Skip to main content
SpringerLink
Log in
Book cover

Perinatal Stem Cells pp 93–110Cite as

Therapeutic Application of Perinatal Mesenchymal Stem Cells in Diabetes Mellitus

  • Chapter
  • First Online:

  • 363 Accesses

Abstract

Diabetes mellitus (DM) is a major global problem, and its complications seriously threaten the human health. The failure of pancreatic islet β-cells and insulin resistance are the main mechanism of the occurrence and the development of DM, and this can be induced by immune damage and inflammatory response. The current antidiabetic drugs, which do not focus on the link of the onset of diabetes, can only relieve or alleviate the symptoms, delay the progression of the disease, but cannot cure the disease. A developing field in diabetes therapy is the application of some stem populations, in particular those defined as “perinatal,” derived from fetus-associated tissues usually discarded at birth. Umbilical cord-derived mesenchymal stem cells (UC-MSCs) are multipotent, self-renewing adult stem cells showing immunoregulatory properties and are capable to secrete an array of soluble cytokines and growth factors. Accumulating evidence showed that UC-MSCs can transdifferentiate into insulin-producing cells (IPCs) in vitro. Animal experiments and small sample clinical trials have validated the effectiveness and safety of UC-MSC therapy for diabetes. This chapter reviews the progress that has been made in UC-MSC treatment for diabetes, discusses the underlying mechanisms, and also raises the remaining hurdles.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD   109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Shen J, Cheng Y, Han Q, et al. Generating insulin-producing cells for diabetic therapy: existing strategies and new development. Ageing Res Rev. 2013;12:469–78.

    Article  CAS  PubMed  Google Scholar 

  2. Borowiak M, Melton DA. How to make beta cells? Curr Opin Cell Biol. 2009;21:727–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Zhou Q, Melton DA. Pathways to new beta cells. Cold Spring Harb Symp Quant Biol. 2008;73:175–81.

    Article  CAS  PubMed  Google Scholar 

  4. Guo T, Hebrok M. Stem cells to pancreatic beta-cells: new sources for diabetes cell therapy. Endocr Rev. 2009;30:214–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Hori Y. Insulin-producing cells derived from stem/progenitor cells: therapeutic implications for diabetes mellitus. Med Mol Morphol. 2009;42:195–200.

    Article  PubMed  Google Scholar 

  6. Johnson JD. The quest to make fully functional human pancreatic beta cells from embryonic stem cells: climbing a mountain in the clouds. Diabetologia. 2016;59:2047–57.

    Article  CAS  PubMed  Google Scholar 

  7. Mayhew CN, Wells JM. Converting human pluripotent stem cells into beta-cells: recent advances and future challenges. Curr Opin Organ Transplant. 2010;15:54–60.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Mfopou JK, Chen B, Sui L, et al. Recent advances and prospects in the differentiation of pancreatic cells from human embryonic stem cells. Diabetes. 2010;59:2094–101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Zhang D, Jiang W, Shi Y, et al. Generation of pancreatic islet cells from human embryonic stem cells. Sci China C Life Sci. 2009;52:615–21.

    Article  PubMed  Google Scholar 

  10. D'amour KA, Bang AG, Eliazer S, et al. Production of pancreatic hormone-expressing endocrine cells from human embryonic stem cells. Nat Biotechnol. 2006;24:1392–401.

    Article  CAS  PubMed  Google Scholar 

  11. Cai J, Yu C, Liu Y, et al. Generation of homogeneous PDX1(+) pancreatic progenitors from human ES cell-derived endoderm cells. J Mol Cell Biol. 2010;2:50–60.

    Article  CAS  PubMed  Google Scholar 

  12. Champeris Tsaniras S, Jones PM. Generating pancreatic beta-cells from embryonic stem cells by manipulating signaling pathways. J Endocrinol. 2010;206:13–26.

    Article  PubMed  CAS  Google Scholar 

  13. Mfopou JK, Chen B, Mateizel I, et al. Noggin, retinoids, and fibroblast growth factor regulate hepatic or pancreatic fate of human embryonic stem cells. Gastroenterology. 2010;138:2233–45, 2245 e2231-2214.

