Stem cell reprogramming for joint preservation to alleviate pain and promote function

Abstract The overall objective of this application is to identify an unlimited supply of immunomodulatory cells that can consistently promote joint tissue preservation when injected in clinically relevant surgical models of osteoarthritis (OA). This is motivated by the critical need to develop novel strategies to alleviate pain and promote function through rehabilitative strategies aimed at preserving joint cartilage in Veterans that suffer from OA. Veterans are three times more likely to develop OA than civilians in part due to the high demands and joint injury risks associated with military service. Distressingly, our Veterans are also more likely to abuse narcotics and opioids that could provide temporary pain relief but lead to devastating long-term consequences. Intra-articular injections of mesenchymal stromal cells (MSCs) are now standard of care for knee OA in a variety of orthopaedic clinics, with increasingly well-documented data showing their efficacy. Yet, clinical care requires point-of-care harvest of autologous cells that may have reduced quality in older and/or osteoarthritic individuals. Here, we propose to leverage critical data obtained from our recently completed randomized controlled trial (NCT03818737) that suggest the superiority of autologous bone marrow derived-MSCs (BM-MSCs) to relieve clinical OA pain over cord tissue MSCs in responder patients. Furthermore, we provide preliminary data in a rat OA model that BM-MSCs provide greater tissue preservation and pain relief than allogeneic sources, but donor variability remains a barrier to a consistent therapeutic benefit. To overcome these limitations, we began using MSCs derived from induced pluripotent stem cells (iMSCs) as therapeutic immunomodulators of joint inflammation in preclinical models of OA. We found that iMSCs from healthy articular chondrocytes (AC-iMSCs) elicited excellent chondro-protection and analgesia, comparable to somatic BM-MSCs. Based on the above, we posit the Central Hypothesis that a somatic cell-derived iMSC product that exhibits robust immunomodulatory action in vitro will yield an unlimited supply of allogeneic medicinal cells that will reduce pain, improve function, and slow tissue degradation in a clinically relevant model of OA. To test this hypothesis, we will first establish the immunomodulatory potential of iMSCs derived from bone marrow MSCs and articular chondrocytes compared to somatic cells (Aim 1). We will then ascertain the in vivo efficacy of the iMSCs with the most immunomodulatory potential using our rat MMT model of OA (Aim 2). Finally, we plan to validate the therapeutic potential of the most effective iMSCs in a clinically relevant pig model of OA (Aim 3).