Encapsulation of metabolically standardized MSC as a novel osteoarthritis therapy – METAB-OA

Osteoarthritis (OA), the most prevalent joint disease, is characterized by structural and functional alterations of all joint components. The most promising cell-based therapy approach for OA relies on the use of pleiotropic mesenchymal stromal/stem cells (MSC) that display tissue-protective and immunoregulatory properties. The intra-articular (IA) injection of MSC in pre-clinical studies as well as in phase I and II clinical trials has been investigated and reported as a safe and well-tolerated treatment for OA. Moreover, Partner 1 (INSERM U1183-IRMB/Montpellier) has demonstrated the capacity of MSC to reduce the clinical severity of OA in experimental animal models by decreasing inflammation and protecting cartilage and bone from degradation. However and despite significant clinical improvement, the benefit of IA injection of MSC in OA patients still remains limited to the short-term. In that respect, it is believed that the poor in vivo survival rate of IA MSC, that strongly limits their residence time in the injured joint, associated to their biological heterogeneity, could collectively reduce their long-term beneficial effects in OA.
Phenotypic and metabolic heterogeneity of MSC subtypes is dynamic and can be exacerbated by manufacturing process at clinical scale. To overcome this first limitation, Partner 1 has recently demonstrated that MSC metabolism governs their immunosuppressive and anti-inflammatory properties and developed an approach of cell expansion able to standardize MSC metabolism. Additionally, Partner 2 (INSERM U1229-RMeS, Nantes) has developed cytoprotective hydrogels and micromolding procedures for cell encapsulation that could contribute to enhance MSC survival and persistence in the injured joint.
Considering the safety and promising therapeutic effect of MSC in OA and the potential role of the MSC metabolic switch in their immunomodulatory properties, METAB-OA aims to investigate whether the metabolic stability of adipose tissue-derived MSC can improve MSC anti-OA potential and whether MSC encapsulation in injectable micro-sized hydrogels can maintain MSC metabolism and survival upon injection and provide a suitable microenvironment supporting MSC functions. Thus the specific objectives of the METABOA, are to: (i) generate pharmacologically-induced glycolytic AT-MSC (iAT-MSC) with enhanced anti-OA properties, (ii) encapsulate iAT-MSC in micromolded hydrogels to protect them from cell death upon injection and limit their dispersion outside the joint space and (iii) investigate whether iAT-MSC encapsulated in alginate microgels and injected in the knee joints of OA rabbits exhibit enhanced and prolonged therapeutic effects.
To address these issues, METAB-OA will be organized in 4 work packages (WP): • WP0: Project management, communication and valorization, • WP1: Generation of a homogeneous population of AT-MSC (iAT-MSC) with enhanced immunosuppressive and chondro-protective properties, • WP2: Generation of micromolded hydrogels to encapsulate and protect iAT-MSC and • WP3: Proof of concept of the efficacy of encapsulated iAT-MSC in a medium-sized animal model of OA. In case of success, METAB-OA innovative project will undoubtedly allow us to consider clinical trials and thus pave the way of new therapeutic avenues in the medical care of OA patients.