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Cell therapy in diabetes: current progress and future prospects

  • Review
  • Life & Medical Sciences
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Science Bulletin

Abstract

Diabetes mellitus, characterized by the impaired metabolism of insulin secretion in β cells, is becoming one of the most prevalent diseases around the world. Recently, cell replacement based on differentiation of various pluripotent stem cells, including embryonic stem cells, induced pluripotent stem cells and multipotent stem cells, such as bone marrow mesenchymal stem cells, adipose-derived stem cells and gnotobiotic porcine skin-derived stem cells, is becoming a promising therapeutic strategy. Cells derived from pancreatic tissues or other tissues that are relevant to β cell differentiation have also been used as cell source. However, in spite of hopeful experimental results, cell therapy in diabetes still confronts certain obstacles, such as purity of cells, functional differentiation of stem cells and possible tumorigenesis, which, in turn, lead to the seeking of new-generation tools, such as xenogenetic materials. In this review, we will summarize the current knowledge and future prospects of cell therapy in diabetes mellitus.

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References

  1. Whiting DR, Guariguata L, Weil C et al (2011) IDF diabetes atlas: global estimates of the prevalence of diabetes for 2011 and 2030. Diabetes Res Clin Pract 94:311–321

    Article  Google Scholar 

  2. Wang X, Ge S, Gonzalez I et al (2006) Formation of pancreatic duct epithelium from bone marrow during neonatal development. Stem Cells 24:307–314

    Article  Google Scholar 

  3. Thatava T, Ma B, Rohde M et al (2006) Chromatin-remodeling factors allow differentiation of bone marrow cells into insulin-producing cells. Stem Cells 24:2858–2867

    Article  Google Scholar 

  4. Chandra V, Swetha G, Phadnis S et al (2009) Generation of pancreatic hormone-expressing islet-like cell aggregates from murine adipose tissue-derived stem cells. Stem Cells 27:1941–1953

  5. Yang JH, Lee SH, Heo YT et al (2010) Generation of insulin-producing cells from gnotobiotic porcine skin-derived stem cells. Biochem Biophys Res Commun 397:679–684

    Article  Google Scholar 

  6. Meier JJ, Bhushan A, Butler PC (2006) The potential for stem cell therapy in diabetes. Pediatr Res 59:65r–73r

    Article  Google Scholar 

  7. Van Hoof D, D’Amour KA, German MS (2009) Derivation of insulin-producing cells from human embryonic stem cells. Stem Cell Res 3:73–87

    Article  Google Scholar 

  8. Bock C, Kiskinis E, Verstappen G et al (2011) Reference maps of human ES and iPS cell variation enable high-throughput characterization of pluripotent cell lines. Cell 144:439–452

    Article  Google Scholar 

  9. Liu X, Wang Y, Li Y et al (2013) Research status and prospect of stem cells in the treatment of diabetes mellitus. Sci China Life Sci 56:306–312

    Article  Google Scholar 

  10. Lumelsky N, Blondel O, Laeng P et al (2001) Differentiation of embryonic stem cells to insulin-secreting structures similar to pancreatic islets. Science 292:1389–1394

    Article  Google Scholar 

  11. Boyd AS, Wu DC, Higashi Y et al (2008) A comparison of protocols used to generate insulin-producing cell clusters from mouse embryonic stem cells. Stem Cells 26:1128–1137

    Article  Google Scholar 

  12. Segev H, Fishman B, Ziskind A et al (2004) Differentiation of human embryonic stem cells into insulin-producing clusters. Stem Cells 22:265–274

    Article  Google Scholar 

  13. Sui L, Mfopou JK, Chen B et al (2013) Transplantation of human embryonic stem cell-derived pancreatic endoderm reveals a site-specific survival, growth, and differentiation. Cell Transpl 22:821–830

    Article  Google Scholar 

  14. Jiang J, Au M, Lu K et al (2007) Generation of insulin-producing islet-like clusters from human embryonic stem cells. Stem Cells 25:1940–1953

    Article  Google Scholar 

  15. Morrison GM, Oikonomopoulou I, Migueles RP et al (2008) Anterior definitive endoderm from ESCs reveals a role for FGF signaling. Cell Stem Cell 3:402–415

