Adipose stem cells from chronic pancreatitis patients improve mouse and human islet survival and function
Lili Song, Zhen Sun, Do-Sung Kim, Wenyu Gou, Charlie Strange, Huansheng Dong, Wanxing Cui, Gary Gilkeson, Katherine A Morgan, David B Adams, Hongjun Wang, Lili Song, Zhen Sun, Do-Sung Kim, Wenyu Gou, Charlie Strange, Huansheng Dong, Wanxing Cui, Gary Gilkeson, Katherine A Morgan, David B Adams, Hongjun Wang
Abstract
Background: Chronic pancreatitis has surgical options including total pancreatectomy to control pain. To avoid surgical diabetes, the explanted pancreas can have islets harvested and transplanted. Immediately following total pancreatectomy with islet autotransplantation (TP-IAT), many islet cells die due to isolation and transplantation stresses. The percentage of patients remaining insulin free after TP-IAT is therefore low. We determined whether cotransplantation of adipose-derived mesenchymal stem cells (ASCs) from chronic pancreatitis patients (CP-ASCs) would protect islets after transplantation.
Methods: In a marginal mass islet transplantation model, islets from C57BL/6 mice were cotransplanted with CP-ASCs into syngeneic streptozotocin-treated diabetic mice. Treatment response was defined by the percentage of recipients reaching normoglycemia, and by the area under the curve for glucose and c-peptide in a glucose tolerance test. Macrophage infiltration, β-cell apoptosis, and islet graft vasculature were measured in transplanted islet grafts by immunohistochemistry. mRNA expression profiling of 84 apoptosis-related genes in islet grafts transplanted alone or with CP-ASCs was measured by the RT2 Profiler™ Apoptosis PCR Array. The impact of insulin-like growth factor-1 (IGF-1) on islet apoptosis was determined in islets stimulated with cytokines (IL-1β and IFN-γ) in the presence and absence of CP-ASC conditioned medium.
Results: CP-ASC-treated mice were more often normoglycemic compared to mice receiving islets alone. ASC cotransplantation reduced macrophage infiltration, β-cell death, suppressed expression of TNF-α and Bcl-2 modifying factor (BMF), and upregulated expressions of IGF-1 and TNF Receptor Superfamily Member 11b (TNFRSF11B) in islet grafts. Islets cultured in conditioned medium from CP-ASCs showed reduced cell death. This protective effect was diminished when IGF-1 was blocked in the conditioned medium by the anti-IGF-1 antibody.
Conclusion: Cotransplantation of islets with ASCs from the adipose of chronic pancreatitis patients improved islet survival and islet function after transplantation. The effects are in part mediated by paracrine secretion of IGF-1, suppression of inflammation, and promotion of angiogenesis. ASCs from chronic pancreatitis patients have the potential to be used as a synergistic therapy to enhance the efficacy of islet transplantation following pancreatectomy.
Keywords: Adipose stem cells; Chronic pancreatitis; Islet survival; Islet transplantation.
Conflict of interest statement
Ethics approval and consent to participateAll mouse surgical procedures were approved by the Animal Care Committee at the Medical University of South Carolina (protocol #AR3055). ASCs were harvested from a small piece of fat tissue from chronic pancreatitis patients undergoing pancreatic surgery who gave informed consent for the study under protocols approved by the Medical University of South Carolina Internal Review Board (Pro00028011).
Consent for publicationNot applicable.
Competing interestsThe authors declare that they have no competing interests.
Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Figures
References
- Dong H, Morgan K, Adams D, Wang H. Prevention of beta cell death in chronic pancreatitis. Adv Biosci Biotechnol. 2012;3(6A):782–7. doi: 10.4236/abb.2012.326098.
- Montana E, Bonner-Weir S, Weir GC. Beta cell mass and growth after syngeneic islet cell transplantation in normal and streptozocin diabetic C57BL/6 mice. J Clin Invest. 1993;91(3):780–7. doi: 10.1172/JCI116297.
- Davalli AM, Scaglia L, Zangen DH, Hollister J, Bonner-Weir S, Weir GC. Vulnerability of islets in the immediate posttransplantation period. Dynamic changes in structure and function. Diabetes. 1996;45(9):1161–7. doi: 10.2337/diab.45.9.1161.
- Wang H, Desai KD, Dong H, Owzarski S, Romagnuolo J, Morgan KA, et al. Prior surgery determines islet yield and insulin requirement in patients with chronic pancreatitis. Transplantation. 2013;95(8):1051–7. doi: 10.1097/TP.0b013e3182845fbb.
