Biomaterial Encapsulation of Human Mesenchymal Stromal Cells Modulates Paracrine Signaling Response and Enhances Efficacy for Treatment of Established Osteoarthritis

Abstract

Mesenchymal stromal cells (MSCs) have shown promise as osteoarthritis (OA) treatments; however, effective translation has been limited by high variability and heterogeneity of MSCs, suboptimal delivery strategies, and poor understanding of critical quality and potency attributes. Furthermore, most pre-clinical studies of MSC therapeutics for OA have focused on delaying OA development and not on treating established OA, which brings added clinical relevance. Thus, the objective of the current study was to assess the effects of biomaterial encapsulation on human MSC (hMSC) secretion of immunomodulatory cytokines in an OA microenvironment and therapeutic efficacy in treating established OA. A Medial Meniscal Transection (MMT) pre-clinical model of OA was implemented. Three weeks post-surgery, after OA was established, intra-articular injections of encapsulated hMSCs or nonencapsulated hMSCs were administered. Six weeks post-surgery, microstructural changes in the knee joint were quantified using microCT. Encapsulated hMSCs reduced articular cartilage degeneration and subchondral bone remodeling. A multiplexed immunoassay panel was used to profile the in vitro secretome of hMSCs in response to IL-1β. Nonencapsulated hMSCs showed an indiscriminate increase in all cytokines in response to IL-1β while encapsulated hMSCs showed a targeted secretory response with increased expression of pro-inflammatory (IL-1β, IL-6, IL-7, IL-8), anti-inflammatory (IL-1RA), and chemotactic (G-CSF, MDC, IP10) cytokines. These data show that biomaterial encapsulation can modulate hMSC paracrine signaling and enhance the therapeutic efficacy of the hMSCs in treating established OA. This cytokine profile provides a foundation for the identification of key factors affecting the overall potency of hMSC therapeutics for OA. Funding Information: This work was supported in part by VA (SPiRE) Grant [I21RX002372-01A1] from the United States (U.S.) Department of Veterans Affairs Rehabilitation Research and Development Service. The research was also supported in part by the DOD PRMRP Grant [PR171379] and PHS Grant [UL1TR000454] from the Clinical and Translational Science Award Program, National Institutes of Health, National Center for Advancing Translational Sciences. Declaration of Interests: There are no conflicts to declare. Ethics Approval Statement: All animal care and experiments were conducted in accordance with the institutional guidelines and approved by the Atlanta Veteran Affairs Medical Center (VAMC) with experimental procedures approved by the Atlanta VAMC Institutional Animal Care and Use Committee (IACUC).