    Article  CAS  PubMed  Google Scholar 

  14. Phillips BW, Hentze H, Rust WL, et al. Directed differentiation of human embryonic stem cells into the pancreatic endocrine lineage. Stem Cells Dev. 2007;16:561–78.

    Article  CAS  PubMed  Google Scholar 

  15. Thatava T, Nelson TJ, Edukulla R, et al. Indolactam V/GLP-1-mediated differentiation of human iPS cells into glucose-responsive insulin-secreting progeny. Gene Ther. 2011;18:283–93.

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  17. Zhang D, Jiang W, Liu M, et al. Highly efficient differentiation of human ES cells and iPS cells into mature pancreatic insulin-producing cells. Cell Res. 2009;19:429–38.

    Article  CAS  PubMed  Google Scholar 

  18. Pagliuca FW, Millman JR, Gürtler M, et al. Generation of functional human pancreatic β cells in vitro. Cell. 2014;159:428–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Rezania A, Bruin JE, Arora P, et al. Reversal of diabetes with insulin-producing cells derived in vitro from human pluripotent stem cells. Nat Biotechnol. 2014;32:1121–33.

    Article  CAS  PubMed  Google Scholar 

  20. Russ HA, Parent AV, Ringler JJ, et al. Controlled induction of human pancreatic progenitors produces functional beta-like cells in vitro. EMBO J. 2015;34:1759–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Dave S. Mesenchymal stem cells derived in vitro transdifferentiated insulin-producing cells: a new approach to treat type 1 diabetes. Adv Biomed Res. 2014;3:266.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Dominguez-Bendala J, Lanzoni G, Inverardi L, et al. Concise review: mesenchymal stem cells for diabetes. Stem Cells Transl Med. 2012;1:59–63.

    Article  CAS  PubMed  Google Scholar 

  23. Hashemian SJ, Kouhnavard M, Nasli-Esfahani E. Mesenchymal stem cells: rising concerns over their application in treatment of type one diabetes mellitus. J Diabetes Res. 2015;2015:675103.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Katuchova J, Harvanova D, Spakova T, et al. Mesenchymal stem cells in the treatment of type 1 diabetes mellitus. Endocr Pathol. 2015;26:95–103.

    Article  CAS  PubMed  Google Scholar 

  25. Klinker MW, Wei CH. Mesenchymal stem cells in the treatment of inflammatory and autoimmune diseases in experimental animal models. World J Stem Cells. 2015;7:556–67.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Bhansali A, Asokumar P, Walia R, et al. Efficacy and safety of autologous bone marrow-derived stem cell transplantation in patients with type 2 diabetes mellitus: a randomized placebo-controlled study. Cell Transplant. 2014;23:1075–85.

    Article  PubMed  Google Scholar 

  27. Bhansali A, Upreti V, Khandelwal N, et al. Efficacy of autologous bone marrow-derived stem cell transplantation in patients with type 2 diabetes mellitus. Stem Cells Dev. 2009;18:1407–16.

    Article  CAS  PubMed  Google Scholar 

  28. Carlsson PO, Schwarcz E, Korsgren O, et al. Preserved beta-cell function in type 1 diabetes by mesenchymal stromal cells. Diabetes. 2015;64:587–92.

    Article  CAS  PubMed  Google Scholar 

  29. Arutyunyan I, Elchaninov A, Makarov A, et al. Umbilical cord as prospective source for mesenchymal stem cell-based therapy. Stem Cells Int. 2016;2016:6901286.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Watson N, Divers R, Kedar R, et al. Discarded Wharton jelly of the human umbilical cord: a viable source for mesenchymal stromal cells. Cytotherapy. 2015;17:18–24.

    Article  PubMed  Google Scholar 

  31. Afelik S, Jensen J. Notch signaling in the pancreas: patterning and cell fate specification. Wiley Interdiscip Rev Dev Biol. 2013;2:531–44.

    Article  CAS  PubMed  Google Scholar 

  32. Serup P. Signaling pathways regulating murine pancreatic development. Semin Cell Dev Biol. 2012;23:663–72.

    Article  CAS  PubMed  Google Scholar 

  33. Edlund H. Pancreatic organogenesis--developmental mechanisms and implications for therapy. Nat Rev Genet. 2002;3:524–32.