- Wang J, Sun Z, Gou W, Adams DB, Cui W, Morgan KA, et al. alpha-1 Antitrypsin Enhances Islet Engraftment by Suppression of Instant Blood-Mediated Inflammatory Reaction. Diabetes. 2017;66(4):970–80. doi: 10.2337/db16-1036.
- Lifson N, Lassa CV, Dixit PK. Relation between blood flow and morphology in islet organ of rat pancreas. Am J Physiol. 1985;249(1 Pt 1):E43–8.
- Bonner-Weir S, Orci L. New perspectives on the microvasculature of the islets of Langerhans in the rat. Diabetes. 1982;31(10):883–9. doi: 10.2337/diab.31.10.883.
- Menger MD, Jaeger S, Walter P, Feifel G, Hammersen F, Messmer K. Angiogenesis and hemodynamics of microvasculature of transplanted islets of Langerhans. Diabetes. 1989;38(Suppl 1):199–201. doi: 10.2337/diab.38.1.S199.
- Brennan DC, Kopetskie HA, Sayre PH, Alejandro R, Cagliero E, Shapiro AM, et al. Long-term follow-up of the Edmonton Protocol of Islet Transplantation in the United States. Am J Transplant. 2016;16(2):509–17. doi: 10.1111/ajt.13458.
- Stagg J, Galipeau J. Mechanisms of immune modulation by mesenchymal stromal cells and clinical translation. Curr Mol Med. 2013;13(5):856–67. doi: 10.2174/1566524011313050016.
- Ge W, Jiang J, Arp J, Liu W, Garcia B, Wang H. Regulatory T-cell generation and kidney allograft tolerance induced by mesenchymal stem cells associated with indoleamine 2,3-dioxygenase expression. Transplantation. 2010;90(12):1312–20. doi: 10.1097/TP.0b013e3181fed001.
- Bartholomew A, Sturgeon C, Siatskas M, Ferrer K, McIntosh K, Patil S, et al. Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp Hematol. 2002;30(1):42–8. doi: 10.1016/S0301-472X(01)00769-X.
- Casiraghi F, Azzollini N, Cassis P, Imberti B, Morigi M, Cugini D, et al. Pretransplant infusion of mesenchymal stem cells prolongs the survival of a semiallogeneic heart transplant through the generation of regulatory T cells. J Immunol. 2008;181(6):3933–46. doi: 10.4049/jimmunol.181.6.3933.
- Ge W, Jiang J, Baroja ML, Arp J, Zassoko R, Liu W, et al. Infusion of mesenchymal stem cells and rapamycin synergize to attenuate alloimmune responses and promote cardiac allograft tolerance. Am J Transplant. 2009;9(8):1760–72. doi: 10.1111/j.1600-6143.2009.02721.x.
- Uccelli A, Laroni A, Freedman MS. Mesenchymal stem cells for the treatment of multiple sclerosis and other neurological diseases. Lancet Neurol. 2011;10(7):649–56. doi: 10.1016/S1474-4422(11)70121-1.
- Ben Nasr M, Vergani A, Avruch J, Liu L, Kefaloyianni E, D'Addio F, et al. Co-transplantation of autologous MSCs delays islet allograft rejection and generates a local immunoprivileged site. Acta Diabetol. 2015;52(5):917–27. doi: 10.1007/s00592-015-0735-y.
- Berman DM, Willman MA, Han D, Kleiner G, Kenyon NM, Cabrera O, et al. Mesenchymal stem cells enhance allogeneic islet engraftment in nonhuman primates. Diabetes. 2010;59(10):2558–68. doi: 10.2337/db10-0136.
- Figliuzzi M, Cornolti R, Perico N, Rota C, Morigi M, Remuzzi G, et al. Bone marrow-derived mesenchymal stem cells improve islet graft function in diabetic rats. Transplant Proc. 2009;41(5):1797–800. doi: 10.1016/j.transproceed.2008.11.015.
- Fiorina P, Jurewicz M, Vergani A, Petrelli A, Carvello M, D'Addio F, et al. Targeting the CXCR4-CXCL12 axis mobilizes autologous hematopoietic stem cells and prolongs islet allograft survival via programmed death ligand 1. J Immunol. 2011;186(1):121–31. doi: 10.4049/jimmunol.1000799.
