Mesenchymal Stem Cell Therapy Promotes Corneal Allograft Survival in Rats by Local and Systemic Immunomodulation

Abstract

y These authors contributed equally to this work.Mesenchymal stem cells (MSCs) are being investigated extensively due to their ability to dampen immune responses. Here, we tested the ability of MSCs from three distinct sources to prolong rat corneal allograft survival. A fully allogeneic rat cornea transplant model (DA to LEW) was used. Recipient rats received 1 Â 10 6 MSCs (syn [LEW], allo [DA] or third-party [Wistar Furth]) intravenously 7 days before transplantation and again on the day of transplantation (day 0). A high percentage of untreated and syn-MSC treated allografts were rejected (80% and 100%, respectively). Preactivation of syn-MSCs with interferon gamma also failed to prolong allograft survival. Conversely, corneal allograft survival was significantly prolonged in allo-MSC treated (90%) and third-party MSC treated (80%) allograft recipients. Flow cytometric analysis revealed less infiltrating natural killer T cells in corneas of both allo-and third-party MSC treated animals, coupled with a higher proportion of splenic CD4þFoxp3þ regulatory T cells, compared to controls. In the case of allo-and third-party MSCs, results from a delayed-type hypersensitivity assay clearly showed that hypo-responsiveness was specific for corneal donor-associated alloantigens. Thus, allo-and third-party MSC treatment prolongs corneal allograft survival by suppressing peripheral immune responses and promoting an intragraft immunoregulatory milieu.

Large-scale secretome analyses unveil the superior immunosuppressive phenotype of umbilical cord stromal cells as compared to other adult mesenchymal stromal cells

“…Notably, constitutive immunoregulation by nonstimulated UCSCs is observed in an OA rabbit model (Saulnier et al, 2015). In this context, ex vivo priming of MSCs is related to few controversial outcomes in vivo, describing increased immunogenicity of prestimulated MSCs (Papadopoulou et al, 2012;Treacy et al, 2014).…”

Extrinsic and Intrinsic Mechanisms by Which Mesenchymal Stem Cells Suppress the Immune System

“…BMSCs have been shown to promote the survival of a fully allo-MHC-mismatched corneal allograft by supressing both local and systemic inflammation. 106 …”

TNF‐α/IL‐1β—licensed mesenchymal stromal cells promote corneal allograft survivalviamyeloid cell‐mediated induction of Foxp3+regulatory T cells in the lung

“…Mesenchymal stromal cells (MSCs), a population of nonhematopoietic stromal cells with potent immunosuppressive and immunomodulatory properties, are being investigated for their ability to inhibit immune-mediated rejection in animal models of allograft transplantation (1)(2)(3)(4)(5)(6). The immune-regulatory capacity of MSCs is well documented and demonstrates that MSCs possess the potential to suppress the proinflammatory responses of both the adaptive and innate arms of the immune system as well as to enrich populations of immune-regulatory cells (7)(8)(9)(10).…”