modes of action. By integrating transcriptomic and proteomic data using Ingenuity Pathway Analysis, we found that reduced chondrogenesis with passage is linked to downregulation of the FOXM1 signalling pathway whilst maintenance of trophic repair is linked to CXCL12. In an attempt at developing functional markers of MSC potency, we identified loss of mRNA expression for MMP13 as correlating with loss of chondrogenic potential of MSCs and continued secretion of high levels of TIMP1 protein as correlating with the maintenance of trophic repair capacity. Since an allogeneic injectable OA therapy would require extensive cell expansion in vitro, we conclude that early passage MMP13 , TIMP1-secreting MSCs should be used for autologous OA therapies designed to act through engraftment and chondrogenesis, whilst later passage MMP13 , TIMP1-secreting MSCs could be exploited for allogeneic OA therapies designed to act through trophic repair. © AlphaMed Press 2020 SIGNIFICANCE STATEMENT: We have shown that mesenchymal stem cell (MSC) chondrogenesis is a transient property of these cells which is lost as they age in vitro, whereas trophic repair potency is maintained until the MSCs cease to grow. These findings are significant as they highlight the importance of defining the intended mode of action when preparing MSCs for injection into osteoarthritic joints. These studies demonstrate that the development of injectable MSC therapies for OA must take into account the transient nature of chondrogenic potency relative to their sustained trophic potency with increasing passage and specific strategies should be adopted to exploit one or other of these mechanisms of action.
© 2020 AlphaMed Press.

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