- Rackham CL, Chagastelles PC, Nardi NB, Hauge-Evans AC, Jones PM, King AJ. Co-transplantation of mesenchymal stem cells maintains islet organisation and morphology in mice. Diabetologia. 2011;54(5):1127–35. doi: 10.1007/s00125-011-2053-4.
- Sordi V, Melzi R, Mercalli A, Formicola R, Doglioni C, Tiboni F, et al. Mesenchymal cells appearing in pancreatic tissue culture are bone marrow-derived stem cells with the capacity to improve transplanted islet function. Stem Cells. 2010;28(1):140–51.
- Ezquer FE, Ezquer ME, Parrau DB, Carpio D, Yanez AJ, Conget PA. Systemic administration of multipotent mesenchymal stromal cells reverts hyperglycemia and prevents nephropathy in type 1 diabetic mice. Biol Blood Marrow Transplant. 2008;14(6):631–40. doi: 10.1016/j.bbmt.2008.01.006.
- Sordi V, Malosio ML, Marchesi F, Mercalli A, Melzi R, Giordano T, et al. Bone marrow mesenchymal stem cells express a restricted set of functionally active chemokine receptors capable of promoting migration to pancreatic islets. Blood. 2005;106(2):419–27. doi: 10.1182/blood-2004-09-3507.
- Uccelli A, Moretta L, Pistoia V. Mesenchymal stem cells in health and disease. Nat Rev Immunol. 2008;8(9):726–36. doi: 10.1038/nri2395.
- Bernardo ME, Fibbe WE. Mesenchymal stromal cells: sensors and switchers of inflammation. Cell Stem Cell. 2013;13(4):392–402. doi: 10.1016/j.stem.2013.09.006.
- Puissant B, Barreau C, Bourin P, Clavel C, Corre J, Bousquet C, et al. Immunomodulatory effect of human adipose tissue-derived adult stem cells: comparison with bone marrow mesenchymal stem cells. Br J Haematol. 2005;129(1):118–29. doi: 10.1111/j.1365-2141.2005.05409.x.
- Tsuji W, Rubin JP, Marra KG. Adipose-derived stem cells: implications in tissue regeneration. World J Stem Cell. 2014;6(3):312–21. doi: 10.4252/wjsc.v6.i3.312.
- Fotino C, Ricordi C, Lauriola V, Alejandro R, Pileggi A. Bone marrow-derived stem cell transplantation for the treatment of insulin-dependent diabetes. Rev Diabet Stud. 2010;7(2):144–57. doi: 10.1900/RDS.2010.7.144.
- Cao M, Pan Q, Dong H, Yuan X, Li Y, Sun Z, et al. Adipose-derived mesenchymal stem cells improve glucose homeostasis in high-fat diet-induced obese mice. Stem Cell Res Ther. 2015;6:208. doi: 10.1186/s13287-015-0201-3.
- Wang H, Lee SS, Gao W, Czismadia E, McDaid J, Ollinger R, et al. Donor treatment with carbon monoxide can yield islet allograft survival and tolerance. Diabetes. 2005;54(5):1400–6. doi: 10.2337/diabetes.54.5.1400.
- Ito T, Itakura S, Todorov I, Rawson J, Asari S, Shintaku J, et al. Mesenchymal stem cell and islet co-transplantation promotes graft revascularization and function. Transplantation. 2010;89(12):1438–45. doi: 10.1097/TP.0b013e3181db09c4.
- Kerby A, Jones ES, Jones PM, King AJ. Co-transplantation of islets with mesenchymal stem cells in microcapsules demonstrates graft outcome can be improved in an isolated-graft model of islet transplantation in mice. Cytotherapy. 2013;15(2):192–200. doi: 10.1016/j.jcyt.2012.10.018.
- Papadaki HA, Kritikos HD, Gemetzi C, Koutala H, Marsh JC, Boumpas DT, et al. Bone marrow progenitor cell reserve and function and stromal cell function are defective in rheumatoid arthritis: evidence for a tumor necrosis factor alpha-mediated effect. Blood. 2002;99(5):1610–9. doi: 10.1182/blood.V99.5.1610.
- Perez-Simon JA, Tabera S, Sarasquete ME, Diez-Campelo M, Canchado J, Sanchez-Abarca LI, et al. Mesenchymal stem cells are functionally abnormal in patients with immune thrombocytopenic purpura. Cytotherapy. 2009;11(6):698–705. doi: 10.3109/14653240903051558.
