Safety and immunomodulatory function of equine mesenchymal stem cells in vitro and in vivo.

摘要

Equine mesenchymal stem cells (MSCs) are being used for their immunomodulatory properties to treat a number of orthopedic conditions. Safety and efficacy of allogeneic (non-self) MSCs compared to autologous (self) MSCs has not been determined in horse, though it has been noted in a number of other species. To understand the safety of allogeneic MSCs, we first examined the clinicopathologic findings after intra-articular injection of autologous and allogeneic placentally-derived MSCs. Allogeneic MSCs did not elicit a systemic response, with minimal local response (joint swelling, lameness). MSC injection, whether autologous or allogeneic, elicited marked inflammation within the synovial fluid. However, there were no significant differences between degree and type of inflammation elicited by self or non-self MSCs.;Next, we determined whether equine allogeneic umbilical cord derived MSCs are well tolerated after multiple intradermal injections. We found no adverse local or systemic response to two intradermal injections of allogeneic MSCs, though MSC injections did result in minor wheal formation. No differences were noted between autologous or allogeneic injection. The second injection of MSCs did not elicit more significant physical or histomorphological alterations compared to the first MSC injection. Neither allogeneic nor autologous MSCs stimulated or suppressed baseline T cell proliferation in vitro prior to or after two MSC administrations.;Finally, we examined the immunomodulatory properties of equine MSCs derived from adipose (AT), bone marrow (BM), umbilical cord blood (CB) or umbilical cord tissue (CT) in vitro. We found that quiescent MSCs, regardless of tissue of origin, did not alter lymphocyte proliferation or secrete mediators, except transforming growth factor-beta. When stimulated, MSCs of all tissue types decreased lymphocyte proliferation, increased prostaglandin E2 (PGE2) and interleukin-6 (IL-6) secretion and decreased production of tumor necrosis factor-&agr; (TNF-&agr;) and interferon-gamma (IFN-gamma). BM-MSCs and CB-MSCs also produced nitric oxide (NO), while AT-MSCs and CT-MSCs did not. Equine MSCs do not produce indoleamine 2,3-dioxygenase (IDO).;In total, these findings indicate that equine allogeneic MSCs are safe for use in vivo and do not elicit a greater inflammatory response when compared to autologous MSCs. Equine MSCs function similarly to MSCs of other species, producing immunomodulatory mediators upon stimulation by activated lymphocytes in vitro. Given this, the creation of an allogeneic MSC bank, similar to a blood bank, for the therapeutic use of allogeneic MSCs to treat inflammation in horses is entirely possible.