Transplantation of betatrophin-expressing adipose-derived mesenchymal stem cells induces β-cell proliferation in diabetic mice

Sun,Liang-Liang; Liu,Tian-Jin; Li,Limei; Tang,Wei; Zou,Jun-Jie; Chen,Xiang-Fang; Zheng,Jiao-Yang; Jiang,Bei-Ge; Shi,Yong-Quan

doi:10.3892/ijmm.2017.2914

Transplantation of betatrophin-expressing adipose-derived mesenchymal stem cells induces β-cell proliferation in diabetic mice

Authors:
- Liang-Liang Sun
- Tian-Jin Liu
- Limei Li
- Wei Tang
- Jun-Jie Zou
- Xiang-Fang Chen
- Jiao-Yang Zheng
- Bei-Ge Jiang
- Yong-Quan Shi
View Affiliations

Affiliations: Department of Endocrinology, Changzheng Hospital, The Second Military Medical University, Shanghai 200003, P.R. China, Institute of Biochemistry and Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, P.R. China, Clinical and Translational Research Center Shanghai East Hospital, Key Laboratory of Arrhythmias of Ministry of Education, Shanghai 200120, P.R. China, Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai 200438, P.R. China
Published online on: March 10, 2017 https://doi.org/10.3892/ijmm.2017.2914
Pages: 936-948
Copyright: © Sun et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Recent progress in regenerative medicine has suggested that mesenchymal stem cell (MSC)-based therapy is a novel potential cure for diabetes. Betatrophin is a newly identified hormone that can increase the production and expansion of insulin-secreting β-cells when administered to mice. In this study, we evaluated the effect of betatrophin overexpression by human adipose-derived MSCs (ADMSCs) by in vitro experiments, as well as following their transplantation into a mice with streptozotocin (STZ)-induced diabetes. The overexpression of betatrophin did not affect the ADMSCs in terms of proliferation, differentiation and morphology. However, the co-culture of human islets with ADMSCs overexpressing betatrophin (ADMSCs-BET) induced islet proliferation, β-cell specific transcription factor expression, and the islet production of insulin under the stimulation of glucose or KCl and Arg. In addition, ADMSCs-BET enhanced the anti-inflammatory and anti-apoptotic effects of the co-cultured islets compared with ADMSCs cultured alone. In mice with STZ-induced diabetes, the transplantation of ADMSCs-BET ameliorated the hyperglycemia and weight loss associated with STZ-induced diabetes; ADMSCs-BET also significantly enhanced the ratio of β-cells per islet compared to the transplantation of ADMSCs alone. Thus, our study demonstrates a novel strategy for inducing β-cell regeneration. ADMSCs-BET may replace insulin injections by increasing the number of endogenous insulin-producing cells in patients with diabetes. This combined strategy of ADMSC transplantation and gene therapy may prove to be a useful therapy for the treatment of diabetes.

View Figures

View References

1	Shaw JE, Sicree RA and Zimmet PZ: Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract. 87:4–14. 2010. View Article : Google Scholar
2	Atkinson MA and Eisenbarth GS: Type 1 diabetes: New perspectives on disease pathogenesis and treatment. Lancet. 358:221–229. 2001. View Article : Google Scholar : PubMed/NCBI
3	Nyenwe EA, Jerkins TW, Umpierrez GE and Kitabchi AE: Management of type 2 diabetes: Evolving strategies for the treatment of patients with type 2 diabetes. Metabolism. 60:1–23. 2011. View Article : Google Scholar
4	Mishra PK, Singh SR, Joshua IG and Tyagi SC: Stem cells as a therapeutic target for diabetes. Front Biosci (Landmark Ed). 15:461–477. 2010. View Article : Google Scholar
5	Couri CE and Voltarelli JC: Stem cell-based therapies and immunomodulatory approaches in newly diagnosed type 1 diabetes. Curr Stem Cell Res Ther. 6:10–15. 2011. View Article : Google Scholar