    Article  Google Scholar 

  16. Tateishi K, He J, Taranova O et al (2008) Generation of insulin-secreting islet-like clusters from human skin fibroblasts. J Biol Chem 283:31601–31607

    Article  Google Scholar 

  17. Shiraki N, Yoshida T, Araki K et al (2008) Guided differentiation of embryonic stem cells into Pdx1-expressing regional-specific definitive endoderm. Stem Cells 26:874–885

    Article  Google Scholar 

  18. Bernardo AS, Cho CH, Mason S et al (2009) Biphasic induction of Pdx1 in mouse and human embryonic stem cells can mimic development of pancreatic beta-cells. Stem Cells 27:341–351

    Article  Google Scholar 

  19. Treff NR, Vincent RK, Budde ML et al (2006) Differentiation of embryonic stem cells conditionally expressing neurogenin 3. Stem Cells 24:2529–2537

    Article  Google Scholar 

  20. Wang P, Rodriguez RT, Wang J et al (2011) Targeting SOX17 in human embryonic stem cells creates unique strategies for isolating and analyzing developing endoderm. Cell Stem Cell 8:335–346

    Article  Google Scholar 

  21. Lavon N, Yanuka O, Benvenisty N (2006) The effect of overexpression of Pdx1 and Foxa2 on the differentiation of human embryonic stem cells into pancreatic cells. Stem Cells 24:1923–1930

    Article  Google Scholar 

  22. Kubo A, Stull R, Takeuchi M et al (2011) Pdx1 and Ngn3 overexpression enhances pancreatic differentiation of mouse ES cell-derived endoderm population. PLoS One 6:e24058

    Article  Google Scholar 

  23. Xu H, Tsang KS, Chan JC et al (2013) The combined expression of Pdx1 and MafA with either Ngn3 or NeuroD improves the differentiation efficiency of mouse embryonic stem cells into insulin-producing cells. Cell Transpl 22:147–158

    Article  Google Scholar 

  24. Kaitsuka T, Noguchi H, Shiraki N et al (2014) Generation of functional insulin-producing cells from mouse embryonic stem cells through 804G cell-derived extracellular matrix and protein transduction of transcription factors. Stem Cells Transl Med 3:114–127

    Article  Google Scholar 

  25. Pagliuca FW, Millman JR, Gurtler M et al (2014) Generation of functional human pancreatic beta cells in vitro. Cell 159:428–439

    Article  Google Scholar 

  26. Turovets N, D’Amour KA, Agapov V et al (2011) Human parthenogenetic stem cells produce enriched populations of definitive endoderm cells after trichostatin A pretreatment. Differentiation 81:292–298

    Article  Google Scholar 

  27. Urban VS, Kiss J, Kovacs J et al (2008) Mesenchymal stem cells cooperate with bone marrow cells in therapy of diabetes. Stem Cells 26:244–253

    Article  Google Scholar 

  28. Khorsandi L, Nejad-Dehbashi F, Ahangarpour A et al (2015) Three-dimensional differentiation of bone marrow-derived mesenchymal stem cells into insulin-producing cells. Tissue Cell 47:66–72

    Article  Google Scholar 

  29. Yuan H, Liu H, Tian R et al (2012) Regulation of mesenchymal stem cell differentiation and insulin secretion by differential expression of Pdx-1. Mol Biol Rep 39:7777–7783

    Article  Google Scholar 

  30. Li L, Li F, Qi H et al (2008) Coexpression of Pdx1 and betacellulin in mesenchymal stem cells could promote the differentiation of nestin-positive epithelium-like progenitors and pancreatic islet-like spheroids. Stem Cells Dev 17:815–823

    Article  Google Scholar 

  31. Moriscot C, de Fraipont F, Richard MJ et al (2005) Human bone marrow mesenchymal stem cells can express insulin and key transcription factors of the endocrine pancreas developmental pathway upon genetic and/or microenvironmental manipulation in vitro. Stem Cells 23:594–603

    Article  Google Scholar 

  32. Wilson LM, Wong SH, Yu N et al (2009) Insulin but not glucagon gene is silenced in human pancreas-derived mesenchymal stem cells. Stem Cells 27:2703–2711

