Date Published: March 7, 2018
Publisher: Public Library of Science
Author(s): Rohini L. Kadle, Salma A. Abdou, Alvaro P. Villarreal-Ponce, Marc A. Soares, Darren L. Sultan, Joshua A. David, Jonathan Massie, William J. Rifkin, Piul Rabbani, Daniel J. Ceradini, Giovanni Camussi.
Mesenchymal stem cells (MSCs) are known to both have powerful immunosuppressive properties and promote allograft tolerance. Determining the environmental oxygen tension and inflammatory conditions under which MSCs are optimally primed for this immunosuppressive function is essential to their utilization in promoting graft tolerance. Of particular interest is the mechanisms governing the interaction between MSCs and regulatory T cells (Tregs), which is relatively unknown. We performed our experiments utilizing rat bone marrow derived MSCs. We observed that priming MSCs in hypoxia promotes maintenance of stem-like characteristics, with greater expression of typical MSC cell-surface markers, increased proliferation, and maintenance of differentiation potential. Addition of autologous MSCs to CD4+/allogeneic endothelial cell (EC) co-culture increases regulatory T cell (Treg) proliferation, which is further enhanced when MSCs are primed in hypoxia. Furthermore, MSC-mediated Treg expansion does not require direct cell-cell contact. The expression of indolamine 2,3-dioxygenase, a mediator of MSC immunomodulation, increases when MSCs are primed in hypoxia, and inhibition of IDO significantly decreases the expansion of Tregs. Priming with inflammatory cytokines IFNγ and TNFα increases also expression of markers associated with MSC immunomodulatory function, but decreases MSC proliferation. The expression of IDO also increases when MSCs are primed with inflammatory cytokines. However, there is no increase in Treg expansion when MSCs are primed with IFNγ, suggesting an alternate mechanism for inflammatory-stimulated MSC immunomodulation. Overall, these results suggest that MSCs primed in hypoxia or inflammatory conditions are optimally primed for immunosuppressive function. These results provide a clearer picture of how to enhance MSC immunomodulation for clinical use.
Mesenchymal stem cells (MSCs) are multipotent progenitor cells which have the potential to differentiate into osteocytes, adipocytes, and chondrocytes . In addition to their regenerative properties, MSCs also have significant immunosuppressive potential [2–4]. MSCs are known to have a role in dampening the innate immune response, by inhibiting maturation and antigen-presenting capacity of dendritic cells [5–7], and decreasing proliferation and cytotoxicity of natural killer cells [8,9]. MSCs also suppress the adaptive immune response, by dampening both CD4+ helper and CD8+ cytotoxic T cell proliferation and exertion of their respective functions [10–13].
MSC-mediated immunosuppression provides a powerful potential tool for decreasing the incidence and severity of acute rejection of transplanted allografts [2,4,7,39]. MSC immunosuppressive potential is not innate, but must be induced by environmental factors . A complete picture of these factors is yet to be fully developed. Our study examined a range of environmental factors that may influence MSC-mediated immunosuppression. Here we describe the impact of environmental stimulation on MSC immunosuppression, and further elucidate the mechanism by which MSC immunosuppression is facilitated, by specifically looking at the interactions between MSCs and Tregs and the role IDO plays in this stimulation.