6	Ezquer FE, Ezquer ME, Parrau DB, Carpio D, Yañez AJ and Conget PA: Systemic administration of multipotent mesenchymal stromal cells reverts hyperglycemia and prevents nephropathy in type 1 diabetic mice. Biol Blood Marrow Transplant. 14:631–640. 2008. View Article : Google Scholar : PubMed/NCBI
7	Deans RJ and Moseley AB: Mesenchymal stem cells: Biology and potential clinical uses. Exp Hematol. 28:875–884. 2000. View Article : Google Scholar : PubMed/NCBI
8	Conget P, Rodriguez F, Kramer S, Allers C, Simon V, Palisson F, Gonzalez S and Yubero MJ: Replenishment of type VII collagen and re-epithelialization of chronically ulcerated skin after intra-dermal administration of allogeneic mesenchymal stromal cells in two patients with recessive dystrophic epidermolysis bullosa. Cytotherapy. 12:429–431. 2010. View Article : Google Scholar : PubMed/NCBI
9	Barry FP and Murphy JM: Mesenchymal stem cells: Clinical applications and biological characterization. Int J Biochem Cell Biol. 36:568–584. 2004. View Article : Google Scholar : PubMed/NCBI
10	Tang DQ, Cao LZ, Burkhardt BR, Xia CQ, Litherland SA, Atkinson MA and Yang LJ: In vivo and in vitro characterization of insulin-producing cells obtained from murine bone marrow. Diabetes. 53:1721–1732. 2004. View Article : Google Scholar : PubMed/NCBI
11	Thakkar UG, Trivedi HL, Vanikar AV and Dave SD: Insulin-secreting adipose-derived mesenchymal stromal cells with bone marrow-derived hematopoietic stem cells from autologous and allogenic sources for type 1 diabetes mellitus. Cytotherapy. 17:940–947. 2015. View Article : Google Scholar : PubMed/NCBI
12	Heineman FW and Balaban RS: Phosphorus-31 nuclear magnetic resonance analysis of transient changes of canine myocardial metabolism in vivo. J Clin Invest. 85:843–852. 1990. View Article : Google Scholar : PubMed/NCBI
13	Ben-Ami E, Berrih-Aknin S and Miller A: Mesenchymal stem cells as an immunomodulatory therapeutic strategy for autoimmune diseases. Autoimmun Rev. 10:410–415. 2011. View Article : Google Scholar : PubMed/NCBI
14	Maccario R, Podestà M, Moretta A, Cometa A, Comoli P, Montagna D, Daudt L, Ibatici A, Piaggio G, Pozzi S, et al: Interaction of human mesenchymal stem cells with cells involved in alloantigen-specific immune response favors the differentiation of CD4⁺ T-cell subsets expressing a regulatory/suppressive phenotype. Haematologica. 90:516–525. 2005.PubMed/NCBI
15	Rasmusson I, Ringdén O, Sundberg B and Le Blanc K: Mesenchymal stem cells inhibit lymphocyte proliferation by mitogens and alloantigens by different mechanisms. Exp Cell Res. 305:33–41. 2005. View Article : Google Scholar : PubMed/NCBI
16	Rasmusson I: Immune modulation by mesenchymal stem cells. Exp Cell Res. 312:2169–2179. 2006. View Article : Google Scholar : PubMed/NCBI
17	Phinney DG and Prockop DJ: Concise review: mesenchymal stem/multipotent stromal cells: the state of transdifferentiation and modes of tissue repair - current views. Stem Cells. 25:2896–2902. 2007. View Article : Google Scholar : PubMed/NCBI
18	Caplan AI and Dennis JE: Mesenchymal stem cells as trophic mediators. J Cell Biochem. 98:1076–1084. 2006. View Article : Google Scholar : PubMed/NCBI
19	Zhang R: Lipasin, a novel nutritionally-regulated liver-enriched factor that regulates serum triglyceride levels. Biochem Biophys Res Commun. 424:786–792. 2012. View Article : Google Scholar : PubMed/NCBI
20	Quagliarini F, Wang Y, Kozlitina J, Grishin NV, Hyde R, Boerwinkle E, Valenzuela DM, Murphy AJ, Cohen JC and Hobbs HH: Atypical angiopoietin-like protein that regulates ANGPTL3. Proc Natl Acad Sci USA. 109:19751–19756. 2012. View Article : Google Scholar : PubMed/NCBI