    Article  CAS  PubMed  Google Scholar 

  34. Gittes GK. Developmental biology of the pancreas: a comprehensive review. Dev Biol. 2009;326:4–35.

    Article  CAS  PubMed  Google Scholar 

  35. Puri S, Hebrok M. Cellular plasticity within the pancreas--lessons learned from development. Dev Cell. 2010;18:342–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Shih HP, Wang A, Sander M. Pancreas organogenesis: from lineage determination to morphogenesis. Annu Rev Cell Dev Biol. 2013;29:81–105.

    Article  CAS  PubMed  Google Scholar 

  37. Stanger BZ, Hebrok M. Control of cell identity in pancreas development and regeneration. Gastroenterology. 2013;144:1170–9.

    Article  PubMed  Google Scholar 

  38. Jonsson J, Carlsson L, Edlund T, et al. Insulin-promoter-factor 1 is required for pancreas development in mice. Nature. 1994;371:606–9.

    Article  CAS  PubMed  Google Scholar 

  39. Offield MF, Jetton TL, Labosky PA, et al. PDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum. Development. 1996;122:983–95.

    CAS  PubMed  Google Scholar 

  40. Stoffers DA, Ferrer J, Clarke WL, et al. Early-onset type-II diabetes mellitus (MODY4) linked to IPF1. Nat Genet. 1997;17:138–9.

    Article  CAS  PubMed  Google Scholar 

  41. Holland AM, Hale MA, Kagami H, et al. Experimental control of pancreatic development and maintenance. Proc Natl Acad Sci U S A. 2002;99:12236–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Gannon M, Ables ET, Crawford L, et al. pdx-1 function is specifically required in embryonic beta cells to generate appropriate numbers of endocrine cell types and maintain glucose homeostasis. Dev Biol. 2008;314:406–17.

    Article  CAS  PubMed  Google Scholar 

  43. Johansson KA, Dursun U, Jordan N, et al. Temporal control of neurogenin3 activity in pancreas progenitors reveals competence windows for the generation of different endocrine cell types. Dev Cell. 2007;12:457–65.

    Article  CAS  PubMed  Google Scholar 

  44. Wang S, Jensen JN, Seymour PA, et al. Sustained Neurog3 expression in hormone-expressing islet cells is required for endocrine maturation and function. Proc Natl Acad Sci U S A. 2009;106:9715–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Collombat P, Mansouri A, Hecksher-Sorensen J, et al. Opposing actions of Arx and Pax4 in endocrine pancreas development. Genes Dev. 2003;17:2591–603.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Henseleit KD, Nelson SB, Kuhlbrodt K, et al. NKX6 transcription factor activity is required for alpha- and beta-cell development in the pancreas. Development. 2005;132:3139–49.

    Article  CAS  PubMed  Google Scholar 

  47. Papizan JB, Singer RA, Tschen SI, et al. Nkx2.2 repressor complex regulates islet beta-cell specification and prevents beta-to-alpha-cell reprogramming. Genes Dev. 2011;25:2291–305.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Sosa-Pineda B, Chowdhury K, Torres M, et al. The Pax4 gene is essential for differentiation of insulin-producing beta cells in the mammalian pancreas. Nature. 1997;386:399–402.

    Article  CAS  PubMed  Google Scholar 

  49. Collombat P, Hecksher-Sorensen J, Broccoli V, et al. The simultaneous loss of Arx and Pax4 genes promotes a somatostatin-producing cell fate specification at the expense of the alpha- and beta-cell lineages in the mouse endocrine pancreas. Development. 2005;132:2969–80.

    Article  CAS  PubMed  Google Scholar 

  50. Dhawan S, Georgia S, Tschen SI, et al. Pancreatic beta cell identity is maintained by DNA methylation-mediated repression of Arx. Dev Cell. 2011;20:419–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Yang YP, Thorel F, Boyer DF, et al. Context-specific alpha-to-beta-cell reprogramming by forced Pdx1 expression. Genes Dev. 2011;25:1680–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Collombat P, Xu X, Ravassard P, et al. The ectopic expression of Pax4 in the mouse pancreas converts progenitor cells into alpha and subsequently beta cells. Cell. 2009;138:449–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Schaffer AE, Taylor BL, Benthuysen JR, et al. Nkx6.1 controls a gene regulatory network required for establishing and maintaining pancreatic Beta cell identity. PLoS Genet. 2013;9:e1003274.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Collombat P, Hecksher-Sorensen J, Krull J, et al. Embryonic endocrine pancreas and mature beta cells acquire alpha and PP cell phenotypes upon Arx misexpression. J Clin Invest. 2007;117:961–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Si YL, Zhao YL, Hao HJ, et al. MSCs: biological characteristics, clinical applications and their outstanding concerns. Ageing Res Rev. 2011;10:93–103.

