Mesenchymal stem cells enhance allogeneic islet engraftment in nonhuman primates.
OBJECTIVE
To test the graft-promoting effects of mesenchymal stem cells (MSCs) in a cynomolgus monkey model of islet/bone marrow transplantation.


METHODS
Cynomolgus MSCs were obtained from iliac crest aspirate and characterized through passage 11 for phenotype, gene expression, differentiation potential, and karyotype. Allogeneic donor MSCs were cotransplanted intraportally with islets on postoperative day (POD) 0 and intravenously with donor marrow on PODs 5 and 11. Recipients were followed for stabilization of blood glucose levels, reduction of exogenous insulin requirement (EIR), C-peptide levels, changes in peripheral blood T regulatory cells, and chimerism. Destabilization of glycemia and increases in EIR were used as signs of rejection; additional intravenous MSCs were administered to test the effect on reversal of rejection.


RESULTS
MSC phenotype and a normal karyotype were observed through passage 11. IL-6, IL-10, vascular endothelial growth factor, TGF-β, hepatocyte growth factor, and galectin-1 gene expression levels varied among donors. MSC treatment significantly enhanced islet engraftment and function at 1 month posttransplant (n = 8), as compared with animals that received islets without MSCs (n = 3). Additional infusions of donor or third-party MSCs resulted in reversal of rejection episodes and prolongation of islet function in two animals. Stable islet allograft function was associated with increased numbers of regulatory T-cells in peripheral blood.


CONCLUSIONS
MSCs may provide an important approach for enhancement of islet engraftment, thereby decreasing the numbers of islets needed to achieve insulin independence. Furthermore, MSCs may serve as a new, safe, and effective antirejection therapy.
Berman
Dora M
DM
Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, Florida, USA.
Willman
Melissa A
MA
Han
Dongmei
D
Kleiner
Gary
G
Kenyon
Norman M
NM
Cabrera
Over
O
Karl
Julie A
JA
Wiseman
Roger W
RW
O'Connor
David H
DH
Bartholomew
Amelia M
AM
Kenyon
Norma S
NS
D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D001786:Blood Glucose / Q000378:metabolism; D002454:Cell Differentiation; D003470:Culture Media; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000601:surgery*; D004815:Epidermal Growth Factor / Q000235:genetics; D051858:Forkhead Transcription Factors / Q000032:analysis; D037483:Galectin 1 / Q000235:genetics; D017228:Hepatocyte Growth Factor / Q000235:genetics; D000949:Histocompatibility Antigens Class II / Q000032:analysis; D006650:Histocompatibility Testing; D007378:Interleukins / Q000235:genetics; D016381:Islets of Langerhans Transplantation / Q000502:physiology*; D007621:Karyotyping; D008252:Macaca fascicularis / Q000276:immunology / Q000502:physiology; D008285:Major Histocompatibility Complex; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000502:physiology; D010641:Phenotype; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D016212:Transforming Growth Factor beta / Q000235:genetics; D014184:Transplantation, Homologous
D015703:Antigens, CD; D001786:Blood Glucose; D003470:Culture Media; D051858:Forkhead Transcription Factors; D037483:Galectin 1; D000949:Histocompatibility Antigens Class II; D007378:Interleukins; D016212:Transforming Growth Factor beta; D004815:Epidermal Growth Factor; D012313:RNA; D017228:Hepatocyte Growth Factor