21	Yi P, Park JS and Melton DA: Betatrophin: A hormone that controls pancreatic β cell proliferation. Cell. 153:747–758. 2013. View Article : Google Scholar : PubMed/NCBI
22	Wang Y, Quagliarini F, Gusarova V, Gromada J, Valenzuela DM, Cohen JC and Hobbs HH: Mice lacking ANGPTL8 (Betatrophin) manifest disrupted triglyceride metabolism without impaired glucose homeostasis. Proc Natl Acad Sci USA. 110:16109–16114. 2013. View Article : Google Scholar : PubMed/NCBI
23	Chen X, Lu P, He W, Zhang J, Liu L, Yang Y, Liu Z, Xie J, Shao S, Du T, et al: Circulating betatrophin levels are increased in patients with type 2 diabetes and associated with insulin resistance. J Clin Endocrinol Metab. 100:E96–E100. 2015. View Article : Google Scholar
24	Gómez-Ambrosi J, Pascual E, Catalán V, Rodríguez A, Ramírez B, Silva C, Gil MJ, Salvador J and Frühbeck G: Circulating betatrophin concentrations are decreased in human obesity and type 2 diabetes. J Clin Endocrinol Metab. 99:E2004–E2009. 2014. View Article : Google Scholar : PubMed/NCBI
25	Kugelberg E: Diabetes: Betatrophin - inducing β-cell expansion to treat diabetes mellitus? Nat Rev Endocrinol. 9:3792013. View Article : Google Scholar
26	Izadpanah R, Joswig T, Tsien F, Dufour J, Kirijan JC and Bunnell BA: Characterization of multipotent mesenchymal stem cells from the bone marrow of rhesus macaques. Stem Cells Dev. 14:440–451. 2005. View Article : Google Scholar : PubMed/NCBI
27	Sekiya I, Colter DC and Prockop DJ: BMP-6 enhances chondrogenesis in a subpopulation of human marrow stromal cells. Biochem Biophys Res Commun. 284:411–418. 2001. View Article : Google Scholar : PubMed/NCBI
28	Yeung TY, Seeberger KL, Kin T, Adesida A, Jomha N, Shapiro AM and Korbutt GS: Human mesenchymal stem cells protect human islets from pro-inflammatory cytokines. PLoS One. 7:e381892012. View Article : Google Scholar : PubMed/NCBI
29	Isaac R, Boura-Halfon S, Gurevitch D, Shainskaya A, Levkovitz Y and Zick Y: Selective serotonin reuptake inhibitors (SSRIs) inhibit insulin secretion and action in pancreatic β cells. J Biol Chem. 288:5682–5693. 2013. View Article : Google Scholar : PubMed/NCBI
30	Bivalacqua TJ, Usta MF, Kendirci M, Pradhan L, Alvarez X, Champion HC, Kadowitz PJ and Hellstrom WJ: Superoxide anion production in the rat penis impairs erectile function in diabetes: Influence of in vivo extracellular superoxide dismutase gene therapy. J Sex Med. 2:187–198. 2005. View Article : Google Scholar
31	Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop DJ and Horwitz E: Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 8:315–317. 2006. View Article : Google Scholar : PubMed/NCBI
32	Kögler G, Sensken S, Airey JA, Trapp T, Müschen M, Feldhahn N, Liedtke S, Sorg RV, Fischer J, Rosenbaum C, et al: A new human somatic stem cell from placental cord blood with intrinsic pluripotent differentiation potential. J Exp Med. 200:123–135. 2004. View Article : Google Scholar : PubMed/NCBI
33	Niemeyer P, Krause U, Fellenberg J, Kasten P, Seckinger A, Ho AD and Simank HG: Evaluation of mineralized collagen and alpha-tricalcium phosphate as scaffolds for tissue engineering of bone using human mesenchymal stem cells. Cells Tissues Organs. 177:68–78. 2004. View Article : Google Scholar : PubMed/NCBI
34	Rackham CL, Dhadda PK, Chagastelles PC, Simpson SJ, Dattani AA, Bowe JE, Jones PM and King AJ: Pre-culturing islets with mesenchymal stromal cells using a direct contact configuration is beneficial for transplantation outcome in diabetic mice. Cytotherapy. 15:449–459. 2013. View Article : Google Scholar : PubMed/NCBI
35	Donath MY and Shoelson SE: Type 2 diabetes as an inflammatory disease. Nat Rev Immunol. 11:98–107. 2011. View Article : Google Scholar : PubMed/NCBI