    Article  CAS  PubMed  Google Scholar 

  56. Mcelreavey KD, Irvine AI, Ennis KT, et al. Isolation, culture and characterisation of fibroblast-like cells derived from the Wharton’s jelly portion of human umbilical cord. Biochem Soc Trans. 1991;19:29S.

    Article  CAS  PubMed  Google Scholar 

  57. Wang HS, Hung SC, Peng ST, et al. Mesenchymal stem cells in the Wharton’s jelly of the human umbilical cord. Stem Cells. 2004;22:1330–7.

    Article  PubMed  Google Scholar 

  58. Lee M, Jeong SY, Ha J, et al. Low immunogenicity of allogeneic human umbilical cord blood-derived mesenchymal stem cells in vitro and in vivo. Biochem Biophys Res Commun. 2014;446:983–9.

    Article  CAS  PubMed  Google Scholar 

  59. Weiss ML, Anderson C, Medicetty S, et al. Immune properties of human umbilical cord Wharton’s jelly-derived cells. Stem Cells. 2008;26:2865–74.

    Article  CAS  PubMed  Google Scholar 

  60. Jin HJ, Bae YK, Kim M, et al. Comparative analysis of human mesenchymal stem cells from bone marrow, adipose tissue, and umbilical cord blood as sources of cell therapy. Int J Mol Sci. 2013;14:17986–8001.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Lu LL, Liu YJ, Yang SG, et al. Isolation and characterization of human umbilical cord mesenchymal stem cells with hematopoiesis-supportive function and other potentials. Haematologica. 2006;91:1017–26.

    CAS  PubMed  Google Scholar 

  62. Wegmeyer H, Broske AM, Leddin M, et al. Mesenchymal stromal cell characteristics vary depending on their origin. Stem Cells Dev. 2013;22:2606–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Amable PR, Teixeira MV, Carias RB, et al. Protein synthesis and secretion in human mesenchymal cells derived from bone marrow, adipose tissue and Wharton’s jelly. Stem Cell Res Ther. 2014;5:53.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Kuchroo P, Dave V, Vijayan A, et al. Paracrine factors secreted by umbilical cord-derived mesenchymal stem cells induce angiogenesis in vitro by a VEGF-independent pathway. Stem Cells Dev. 2015;24:437–50.

    Article  CAS  PubMed  Google Scholar 

  65. Li X, Bai J, Ji X, et al. Comprehensive characterization of four different populations of human mesenchymal stem cells as regards their immune properties, proliferation and differentiation. Int J Mol Med. 2014;34:695–704.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Pires AO, Mendes-Pinheiro B, Teixeira FG, et al. Unveiling the differences of secretome of human bone marrow mesenchymal stem cells, adipose tissue-derived stem cells, and human umbilical cord perivascular cells: a proteomic analysis. Stem Cells Dev. 2016;25:1073–83.

    Article  CAS  PubMed  Google Scholar 

  67. Du WJ, Chi Y, Yang ZX, et al. Heterogeneity of proangiogenic features in mesenchymal stem cells derived from bone marrow, adipose tissue, umbilical cord, and placenta. Stem Cell Res Ther. 2016;7:163.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Datta I, Mishra S, Mohanty L, et al. Neuronal plasticity of human Wharton’s jelly mesenchymal stromal cells to the dopaminergic cell type compared with human bone marrow mesenchymal stromal cells. Cytotherapy. 2011;13:918–32.

    Article  CAS  PubMed  Google Scholar 

  69. Balasubramanian S, Thej C, Venugopal P, et al. Higher propensity of Wharton’s jelly derived mesenchymal stromal cells towards neuronal lineage in comparison to those derived from adipose and bone marrow. Cell Biol Int. 2013;37:507–15.

