Immunomodulatory effects of mesenchymal stem cells in a rat organ transplant model.
BACKGROUND
Recent reports suggest that mesenchymal stem cells (MSCs) have immunomodulatory properties. Mesenchymal stem cells can suppress the immune response toward alloantigen in vitro by inhibiting T cell proliferation in mixed-lymphocyte reactions (MLRs). However, relatively little has been reported regarding the immunomodulative potential of MSCs in vivo. Herein the authors confirm the immunomodulatory effects of rat MSCs in vitro and tested for tolerogenic features in a model of allogeneic heart transplantation.


METHODS
Mesenchymal stem cells were obtained from bone marrow aspirates of male Lewis rats (major histocompatibility complex [MHC] haplotype RT1) and ACI rats (RT1). Lewis MSCs were cocultured with ACI spleen cells to reveal direct effects of MSCs on lymphocytes. In addition, MSCs were added to MLRs between ACI T cells as responders and irradiated Lewis spleen cells as stimulators. Finally, MSCs were administered in an allogeneic heart transplantation model at different doses (with and without cyclosporin A [CsA]).


RESULTS
Mesenchymal stem cells appeared with typical spindle-shaped morphology in culture and readily differentiated into adipocytes when exposed to differentiation media. Mesenchymal stem cells expressed MHC class I, but not class II or costimulatory molecules. In vitro, MSCs phagocytosed ACI spleen cells. When introduced into an MLR, donor MSCs suppressed the proliferation of stimulated T cells. However, in vivo, MSC injection did not prolong allograft survival. In addition, concurrent treatment with low-dose CsA and MSCs accelerated allograft rejection.


CONCLUSIONS
The present data confirm previous reports suggesting that MSCs have immunomodulatory properties in vitro. However, their tolerogenic properties in vivo must be questioned, as MSC injections were not only ineffective at prolonging allograft survival, but tended to promote rejection.
Inoue
Seiichiro
S
Department of Surgery, University of Regensburg, Regensburg, Germany.
Popp
Felix C
FC
Koehl
Gudrun E
GE
Piso
Pompiliu
P
Schlitt
Hans J
HJ
Geissler
Edward K
EK
Dahlke
Marc H
MH
D017667:Adipocytes / Q000166:cytology / Q000502:physiology; D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology; D006084:Graft Rejection / Q000503:physiopathology; D016027:Heart Transplantation / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000032:analysis; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000276:immunology*; D015778:Minor Histocompatibility Antigens; D051381:Rats; D011912:Rats, Inbred ACI; D011917:Rats, Inbred Lew; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D023001:Transplantation Tolerance / Q000502:physiology; D014184:Transplantation, Homologous / Q000276:immunology*
D015395:Histocompatibility Antigens Class I; D007166:Immunosuppressive Agents; D015778:Minor Histocompatibility Antigens; C490627:Mr1 protein, rat; D016572:Cyclosporine