36	Barshes NR, Wyllie S and Goss JA: Inflammation-mediated dysfunction and apoptosis in pancreatic islet transplantation: Implications for intrahepatic grafts. J Leukoc Biol. 77:587–597. 2005. View Article : Google Scholar : PubMed/NCBI
37	Biarnés M, Montolio M, Nacher V, Raurell M, Soler J and Montanya E: Beta-cell death and mass in syngeneically transplanted islets exposed to short- and long-term hyperglycemia. Diabetes. 51:66–72. 2002. View Article : Google Scholar : PubMed/NCBI
38	Zaccone P, Phillips J, Conget I, Gomis R, Haskins K, Minty A, Bendtzen K, Cooke A and Nicoletti F: Interleukin-13 prevents autoimmune diabetes in NOD mice. Diabetes. 48:1522–1528. 1999. View Article : Google Scholar : PubMed/NCBI
39	Kaminski A, Kaminski ER and Morgan NG: Pre-incubation with interleukin-4 mediates a direct protective effect against the loss of pancreatic beta-cell viability induced by proinflammatory cytokines. Clin Exp Immunol. 148:583–588. 2007. View Article : Google Scholar : PubMed/NCBI
40	Jiang R, Han Z, Zhuo G, Qu X, Li X, Wang X, Shao Y, Yang S and Han ZC: Transplantation of placenta-derived mesenchymal stem cells in type 2 diabetes: A pilot study. Front Med. 5:94–100. 2011. View Article : Google Scholar : PubMed/NCBI
41	Abdi R, Fiorina P, Adra CN, Atkinson M and Sayegh MH: Immunomodulation by mesenchymal stem cells: A potential therapeutic strategy for type 1 diabetes. Diabetes. 57:1759–1767. 2008. View Article : Google Scholar : PubMed/NCBI
42	Zhu YG, Qu JM, Zhang J, Jiang HN and Xu JF: Novel interventional approaches for ALI/ARDS: Cell-based gene therapy. Mediators Inflamm. 2011:5601942011. View Article : Google Scholar : PubMed/NCBI
43	Devaney J, Contreras M and Laffey JG: Clinical review: gene-based therapies for ALI/ARDS: where are we now? Crit Care. 15:2242011. View Article : Google Scholar : PubMed/NCBI
44	Nayak S and Herzog RW: Progress and prospects: Immune responses to viral vectors. Gene Ther. 17:295–304. 2010. View Article : Google Scholar
45	Raper SE, Chirmule N, Lee FS, Wivel NA, Bagg A, Gao GP, Wilson JM and Batshaw ML: Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer. Mol Genet Metab. 80:148–158. 2003. View Article : Google Scholar : PubMed/NCBI
46	Lu Y, Wang Z and Zhu M: Human bone marrow mesenchymal stem cells transfected with human insulin genes can secrete insulin stably. Ann Clin Lab Sci. 36:127–136. 2006.PubMed/NCBI
47	Xu J, Lu Y, Ding F, Zhan X, Zhu M and Wang Z: Reversal of diabetes in mice by intrahepatic injection of bone-derived GFP-murine mesenchymal stem cells infected with the recombinant retrovirus-carrying human insulin gene. World J Surg. 31:1872–1882. 2007. View Article : Google Scholar : PubMed/NCBI
48	Jiao Y, Le Lay J, Yu M, Naji A and Kaestner KH: Elevated mouse hepatic betatrophin expression does not increase human β-cell replication in the transplant setting. Diabetes. 63:1283–1288. 2014. View Article : Google Scholar :
49	Cox AR, Lam CJ, Bonnyman CW, Chavez J, Rios JS and Kushner JA: Angiopoietin-like protein 8 (ANGPTL8)/betatrophin overexpression does not increase beta cell proliferation in mice. Diabetologia. 58:1523–1531. 2015. View Article : Google Scholar : PubMed/NCBI
50	Volarevic V, Arsenijevic N, Lukic ML and Stojkovic M: Concise review: Mesenchymal stem cell treatment of the complications of diabetes mellitus. Stem Cells. 29:5–10. 2011. View Article : Google Scholar : PubMed/NCBI
51	Sun Y, Chen L, Hou XG, Hou WK, Dong JJ, Sun L, Tang KX, Wang B, Song J, Li H, et al: Differentiation of bone marrow-derived mesenchymal stem cells from diabetic patients into insulin-producing cells in vitro. Chin Med J (Engl). 120:771–776. 2007.