    Article  Google Scholar 

  33. Yoshida S, Ishikawa F, Kawano N et al (2005) Human cord blood–derived cells generate insulin-producing cells in vivo. Stem Cells 23:1409–1416

    Article  Google Scholar 

  34. Li Y, Zhao LJ, Xia FZ et al (2012) Transdifferentiation of hepatic oval cells into pancreatic islet beta-cells. Front Biosci (Landmark Ed) 17:2391–2395

    Article  Google Scholar 

  35. Li H, Li X, Lam KS et al (2008) Adeno-associated virus-mediated pancreatic and duodenal homeobox gene-1 expression enhanced differentiation of hepatic oval stem cells to insulin-producing cells in diabetic rats. J Biomed Sci 15:487–497

    Article  Google Scholar 

  36. Kodama S, Kuhtreiber W, Fujimura S et al (2003) Islet regeneration during the reversal of autoimmune diabetes in NOD mice. Science 302:1223–1227

    Article  Google Scholar 

  37. Kim B, Yoon BS, Moon JH et al (2012) Differentiation of human labia minora dermis-derived fibroblasts into insulin-producing cells. Exp Mol Med 44:26–35

    Article  Google Scholar 

  38. Pennarossa G, Maffei S, Campagnol M et al (2013) Brief demethylation step allows the conversion of adult human skin fibroblasts into insulin-secreting cells. Proc Natl Acad Sci USA 110:8948–8953

    Article  Google Scholar 

  39. Dor Y, Brown J, Martinez OI et al (2004) Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation. Nature 429:41–46

    Article  Google Scholar 

  40. Smukler SR, Arntfield ME, Razavi R et al (2011) The adult mouse and human pancreas contain rare multipotent stem cells that express insulin. Cell Stem Cell 8:281–293

    Article  Google Scholar 

  41. Kawakami M, Hirayama A, Tsuchiya K et al (2010) Promotion of beta-cell differentiation by the alkaloid conophylline in porcine pancreatic endocrine cells. Biomed Pharmacother 64:226–231

    Article  Google Scholar 

  42. Stevenson K, Chen D, MacIntyre A et al (2011) Pancreatic-derived pathfinder cells enable regeneration of critically damaged adult pancreatic tissue and completely reverse streptozotocin-induced diabetes. Rejuvenation Res 14:163–171

    Article  Google Scholar 

  43. Ta M, Choi Y, Atouf F et al (2006) The defined combination of growth factors controls generation of long-term-replicating islet progenitor-like cells from cultures of adult mouse pancreas. Stem Cells 24:1738–1749

    Article  Google Scholar 

  44. Choi Y, Ta M, Atouf F et al (2004) Adult pancreas generates multipotent stem cells and pancreatic and nonpancreatic progeny. Stem Cells 22:1070–1084

    Article  Google Scholar 

  45. Xu X, D’Hoker J, Stange G et al (2008) Beta cells can be generated from endogenous progenitors in injured adult mouse pancreas. Cell 132:197–207

    Article  Google Scholar 

  46. Sancho R, Gruber R, Gu G et al (2014) Loss of Fbw7 reprograms adult pancreatic ductal cells into alpha, delta, and beta cells. Cell Stem Cell 15:139–153

    Article  Google Scholar 

  47. Lemper M, Leuckx G, Heremans Y et al (2014) Reprogramming of human pancreatic exocrine cells to beta-like cells. Cell Death Differ. doi:10.1038/cdd.2014.193

    Google Scholar 

  48. Collombat P, Xu X, Ravassard P et al (2009) The ectopic expression of Pax4 in the mouse pancreas converts progenitor cells into alpha and subsequently beta cells. Cell 138:449–462

    Article  Google Scholar 

  49. Liu Z, Habener JF (2009) Alpha cells beget beta cells. Cell 138:424–426

    Article  Google Scholar 

  50. Chung CH, Hao E, Piran R et al (2010) Pancreatic beta-cell neogenesis by direct conversion from mature alpha-cells. Stem Cells 28:1630–1638

