Mesenchymal stem cells enhance allogeneic islet engraftment in nonhuman primates

Dora Berman-Weinberg, Melissa A. Willman, Dongmei Han, Gary Kleiner, Norman M. Kenyon, Over Cabrera, Julie A. Karl, Roger W. Wiseman, David H. O'Connor, Amelia M. Bartholomew, Norma S Kenyon

Research output: Contribution to journalArticle

126 Citations (Scopus)

Abstract

OBJECTIVE - To test the graft-promoting effects of mesenchymal stem cells (MSCs) in a cynomolgus monkey model of islet/bone marrow transplantation. RESEARCH DESIGN AND 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.

Original languageEnglish
Pages (from-to)2558-2568
Number of pages11
JournalDiabetes
Volume59
Issue number10
DOIs
StatePublished - Oct 1 2010

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Mesenchymal Stromal Cells
Primates
Regulatory T-Lymphocytes
Insulin
Karyotype
Galectin 1
Phenotype
Gene Expression
Chimerism
Hepatocyte Growth Factor
Macaca fascicularis
C-Peptide
Bone Marrow Transplantation
Interleukin-10
Immunosuppression
Vascular Endothelial Growth Factor A
Allografts
Blood Glucose
Interleukin-6
Research Design

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Mesenchymal stem cells enhance allogeneic islet engraftment in nonhuman primates. / Berman-Weinberg, Dora; Willman, Melissa A.; Han, Dongmei; Kleiner, Gary; Kenyon, Norman M.; Cabrera, Over; Karl, Julie A.; Wiseman, Roger W.; O'Connor, David H.; Bartholomew, Amelia M.; Kenyon, Norma S.

In: Diabetes, Vol. 59, No. 10, 01.10.2010, p. 2558-2568.

Research output: Contribution to journalArticle

Berman-Weinberg, D, Willman, MA, Han, D, Kleiner, G, Kenyon, NM, Cabrera, O, Karl, JA, Wiseman, RW, O'Connor, DH, Bartholomew, AM & Kenyon, NS 2010, 'Mesenchymal stem cells enhance allogeneic islet engraftment in nonhuman primates', Diabetes, vol. 59, no. 10, pp. 2558-2568. https://doi.org/10.2337/db10-0136
Berman-Weinberg D, Willman MA, Han D, Kleiner G, Kenyon NM, Cabrera O et al. Mesenchymal stem cells enhance allogeneic islet engraftment in nonhuman primates. Diabetes. 2010 Oct 1;59(10):2558-2568. https://doi.org/10.2337/db10-0136
Berman-Weinberg, Dora ; Willman, Melissa A. ; Han, Dongmei ; Kleiner, Gary ; Kenyon, Norman M. ; Cabrera, Over ; Karl, Julie A. ; Wiseman, Roger W. ; O'Connor, David H. ; Bartholomew, Amelia M. ; Kenyon, Norma S. / Mesenchymal stem cells enhance allogeneic islet engraftment in nonhuman primates. In: Diabetes. 2010 ; Vol. 59, No. 10. pp. 2558-2568.
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abstract = "OBJECTIVE - To test the graft-promoting effects of mesenchymal stem cells (MSCs) in a cynomolgus monkey model of islet/bone marrow transplantation. RESEARCH DESIGN AND 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.",
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AU - Berman-Weinberg, Dora

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AU - Han, Dongmei

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AU - Kenyon, Norman M.

AU - Cabrera, Over

AU - Karl, Julie A.

AU - Wiseman, Roger W.

AU - O'Connor, David H.

AU - Bartholomew, Amelia M.

AU - Kenyon, Norma S

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N2 - OBJECTIVE - To test the graft-promoting effects of mesenchymal stem cells (MSCs) in a cynomolgus monkey model of islet/bone marrow transplantation. RESEARCH DESIGN AND 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.

AB - OBJECTIVE - To test the graft-promoting effects of mesenchymal stem cells (MSCs) in a cynomolgus monkey model of islet/bone marrow transplantation. RESEARCH DESIGN AND 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.

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