PLOD2, a key factor for MRL MSC metabolism and chondroprotective properties

Abstract

Background Initially discovered for its ability to regenerate ear holes, the Murphy Roth Large (MRL) mouse has been the subject of multiple research studies aimed at evaluating its ability to regenerate other body tissues and at deciphering the mechanisms underlying it. These enhanced abilities to regenerate, retained during adulthood, protect the MRL mouse from degenerative diseases such as osteoarthritis (OA). Here, we hypothesized that mesenchymal stromal/stem cells (MSC) derived from the regenerative MRL mouse could be involved in their regenerative potential through the release of pro-regenerative mediators. Method To address this hypothesis, we compared the secretome of MRL and BL6 MSC and identified several candidate molecules expressed at significantly higher levels by MRL MSC than by BL6 MSC. We selected one candidate, Plod2, and performed functional in vitro assays to evaluate its role on MRL MSC properties including metabolic profile, migration, and chondroprotective effects. To assess its contribution to MRL protection against OA, we used an experimental model for osteoarthritis induced by collagenase (CiOA). Results Among the candidate molecules highly expressed by MRL MSC, we focused our attention on procollagen-lysine,2-oxoglutarate 5-dioxygenase 2 (PLOD2). Plod2 silencing induced a decrease in the glycolytic function of MRL MSC, resulting in the alteration of their migratory and chondroprotective abilities in vitro. In vivo, we showed that Plod2 silencing in MRL MSC significantly impaired their capacity to protect mouse from developing OA. Conclusion Our results demonstrate that the chondroprotective and therapeutic properties of MRL MSC in the CiOA experimental model are in part mediated by PLOD2.

1. Introduction

Regeneration ability is a property that varies widely during development and among species. Indeed, while able to regenerate at early embryonic stages, adult mammals will trigger a tissue repair mechanism resulting in scar formation after tissue injury and limiting the structural and functional recovery [1, 2]. In contrast, some species, such as salamander [3], zebrafish [4] and hydra [5, 6], maintain their regenerative properties during their all-life [7–9]. Rare exceptions, such as the super healer Murphy Roths Large (MRL) mouse, exist among mammals.

Indeed, the adult MRL mouse is a competent model for tissue regeneration, suggesting that crucial regenerative mechanisms are conserved in this mammalian model. MRL mouse possesses the extraordinary potential to regenerate multiple musculoskeletal tissues such as the outer ear, articular cartilage, and digits without scarring [10–15]. Among the conserved mechanisms underlying regeneration, the emphasis on aerobic glycolytic energy metabolism has been reported to be essential in several regenerative species including the MRL mouse [16–18].

MRL mice are protected from developing joint diseases such as osteoarthritis (OA) [11, 19]. Identifying the mechanisms underlying articular cartilage regeneration and protection from osteoarthritis (OA) would allow the development of novel therapies for OA patients. Indeed, OA is a complex disease characterized partly by the degradation of articular cartilage and for which no curative treatment exists to date. One therapeutic option studied is the intra-articular administration of mesenchymal stem/stromal cells (MSC). The trophic activities of MSC introduced exogenously have been shown to protect from cartilage degradation and OA development in the collagenase-induced OA (CiOA) model [20–22]. This experimental model reproduces some events characteristic of the human OA disease, such as moderate inflammation of the synovial me