- de Oliveira GL, de Lima KW, Colombini AM, Pinheiro DG, Panepucci RA, Palma PV, et al. Bone marrow mesenchymal stromal cells isolated from multiple sclerosis patients have distinct gene expression profile and decreased suppressive function compared with healthy counterparts. Cell Transplant. 2015;24(2):151–65. doi: 10.3727/096368913X675142.
- Yaochite JN, de Lima KW, Caliari-Oliveira C, Palma PV, Couri CE, Simoes BP, et al. Multipotent mesenchymal stromal cells from patients with newly diagnosed type 1 diabetes mellitus exhibit preserved in vitro and in vivo immunomodulatory properties. Stem Cell Res Ther. 2016;7(1):14. doi: 10.1186/s13287-015-0261-4.
- Hsiao ST, Asgari A, Lokmic Z, Sinclair R, Dusting GJ, Lim SY, et al. Comparative analysis of paracrine factor expression in human adult mesenchymal stem cells derived from bone marrow, adipose, and dermal tissue. Stem Cells Dev. 2012;21(12):2189–203. doi: 10.1089/scd.2011.0674.
- Davis NE, Hamilton D, Fontaine MJ. Harnessing the immunomodulatory and tissue repair properties of mesenchymal stem cells to restore beta cell function. Curr Diab Rep. 2012;12(5):612–22. doi: 10.1007/s11892-012-0305-4.
- Park KS, Kim YS, Kim JH, Choi BK, Kim SH, Oh SH, et al. Influence of human allogenic bone marrow and cord blood-derived mesenchymal stem cell secreting trophic factors on ATP (adenosine-5'-triphosphate)/ADP (adenosine-5'-diphosphate) ratio and insulin secretory function of isolated human islets from cadaveric donor. Transplant Proc. 2009;41(9):3813–8. doi: 10.1016/j.transproceed.2009.06.193.
- Zhu YG, Feng XM, Abbott J, Fang XH, Hao Q, Monsel A, et al. Human mesenchymal stem cell microvesicles for treatment of Escherichia coli endotoxin-induced acute lung injury in mice. Stem Cells. 2014;32(1):116–25. doi: 10.1002/stem.1504.
- Kono TM, Sims EK, Moss DR, Yamamoto W, Ahn G, Diamond J, et al. Human adipose-derived stromal/stem cells protect against STZ-induced hyperglycemia: analysis of hASC-derived paracrine effectors. Stem Cells. 2014;32(7):1831–42. doi: 10.1002/stem.1676.
- Reinisch A, Thomas D, Corces MR, Zhang X, Gratzinger D, Hong WJ, et al. A humanized bone marrow ossicle xenotransplantation model enables improved engraftment of healthy and leukemic human hematopoietic cells. Nat Med. 2016;22(7):812-21.
- Gehmert S, Wenzel C, Loibl M, Brockhoff G, Huber M, Krutsch W, et al. Adipose tissue-derived stem cell secreted IGF-1 protects myoblasts from the negative effect of myostatin. Biomed Res Int. 2014;2014:129048. doi: 10.1155/2014/129048.
- Casellas A, Salavert A, Agudo J, Ayuso E, Jimenez V, Moya M, et al. Expression of IGF-I in pancreatic islets prevents lymphocytic infiltration and protects mice from type 1 diabetes. Diabetes. 2006;55(12):3246–55. doi: 10.2337/db06-0328.
- Chen Z, Morris DL, Jiang L, Liu Y, Rui L. SH2B1 in beta-cells regulates glucose metabolism by promoting beta-cell survival and islet expansion. Diabetes. 2014;63(2):585–95. doi: 10.2337/db13-0666.
- Liu W, Chin-Chance C, Lee EJ, Lowe WL., Jr Activation of phosphatidylinositol 3-kinase contributes to insulin-like growth factor I-mediated inhibition of pancreatic beta-cell death. Endocrinology. 2002;143(10):3802–12. doi: 10.1210/en.2002-220058.
- Gunawardana SC, Piston DW. Reversal of type 1 diabetes in mice by brown adipose tissue transplant. Diabetes. 2012;61(3):674–82. doi: 10.2337/db11-0510.
- Gunawardana SC, Piston DW. Insulin-independent reversal of type 1 diabetes in nonobese diabetic mice with brown adipose tissue transplant. Am J Physiol Endocrinol Metab. 2015;308(12):E1043–55. doi: 10.1152/ajpendo.00570.2014.
Source: PubMed