Microrna profile of mesenchymal stromal cells: a tool to predict their therapeutic efficasy in osteoarthritis

Abstract

Background & Aim Osteoarthritis (OA) is a joint disease affecting > 5 million Canadians. Patients have limited palliative and joint-replacement surgical options, emphasizing the need for new curative therapies. Stromal cell therapy is emerging as a compelling treatment for OA. Our first-in-Canada Ph1/2 trial with bone marrow mesenchymal stromal cells (BM-MSCs) in OA patients showed significant improvements in patient outcomes. Although, MSCs showed beneficial effects in all the patients, we found variabilities in MSCs efficacy among participants. The goal of this study is to identify novel microRNAs (miRs) that correlate with therapeutic efficacy of MSCs in the context of OA. Methods, Results & Conclusion We have identified a panel of predictive anti-inflammatory markers (i.e. IL10, HGF, IL6, TSG6, PGE2) on MSCs that is strongly indicative of clinical efficacy in OA. To expend this panel, we conducted an unbiased miR sequencing on our clinical trial MSC samples. We are correlating differential miR expression with patient outcomes. We identified 25 miRs differentially expressed between MSCs from responder (5/5 on KOOS sub-scale responses are clinically significant) and mild responder (2-3/5 KOOS sub-scale responses are clinically significant) participants. Amongst these, 12 miRs showed higher expression in MSCs from responder participants and 13 miRs appeared to be expressed at lower level when compared to those levels in MSCs from mild responder participants. Interestingly, miR target and pathway analysis revealed that the identified miRs are associated with Toll like receptors, IL-4, IL-13, IL12, IL-1 and IL-10 cascades; as well as TGF-β, wnt and Smad signaling. Thus, contributing to immune response, fibrosis and consequently OA pathology. We have selected 10 miRs out of 25 differentially expressed miRs based on the relevance of their targets to OA pathology for further analysis. Currently, we are verifying these miRs by qPCR and their significance in OA pathology will be confirmed via knock down/overexpression experiments. This will help us to better understand and predict potent MSCs, and/or OA patients that are responders to MSC therapies. In conclusion, microRNA profile of MSCs contributes to therapeutic efficacy of MSCs. Understanding therapeutically relevant mechanism of action of MSCs will help to develop enhanced MSCs; and define potency criterion for screening effective MSCs in OA patients. This in turn will enable a successful MSC pivotal clinical trial in OA.