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Abstract Background: The regenerative potential of mesenchymal stromal/stem cells (MSCs) has been extensively studied in clinical trials over the past decade. Despite the promising regenerative properties documented in preclinical studies, such as those for osteoarthritis (OA), the therapeutic translation of these results in patients has not been fully conclusive. One factor contributing to this therapeutic barrier could be the presence of senescent cells in the OA joint. Methods: This study explores a novel approach to the treatment of OA by combining the therapeutic potential of adipose tissue-derived MSCs (AD-MSCs) with Rapamycin, a clinically approved immunosuppressive drug with anti-senescent properties. We first investigated the effects of Rapamycin on senescence and fibrosis markers in freshly isolated OA chondrocytes by immunostaining. We next evaluated the in vitro differentiation capacities of AD-MSCs, their regulatory immune functions on activated immune cells and their regenerative effects on OA chondrocyte signature in presence of Rapamycin. Results: Rapamycin was found to reduce in OA chondrocytes the senescence marker p15ink4b and the fibrotic marker COL1A1 in a dose-dependent manner without affecting the expression of the master chondrogenic markers SOX9 and COL2. The drug enhanced the differentiation of AD-MSCs into chondrocytes and reduced their adipogenesis. In addition, Rapamycin improved the immunoregulatory functions of AD-MSCs by promoting the expression of immunosuppressive elements such as IDO1, PTGS2, and PDL-1/CD274, the latter at the cell surface. Finally, by comparative RNA sequencing analysis, we revealed that AD-MSCs in presence of Rapamycin exhibited an improved chondroprotective regenerative effects on cocultivated OA chondrocytes. Conclusions: Our findings propose that the combination of Rapamycin and AD-MSCs enhances the therapeutic efficacy of these cells on senescence-driven degenerative diseases such as OA. Overall, our data also open avenue for the identification of some factors that could contribute to the enhanced anti-fibrotic and anti-inflammatory properties of AD-MSCs in response to Rapamycin.
Véret et al. (Sat,) studied this question.