Microrna profile of mesenchymal stromal cells: A tool to predict their therapeutic efficacy in osteoarthritis

Abstract

Purpose: 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. Pro-inflammatory monocytes/macrophages were reduced in the synovial fluid (SF), suggestive of a clinical MSC anti-inflammatory action. 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: 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 have conducted an unbiased miR sequencing on our clinical trial MSC samples exposed to pooled synovial fluid from eight OA patients in the same trial. We are correlating differential miR expression with patient outcomes. Results: We have identified 25 miRs differentially expressed between MSCs from responder (5/ out of 5 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, we found that the identified miRs are associated with immune response, fibrosis, OA pathology and three linage differentiation of MSCs. Currently, we are verifying the miRs and their targets by qPCR to better understand and predict potent MSCs, and/or OA patients that are responders to MSC therapies. Conclusions: 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.