Abstract
Initially discovered for its capacity to regenerate ear holes, the MRL mouse has been subjected to multiple investigations to assess their capacity to regenerate other body tissues. This enhanced abilities to regenerate conserved at its adult stage might protect the MRL mouse from degenerative diseases such as osteoarthritis (OA). Although recognized as the most prevalent joint disease, OA remains a disease with a huge unmet medical need. Cellular therapy based on the use of mesenchymal stromal cells (MSC) to treat OA has become a thriving area of research with promising results in preclinical studies. However, MSC multilevel heterogeneity has hampered their efficacy and dampens their clinical translatability.We hypothesized that MSC derived from regenerative mammalian models such as the MRL mouse could mediate this regenerative ability through their intrinsic properties. To this aim, we compared the secretome of MRL and BL6 MSC and identified several factors overexpressed by MRL-MSC as compared to BL6-MSC. Among them, we identified and focused our attention on procollagen-lysine,2-oxoglutarate 5-dioxygenase 2 (PLOD2), coding for the lysyl hydrolase LH2 in charge of post-translational modifications of collagen for its stability and stiffness. PLOD2 is induced by hypoxia-inducible factor 1-alpha (HIF-1) which contribute to the glycolytic metabolism of MRL mouse. Plod2 silencing induced a decrease of the glycolytic function of MRL-MSC resulting in the alteration of their migratory and chondroprotective abilities in vitro. In vivo, in the collagenase-induced osteoarthritis mouse model, MRL-MSC deficient for plod2 lose their therapeutical effect as compared to their wild-type counterpart.In conclusion, these results demonstrate that PLOD2 governs the glycolytic metabolism of MRL-MSC and which seems to play a central role for its regenerative capacities. This suggests a therapeutic application for osteoarthritis.