    Article  Google Scholar 

  51. Habener JF, Stanojevic V (2012) Alpha-cell role in beta-cell generation and regeneration. Islets 4:188–198

    Article  Google Scholar 

  52. Ameri J, Stahlberg A, Pedersen J et al (2010) FGF2 specifies hESC-derived definitive endoderm into foregut/midgut cell lineages in a concentration-dependent manner. Stem Cells 28:45–56

    Google Scholar 

  53. Teo AK, Ali Y, Wong KY et al (2012) Activin and BMP4 synergistically promote formation of definitive endoderm in human embryonic stem cells. Stem Cells 30:631–642

    Article  Google Scholar 

  54. Li L, Yi Z, Seno M et al (2004) Activin A and betacellulin: effect on regeneration of pancreatic beta-cells in neonatal streptozotocin-treated rats. Diabetes 53:608–615

    Article  Google Scholar 

  55. Mfopou JK, De Groote V, Xu X et al (2007) Sonic hedgehog and other soluble factors from differentiating embryoid bodies inhibit pancreas development. Stem Cells 25:1156–1165

    Article  Google Scholar 

  56. Afelik S, Pool B, Schmerr M et al (2015) Wnt7b is required for epithelial progenitor growth and operates during epithelial-to-mesenchymal signaling in pancreatic development. Dev Biol 399:204–217

    Article  Google Scholar 

  57. Shi Y, Hou L, Tang F et al (2005) Inducing embryonic stem cells to differentiate into pancreatic beta cells by a novel three-step approach with activin A and all-trans retinoic acid. Stem Cells 23:656–662

    Article  Google Scholar 

  58. Zhang D, Jiang W, Liu M et al (2009) Highly efficient differentiation of human ES cells and iPS cells into mature pancreatic insulin-producing cells. Cell Res 19:429–438

    Article  Google Scholar 

  59. Kao DI, Lacko LA, Ding BS et al (2015) Endothelial cells control pancreatic cell fate at defined stages through EGFL7 signaling. Stem Cell Rep 4:181–189

    Article  Google Scholar 

  60. Lammert E, Cleaver O, Melton D (2001) Induction of pancreatic differentiation by signals from blood vessels. Science 294:564–567

    Article  Google Scholar 

  61. He J, Yang Z, Yang H et al (2015) Regulation of insulin sensitivity, insulin production, and pancreatic beta cell survival by angiotensin-(1-7) in a rat model of streptozotocin-induced diabetes mellitus. Peptides 64:49–54

    Article  Google Scholar 

  62. Karnieli O, Izhar-Prato Y, Bulvik S et al (2007) Generation of insulin-producing cells from human bone marrow mesenchymal stem cells by genetic manipulation. Stem Cells 25:2837–2844

    Article  Google Scholar 

  63. Sordi V, Melzi R, Mercalli A et al (2010) Mesenchymal cells appearing in pancreatic tissue culture are bone marrow-derived stem cells with the capacity to improve transplanted islet function. Stem Cells 28:140–151

    Article  Google Scholar 

  64. Kroon E, Martinson LA, Kadoya K et al (2008) Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo. Nat Biotechnol 26:443–452

    Article  Google Scholar 

  65. Schneider S, Feilen PJ, Brunnenmeier F et al (2005) Long-term graft function of adult rat and human islets encapsulated in novel alginate-based microcapsules after transplantation in immunocompetent diabetic mice. Diabetes 54:687–693

    Article  Google Scholar 

  66. Matveyenko AV, Singh I, Shin BC et al (2010) Differential effects of prenatal and postnatal nutritional environment on ss-cell mass development and turnover in male and female rats. Endocrinology 151:5647–5656

    Article  Google Scholar 

  67. Hamilton DC, Shih HH, Schubert RA et al (2015) A silk-based encapsulation platform for pancreatic islet transplantation improves islet function in vivo. J Tissue Eng Regen Med. doi:10.1002/term.1990

    Google Scholar 

  68. Nishimura R, Ushiyama A, Sekiguchi S et al (2013) Effects of glucagon-like peptide 1 analogue on the early phase of revascularization of transplanted pancreatic islets in a subcutaneous site. Transpl Proc 45:1892–1894