    Article  CAS  PubMed  Google Scholar 

  70. Chen MY, Lie PC, Li ZL, et al. Endothelial differentiation of Wharton’s jelly-derived mesenchymal stem cells in comparison with bone marrow-derived mesenchymal stem cells. Exp Hematol. 2009;37:629–40.

    Article  CAS  PubMed  Google Scholar 

  71. Wu LF, Wang NN, Liu YS, et al. Differentiation of Wharton’s jelly primitive stromal cells into insulin-producing cells in comparison with bone marrow mesenchymal stem cells. Tissue Eng Part A. 2009;15:2865–73.

    Article  CAS  PubMed  Google Scholar 

  72. Manochantr S, U-pratya Y, Kheolamai P, et al. Immunosuppressive properties of mesenchymal stromal cells derived from amnion, placenta, Wharton’s jelly and umbilical cord. Intern Med J. 2013;43:430–9.

    Article  CAS  PubMed  Google Scholar 

  73. Najar M, Raicevic G, Boufker HI, et al. Adipose-tissue-derived and Wharton’s jelly-derived mesenchymal stromal cells suppress lymphocyte responses by secreting leukemia inhibitory factor. Tissue Eng Part A. 2010;16:3537–46.

    Article  CAS  PubMed  Google Scholar 

  74. Vellasamy S, Sandrasaigaran P, Vidyadaran S, et al. Mesenchymal stem cells of human placenta and umbilical cord suppress T-cell proliferation at G0 phase of cell cycle. Cell Biol Int. 2013;37:250–6.

    Article  CAS  PubMed  Google Scholar 

  75. Vellasamy S, Tong CK, Azhar NA, et al. Human mesenchymal stromal cells modulate T-cell immune response via transcriptomic regulation. Cytotherapy. 2016;18:1270–83.

    Article  CAS  PubMed  Google Scholar 

  76. Yang H, Sun J, Li Y, et al. Human umbilical cord-derived mesenchymal stem cells suppress proliferation of PHA-activated lymphocytes in vitro by inducing CD4(+)CD25(high)CD45RA(+) regulatory T cell production and modulating cytokine secretion. Cell Immunol. 2016;302:26–31.

    Article  CAS  PubMed  Google Scholar 

  77. Chen K, Wang D, Du WT, et al. Human umbilical cord mesenchymal stem cells hUC-MSCs exert immunosuppressive activities through a PGE2-dependent mechanism. Clin Immunol. 2010;135:448–58.

    Article  CAS  PubMed  Google Scholar 

  78. Li X, Xu Z, Bai J, et al. Umbilical cord tissue-derived mesenchymal stem cells induce T lymphocyte apoptosis and cell cycle arrest by expression of indoleamine 2, 3-dioxygenase. Stem Cells Int. 2016;2016:7495135.

    PubMed  PubMed Central  Google Scholar 

  79. He H, Nagamura-Inoue T, Takahashi A, et al. Immunosuppressive properties of Wharton’s jelly-derived mesenchymal stromal cells in vitro. Int J Hematol. 2015;102:368–78.

    Article  CAS  PubMed  Google Scholar 

  80. Tipnis S, Viswanathan C, Majumdar AS. Immunosuppressive properties of human umbilical cord-derived mesenchymal stem cells: role of B7-H1 and IDO. Immunol Cell Biol. 2010;88:795–806.

    Article  PubMed  Google Scholar 

  81. Yoo KH, Jang IK, Lee MW, et al. Comparison of immunomodulatory properties of mesenchymal stem cells derived from adult human tissues. Cell Immunol. 2009;259:150–6.

    Article  CAS  PubMed  Google Scholar 

  82. Cutler AJ, Limbani V, Girdlestone J, et al. Umbilical cord-derived mesenchymal stromal cells modulate monocyte function to suppress T cell proliferation. J Immunol. 2010;185:6617–23.

    Article  CAS  PubMed  Google Scholar 

  83. Che N, Li X, Zhou S, et al. Umbilical cord mesenchymal stem cells suppress B-cell proliferation and differentiation. Cell Immunol. 2012;274:46–53.

    Article  CAS  PubMed  Google Scholar 

  84. Ji YR, Yang ZX, Han ZB, et al. Mesenchymal stem cells support proliferation and terminal differentiation of B cells. Cell Physiol Biochem. 2012;30:1526–37.