52	Li HT, Jiang FX, Shi P, Zhang T, Liu XY, Lin XW and Pang XN: In vitro reprogramming of rat bone marrow-derived mesenchymal stem cells into insulin-producing cells by genetically manipulating negative and positive regulators. Biochem Biophys Res Commun. 420:793–798. 2012. View Article : Google Scholar : PubMed/NCBI
53	Guo QS, Zhu MY, Wang L, Fan XJ, Lu YH, Wang ZW, Zhu SJ, Wang Y and Huang Y: Combined transfection of the three transcriptional factors, PDX-1, NeuroD1, and MafA, causes differentiation of bone marrow mesenchymal stem cells into insulin-producing cells. Exp Diabetes Res. 2012:6720132012.PubMed/NCBI
54	Wang Y, Chen X, Cao W and Shi Y: Plasticity of mesenchymal stem cells in immunomodulation: Pathological and therapeutic implications. Nat Immunol. 15:1009–1016. 2014. View Article : Google Scholar : PubMed/NCBI
55	Laakso M: Not for the eyes only: AX6 and glucose metabolism. Diabetologia. 52:381–384. 2009. View Article : Google Scholar : PubMed/NCBI
56	Lyttle BM, Li J, Krishnamurthy M, Fellows F, Wheeler MB, Goodyer CG and Wang R: Transcription factor expression in the developing human fetal endocrine pancreas. Diabetologia. 51:1169–1180. 2008. View Article : Google Scholar : PubMed/NCBI
57	St-Onge L, Sosa-Pineda B, Chowdhury K, Mansouri A and Gruss P: Pax6 is required for differentiation of glucagon-producing alpha-cells in mouse pancreas. Nature. 387:406–409. 1997. View Article : Google Scholar : PubMed/NCBI
58	Grapp M, Teichler S, Kitz J, Dibaj P, Dickel C, Knepel W and Krätzner R: The homeodomain of AX6 is essential for AX6-dependent activation of the rat glucagon gene promoter: Evidence for a PH0 -like binding that induces an active conformation. Biochim Biophys Acta. 1789:403–412. 2009. View Article : Google Scholar : PubMed/NCBI
59	Thorel F, Népote V, Avril I, Kohno K, Desgraz R, Chera S and Herrera PL: Conversion of adult pancreatic alpha-cells to beta-cells after extreme beta-cell loss. Nature. 464:1149–1154. 2010. View Article : Google Scholar : PubMed/NCBI
60	Shen J, Cheng Y, Han Q, Mu Y and Han W: Generating insulin-producing cells for diabetic therapy: Existing strategies and new development. Ageing Res Rev. 12:469–478. 2013. View Article : Google Scholar : PubMed/NCBI
61	English K: Mechanisms of mesenchymal stromal cell immunomodulation. Immunol Cell Biol. 91:19–26. 2013. View Article : Google Scholar
62	Tolar J, Le Blanc K, Keating A and Blazar BR: Concise review: Hitting the right spot with mesenchymal stromal cells. Stem Cells. 28:1446–1455. 2010. View Article : Google Scholar : PubMed/NCBI
63	Kuo YR, Wang CT, Cheng JT, Kao GS, Chiang YC and Wang CJ: Adipose-derived stem cells accelerate diabetic wound healing through the induction of autocrine and paracrine effects. Cell Transplant. 25:71–81. 2016. View Article : Google Scholar
64	Wang H, Qiu X, Ni P, Qiu X, Lin X, Wu W, Xie L, Lin L, Min J, Lai X, et al: Immunological characteristics of human umbilical cord mesenchymal stem cells and the therapeutic effects of their transplantion on hyperglycemia in diabetic rats. Int J Mol Med. 33:263–270. 2014.
65	Horie M, Choi H, Lee RH, Reger RL, Ylostalo J, Muneta T, Sekiya I and Prockop DJ: Intra-articular injection of human mesenchymal stem cells (MSCs) promote rat meniscal regeneration by being activated to express Indian hedgehog that enhances expression of type II collagen. Osteoarthritis Cartilage. 20:1197–1207. 2012. View Article : Google Scholar : PubMed/NCBI
66	Lin CS, Lin G and Lue TF: Allogeneic and xenogeneic transplantation of adipose-derived stem cells in immunocompetent recipients without immunosuppressants. Stem Cells Dev. 21:2770–2778. 2012. View Article : Google Scholar : PubMed/NCBI