    Article  Google Scholar 

  69. Coronel MM, Stabler CL (2013) Engineering a local microenvironment for pancreatic islet replacement. Curr Opin Biotechnol 24:900–908

    Article  Google Scholar 

  70. Leung KK, Liang J, Ma MT et al (2012) Angiotensin II type 2 receptor is critical for the development of human fetal pancreatic progenitor cells into islet-like cell clusters and their potential for transplantation. Stem Cells 30:525–536

    Article  Google Scholar 

  71. Li G, Huang LS, Jiang MH et al (2010) Implantation of bFGF-treated islet progenitor cells ameliorates streptozotocin-induced diabetes in rats. Acta Pharmacol Sin 31:1454–1463

    Article  Google Scholar 

  72. Dufrane D, Gianello P (2012) Pig islet for xenotransplantation in human: structural and physiological compatibility for human clinical application. Transpl Rev (Orlando) 26:183–188

    Article  Google Scholar 

  73. Lee JI, Shin JS, Jung WY et al (2013) Porcine islet adaptation to metabolic need of monkeys in pig-to-monkey intraportal islet xenotransplantation. Transpl Proc 45:1866–1868

    Article  Google Scholar 

  74. van der Windt DJ, Marigliano M, He J et al (2012) Early islet damage after direct exposure of pig islets to blood: has humoral immunity been underestimated? Cell Transpl 21:1791–1802

    Article  Google Scholar 

  75. Lee SH, Hao E, Savinov AY et al (2009) Human beta-cell precursors mature into functional insulin-producing cells in an immunoisolation device: implications for diabetes cell therapies. Transplantation 87:983–991

    Article  Google Scholar 

  76. Bruin JE, Rezania A, Xu J et al (2013) Maturation and function of human embryonic stem cell-derived pancreatic progenitors in macroencapsulation devices following transplant into mice. Diabetologia 56:1987–1998

    Article  Google Scholar 

  77. Barnett BP, Arepally A, Karmarkar PV et al (2007) Magnetic resonance-guided, real-time targeted delivery and imaging of magnetocapsules immunoprotecting pancreatic islet cells. Nat Med 13:986–991

    Article  Google Scholar 

  78. Hering BJ, Wijkstrom M, Graham ML et al (2006) Prolonged diabetes reversal after intraportal xenotransplantation of wild-type porcine islets in immunosuppressed nonhuman primates. Nat Med 12:301–303

    Article  Google Scholar 

  79. Cardona K, Korbutt GS, Milas Z et al (2006) Long-term survival of neonatal porcine islets in nonhuman primates by targeting costimulation pathways. Nat Med 12:304–306

    Article  Google Scholar 

  80. Speier S, Nyqvist D, Cabrera O et al (2008) Noninvasive in vivo imaging of pancreatic islet cell biology. Nat Med 14:574–578

    Article  Google Scholar 

  81. Yolcu ES, Zhao H, Shirwan H (2013) Immunomodulation with SA-FasL protein as an effective means of preventing islet allograft rejection in chemically diabetic NOD mice. Transpl Proc 45:1889–1891

    Article  Google Scholar 

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Acknowledgments

This work was supported by the National Basic Research Program of China (2013CB967102) and the National Natural Science Foundation of China (31201112). We thank Yangjie Lu from Institute of Zoology, Chinese Academy of Sciences, for her valuable comments on our manuscript writing.

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Authors and Affiliations

  1. College of Life Sciences, Northeast Agricultural University of China, Harbin, 150030, China

    Ying Wang & Zhonghua Liu

  2. State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China

    Ying Wang, Tang Hai, Lei Liu & Qi Zhou

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  1. Ying Wang
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  2. Tang Hai
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  3. Lei Liu
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  4. Zhonghua Liu
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Correspondence to Zhonghua Liu or Qi Zhou.

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SPECIAL TOPIC: Stem cell, Basis and Application

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Wang, Y., Hai, T., Liu, L. et al. Cell therapy in diabetes: current progress and future prospects. Sci. Bull. 60, 1744–1751 (2015). https://doi.org/10.1007/s11434-015-0844-6

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