    Article  CAS  PubMed  Google Scholar 

  85. Ruggeri L, Mancusi A, Burchielli E, et al. NK cell alloreactivity and allogeneic hematopoietic stem cell transplantation. Blood Cells Mol Dis. 2008;40:84–90.

    Article  CAS  PubMed  Google Scholar 

  86. Vivier E, Raulet DH, Moretta A, et al. Innate or adaptive immunity? The example of natural killer cells. Science. 2011;331:44–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Chatterjee D, Marquardt N, Tufa DM, et al. Role of gamma-secretase in human umbilical-cord derived mesenchymal stem cell mediated suppression of NK cell cytotoxicity. Cell Commun Signal. 2014;12:63.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Chatterjee D, Marquardt N, Tufa DM, et al. Human umbilical cord-derived mesenchymal stem cells utilize activin-A to suppress interferon-gamma production by natural killer cells. Front Immunol. 2014;5:662.

    PubMed  PubMed Central  Google Scholar 

  89. Chazaud B. Macrophages: supportive cells for tissue repair and regeneration. Immunobiology. 2014;219:172–8.

    Article  CAS  PubMed  Google Scholar 

  90. Forbes SJ, Rosenthal N. Preparing the ground for tissue regeneration: from mechanism to therapy. Nat Med. 2014;20:857–69.

    Article  CAS  PubMed  Google Scholar 

  91. Novak ML, Koh TJ. Phenotypic transitions of macrophages orchestrate tissue repair. Am J Pathol. 2013;183:1352–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Wynn TA, Vannella KM. Macrophages in tissue repair, regeneration, and fibrosis. Immunity. 2016;44:450–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Selleri S, Bifsha P, Civini S, et al. Human mesenchymal stromal cell-secreted lactate induces M2-macrophage differentiation by metabolic reprogramming. Oncotarget. 2016;7:30193–210.

    PubMed  PubMed Central  Google Scholar 

  94. Dayan V, Yannarelli G, Billia F, et al. Mesenchymal stromal cells mediate a switch to alternatively activated monocytes/macrophages after acute myocardial infarction. Basic Res Cardiol. 2011;106:1299–310.

    Article  CAS  PubMed  Google Scholar 

  95. Li W, Zhang Q, Wang M, et al. Macrophages are involved in the protective role of human umbilical cord-derived stromal cells in renal ischemia-reperfusion injury. Stem Cell Res. 2013;10:405–16.

    Article  CAS  PubMed  Google Scholar 

  96. Deng W, Chen W, Zhang Z, et al. Mesenchymal stem cells promote CD206 expression and phagocytic activity of macrophages through IL-6 in systemic lupus erythematosus. Clin Immunol. 2015;161:209–16.

    Article  CAS  PubMed  Google Scholar 

  97. Xie Z, Hao H, Tong C, et al. Human umbilical cord-derived mesenchymal stem cells elicit macrophages into an anti-inflammatory phenotype to alleviate insulin resistance in type 2 diabetic rats. Stem Cells. 2016;34:627–39.

    Article  CAS  PubMed  Google Scholar 

  98. Chao KC, Chao KF, Fu YS, et al. Islet-like clusters derived from mesenchymal stem cells in Wharton’s Jelly of the human umbilical cord for transplantation to control type 1 diabetes. PLoS One. 2008;3:e1451.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Moshrefi M, Yari N, Nabipour F, et al. Transplantation of differentiated umbilical cord mesenchymal cells under kidney capsule for control of type I diabetes in rat. Tissue Cell. 2015;47:395–405.

    Article  CAS  PubMed  Google Scholar 

  100. Wang HS, Shyu JF, Shen WS, et al. Transplantation of insulin-producing cells derived from umbilical cord stromal mesenchymal stem cells to treat NOD mice. Cell Transplant. 2011;20:455–66.

    Article  CAS  PubMed  Google Scholar 

  101. Yu YB, Bian JM, Gu DH. Transplantation of insulin-producing cells to treat diabetic rats after 90% pancreatectomy. World J Gastroenterol. 2015;21:6582–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Tsai PJ, Wang HS, Shyr YM, et al. Transplantation of insulin-producing cells from umbilical cord mesenchymal stem cells for the treatment of streptozotocin-induced diabetic rats. J Biomed Sci. 2012;19:47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Seyedi F, Farsinejad A, Moshrefi M, et al. In vitro evaluation of different protocols for the induction of mesenchymal stem cells to insulin-producing cells. In Vitro Cell Dev Biol Anim. 2015;51:866–78.

