Congenic mesenchymal stem cell therapy reverses hyperglycemia in experimental type 1 diabetes.
OBJECTIVE
A number of clinical trials are underway to test whether mesenchymal stem cells (MSCs) are effective in treating various diseases, including type 1 diabetes. Although this cell therapy holds great promise, the optimal source of MSCs has yet to be determined with respect to major histocompatibility complex matching. Here, we examine this question by testing the ability of congenic MSCs, obtained from the NOR mouse strain, to reverse recent-onset type 1 diabetes in NOD mice, as well as determine the immunomodulatory effects of NOR MSCs in vivo.


METHODS
NOR MSCs were evaluated with regard to their in vitro immunomodulatory function in the context of autoreactive T-cell proliferation and dendritic cell (DC) generation. The in vivo effect of NOR MSC therapy on reversal of recent-onset hyperglycemia and on immunogenic cell subsets in NOD mice was also examined.


RESULTS
NOR MSCs were shown to suppress diabetogenic T-cell proliferation via PD-L1 and to suppress generation of myeloid/inflammatory DCs predominantly through an IL-6-dependent mechanism. NOR MSC treatment of experimental type 1 diabetes resulted in long-term reversal of hyperglycemia, and therapy was shown to alter diabetogenic cytokine profile, to diminish T-cell effector frequency in the pancreatic lymph nodes, to alter antigen-presenting cell frequencies, and to augment the frequency of the plasmacytoid subset of DCs.


CONCLUSIONS
These studies demonstrate the inimitable benefit of congenic MSC therapy in reversing experimental type 1 diabetes. These data should benefit future clinical trials using MSCs as treatment for type 1 diabetes.
Jurewicz
Mollie
M
Transplantation Research Center, Children's Hospital and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Yang
Sunmi
S
Augello
Andrea
A
Godwin
Jonathan G
JG
Moore
Robert F
RF
Azzi
Jamil
J
Fiorina
Paolo
P
Atkinson
Mark
M
Sayegh
Mohamed H
MH
Abdi
Reza
R
D000818:Animals; D015703:Antigens, CD / Q000032:analysis / Q000276:immunology; D001324:Autoantigens / Q000276:immunology; D002454:Cell Differentiation; D016207:Cytokines / Q000032:analysis; D003713:Dendritic Cells / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000473:pathology / Q000601:surgery*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D051379:Mice; D016688:Mice, Inbred NOD; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D013601:T-Lymphocytes / Q000473:pathology
D015703:Antigens, CD; D001324:Autoantigens; D016207:Cytokines; D011948:Receptors, Antigen, T-Cell