Human mesenchymal stem cells derived from umbilical cord and bone marrow exert immunomodulatory effects in different mechanisms

BACKGROUND Mesenchymal stem cells(MSCs)are an attractive tool to treat graft-versus-host disease because of their unique immunoregulatory properties.Although human bone marrow-derived MSCs(BM-MSCs)were the most widely used MSCs in cell therapy until recently,MSCs derived from human umbilical cords(UC-MSCs)have gained popularity as cell therapy material for their ethical and noninvasive collection.AIM To investigate the difference in mechanisms of the immunosuppressive effects of UC-MSCs and BM-MSCs.METHODS To analyze soluble factors expressed by MSCs,such as indolamine 2,3-dioxygenase,cyclooxygenase-2,prostaglandin E2 and interleukin(IL)-6,inflammatory environments in vitro were reconstituted with combinations of interferon-gamma(IFN-γ),tumor necrosis factor alpha and IL-1βor with IFN-γalone.Activated T cells were cocultured with MSCs treated with indomethacin and/or anti-IL-10.To assess the ability of MSCs to inhibit T helper 17 cells and induce regulatory T cells,induced T helper 17 cells were cocultured with MSCs treated with indomethacin or anti-IL-10.Xenogeneic graft-versus-host disease was induced in NOG mice(NOD/Shi-scid/IL-2Rγnull)and UC-MSCs or BM-MSCs were treated as cell therapies.RESULTS Our data demonstrated that BM-MSCs and UC-MSCs shared similar phenotypic characteristics and immunomodulation abilities.BM-MSCs expressed more indolamine 2,3-dioxygenase after cytokine stimulation with different combinations of IFN-γ,tumor necrosis factor alpha-αand IL-1βor IFN-γalone.UC-MSCs expressed more prostaglandin E2,IL-6,programmed death-ligand 1 and 2 in the in vitro inflammatory environment.Cyclooxygenase-2 and IL-10 were key factors in the immunomodulatory mechanisms of both MSCs.In addition,UC-MSCs inhibited more T helper 17 cells and induced more regulatory T cells than BM-MSCs.UC-MSCs and BM-MSCs exhibited similar effects on attenuating graft-versus-host disease.CONCLUSION UC-MSCs and BM-MSCs exert similar immunosuppressive effects with different mechanisms involved.These findings suggest that UC-MSCs have distinct immunoregulatory functions and may substitute BM-MBSCs in the field of cell therapy.

Negative impact of bone-marrow-derived mesenchymal stem cells on dextran sulfate sodium-induced colitis

AIM:To investigate the effects of mesenchymal stem cells(MSCs)on dextran sulfate sodium-induced inflammatory bowel disease(IBD).METHODS:C57BL/6 mice were fed 3.5%(g/L)dextran sulfate sodium.On day seven,the mice received intraperitoneal injections of 1×106 MSCs.The survival rate,disease activity index values,and body weight,were monitored daily.On day ten,colon lengths and histopathologic changes were assessed.In addition,immunoregulatory changes following MSC administration were evaluated by determining the levels of effector T cell responses in the spleen and mesenteric lymph nodes,and the expression levels of inflammatory cytokines in homogenized colons.RESULTS:Intraperitoneal administration of MSCs did not prevent development of colitis and did not reduce the clinicopathologic severity of IBD.No significant difference was evident in either survival rate or disease activity index score between the control and MSCtreated group.Day ten-sacrificed mice exhibited no significant difference in either colon length or histopathologic findings.Indeed,the MSC-treated group exhibited elevated levels of interleukin(IL)-6 and transforming growth factor-β,and a reduced level of IL-10,in spleens,mesenteric lymph nodes,and homogenized colons.The IL-17 level was lower in the mesenteric lymph nodes of the MSC-treated group(P=0.0126).In homogenized colons,the IL-17 and tumor necrosis factor-α(P=0.0092)expression levels were also lower in the treated group.CONCLUSION:MSC infusion provided no significanthistopathologic or clinical improvement,thus representing a limited therapeutic approach for IBD.Functional enhancement of MSCs is needed in further study.