    Article  CAS  PubMed  Google Scholar 

  104. Seyedi F, Farsinejad A, Nematollahi-Mahani SA, et al. Suspension culture alters insulin secretion in induced human umbilical cord matrix-derived mesenchymal cells. Cell J. 2016;18:52–61.

    PubMed  PubMed Central  Google Scholar 

  105. Qu H, Liu X, Ni Y, et al. Laminin 411 acts as a potent inducer of umbilical cord mesenchymal stem cell differentiation into insulin-producing cells. J Transl Med. 2014;12:135.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Aviv V, Meivar-Levy I, Rachmut IH, et al. Exendin-4 promotes liver cell proliferation and enhances the PDX-1-induced liver to pancreas transdifferentiation process. J Biol Chem. 2009;284:33509–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Ferber S, Halkin A, Cohen H, et al. Pancreatic and duodenal homeobox gene 1 induces expression of insulin genes in liver and ameliorates streptozotocin-induced hyperglycemia. Nat Med. 2000;6:568–72.

    Article  CAS  PubMed  Google Scholar 

  108. Jin CX, Li WL, Xu F, et al. Conversion of immortal liver progenitor cells into pancreatic endocrine progenitor cells by persistent expression of Pdx-1. J Cell Biochem. 2008;104:224–36.

    Article  CAS  PubMed  Google Scholar 

  109. Shternhall-Ron K, Quintana FJ, Perl S, et al. Ectopic PDX-1 expression in liver ameliorates type 1 diabetes. J Autoimmun. 2007;28:134–42.

    Article  CAS  PubMed  Google Scholar 

  110. Wang XL, Hu P, Guo XR, et al. Reprogramming human umbilical cord mesenchymal stromal cells to islet-like cells with the use of in vitro-synthesized pancreatic-duodenal homebox 1 messenger RNA. Cytotherapy. 2014;16:1519–27.

    Article  CAS  PubMed  Google Scholar 

  111. He D, Wang J, Gao Y, et al. Differentiation of PDX1 gene-modified human umbilical cord mesenchymal stem cells into insulin-producing cells in vitro. Int J Mol Med. 2011;28:1019–24.

    CAS  PubMed  Google Scholar 

  112. Guan LX, Guan H, Li HB, et al. Therapeutic efficacy of umbilical cord-derived mesenchymal stem cells in patients with type 2 diabetes. Exp Ther Med. 2015;9:1623–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Liu X, Zheng P, Wang X, et al. A preliminary evaluation of efficacy and safety of Wharton’s jelly mesenchymal stem cell transplantation in patients with type 2 diabetes mellitus. Stem Cell Res Ther. 2014;5:57.

    Article  PubMed  PubMed Central  Google Scholar 

  114. Hu J, Wang Y, Gong H, et al. Long term effect and safety of Wharton’s jelly-derived mesenchymal stem cells on type 2 diabetes. Exp Ther Med. 2016;12:1857–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Kong D, Zhuang X, Wang D, et al. Umbilical cord mesenchymal stem cell transfusion ameliorated hyperglycemia in patients with type 2 diabetes mellitus. Clin Lab. 2014;60:1969–76.

    Article  CAS  PubMed  Google Scholar 

  116. Hu J, Yu X, Wang Z, et al. Long term effects of the implantation of Wharton’s jelly-derived mesenchymal stem cells from the umbilical cord for newly-onset type 1 diabetes mellitus. Endocr J. 2013;60:347–57.

    Article  CAS  PubMed  Google Scholar 

  117. Cai J, Wu Z, Xu X, et al. Umbilical cord mesenchymal stromal cell with autologous bone marrow cell transplantation in established type 1 diabetes: a pilot randomized controlled open-label clinical study to assess safety and impact on insulin secretion. Diabetes Care. 2016;39:149–57.

