Description
Objectives
Mesenchymal stem cells (MSCs) are promising for the treatment of osteoarthritis (OA) due to their regenerative and immunomodulatory potential, but heterogeneity in their preparations remains a challenge for clinical translation. Selecting MSCs for integrin α10β1 (integrin a10-MSCs) leads to homogeneous and consistent MSCs preparations. Safety and efficacy of intra-articular injection of allogeneic integrin a10-MSCs have been shown in two independent experimental OA horse studies, and in vivo homing, repair and engraftment of human integrin a10-MSCs in a rabbit osteochondral defect model. The aim of the current study was to gain more insight in the immunomodulatory capacity of human integrin a10-MSCs.
Methods
MSCs were culture expanded from the stromal vascular fraction of lipoaspirates and selected for integrin α10β1. A T-cell proliferation assay was performed by coculturing integrin a10-MSCs with various ratios of Carboxyfluorescein N-succinimidyl ester labelled human peripheral blood mononuclear cells (PBMCs) stimulated with anti-CD3/CD28 to induce proliferation of CD4+ T cells. In a macrophage polarization assay, integrin a10-MSCs were cocultured with THP-1 cells that were differentiated in macrophages by phorbol 12-myristate 13-acetate and stimulated to M1 macrophages by lipopolysaccharide, subsequently analysing the M2 macrophage cell surface markers CD163 and CD206. Secretion of immunomodulatory factors was evaluated after stimulation of integrin a10-MSCs with pro-inflammatory cytokines.
Results
Human integrin a10-MSCs suppressed T-cell proliferation at ratios of MSCs versus PBMCs of 1:2 and 1:5 (Fig. 1A), and switched M1 macrophages to M2 macrophages as judged by induction of specific cell surface markers (Fig. 1B). Treatment of the integrin a10-MSCs with pro-inflammatory cytokines, stimulated secretion of the immunomodulatory factors indoleamine 2,3-dioxygenase and prostaglandin E2.
Conclusions
This study showed that human integrin a10-MSCs can suppress T-cell proliferation, polarize macrophages to the more regenerative M2 phenotype and secrete immunomodulatory factors. These immunomodulatory capacities, together with the previously observed regenerative capacities, suggests that human integrin α10β1-selected MSCs are a promising therapy for osteoarthritis with dual mechanisms of action consisting of both resolving inflammation and cartilage tissue repair.