    Article  CAS  PubMed  Google Scholar 

  118. Yaochite JN, Caliari-Oliveira C, De Souza LE, et al. Therapeutic efficacy and biodistribution of allogeneic mesenchymal stem cells delivered by intrasplenic and intrapancreatic routes in streptozotocin-induced diabetic mice. Stem Cell Res Ther. 2015;6:31.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  119. Kebriaei P, Isola L, Bahceci E, et al. Adult human mesenchymal stem cells added to corticosteroid therapy for the treatment of acute graft-versus-host disease. Biol Blood Marrow Transplant. 2009;15:804–11.

    Article  CAS  PubMed  Google Scholar 

  120. Herrmann R, Sturm M, Shaw K, et al. Mesenchymal stromal cell therapy for steroid-refractory acute and chronic graft versus host disease: a phase 1 study. Int J Hematol. 2012;95:182–8.

    Article  CAS  PubMed  Google Scholar 

  121. Prasad VK, Lucas KG, Kleiner GI, et al. Efficacy and safety of ex vivo cultured adult human mesenchymal stem cells (Prochymal) in pediatric patients with severe refractory acute graft-versus-host disease in a compassionate use study. Biol Blood Marrow Transplant. 2011;17:534–41.

    Article  CAS  PubMed  Google Scholar 

  122. Zhou H, Guo M, Bian C, et al. Efficacy of bone marrow-derived mesenchymal stem cells in the treatment of sclerodermatous chronic graft-versus-host disease: clinical report. Biol Blood Marrow Transplant. 2010;16:403–12.

    Article  CAS  PubMed  Google Scholar 

  123. Hao H, Liu J, Shen J, et al. Multiple intravenous infusions of bone marrow mesenchymal stem cells reverse hyperglycemia in experimental type 2 diabetes rats. Biochem Biophys Res Commun. 2013;436:418–23.

    Article  CAS  PubMed  Google Scholar 

  124. Hu J, Wang F, Sun R, et al. Effect of combined therapy of human Wharton’s jelly-derived mesenchymal stem cells from umbilical cord with sitagliptin in type 2 diabetic rats. Endocrine. 2014;45:279–87.

    Article  CAS  PubMed  Google Scholar 

  125. Caplan AI, Dennis JE. Mesenchymal stem cells as trophic mediators. J Cell Biochem. 2006;98:1076–84.

    Article  CAS  PubMed  Google Scholar 

  126. Ohnishi S, Yasuda T, Kitamura S, et al. Effect of hypoxia on gene expression of bone marrow-derived mesenchymal stem cells and mononuclear cells. Stem Cells. 2007;25:1166–77.

    Article  CAS  PubMed  Google Scholar 

  127. Kim J, Piao Y, Pak YK, et al. Umbilical cord mesenchymal stromal cells affected by gestational diabetes mellitus display premature aging and mitochondrial dysfunction. Stem Cells Dev. 2015;24:575–86.

    Article  CAS  PubMed  Google Scholar 

  128. Wajid N, Naseem R, Anwar SS, et al. The effect of gestational diabetes on proliferation capacity and viability of human umbilical cord-derived stromal cells. Cell Tissue Bank. 2015;16:389–97.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgment

The authors’ work was supported by the 863 Projects of the Ministry of Science and Technology of PR China (No. 2013AA020105 and 2012AA020502).

Disclosure: None of the authors have any conflicts of interest relating to this work.

Author information

Authors and Affiliations

  1. Department of Endocrinology, Chinese PLA General Hospital, Beijing, China

    Y. Cheng

  2. Department of Molecular Biology, Institute of Basic Medicine, School of Life Science, Chinese PLA General Hospital, Beijing, China

    Y. Cheng & H. J. Hao

  3. Department of Endocrinology, Chinese PLA 309 Hospital, Beijing, China

    J. Shen

Authors
  1. Y. Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J. Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. H. J. Hao
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Beijing Engineering Laboratory of Perinatal Stem Cells, Jiangxi Engineering Research Center for Stem Cell, Health & Biotech Co., Beijing, China

    Zhong Chao Han

  2. Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan

    Tsuneo A. Takahashi

  3. State Key Lab of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences, Tianjin, China

    Zhibo Han

  4. School of Medicine, Nankai University, Tianjin, China

    Zongjin Li

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Cheng, Y., Shen, J., Hao, H.J. (2019). Therapeutic Application of Perinatal Mesenchymal Stem Cells in Diabetes Mellitus. In: Han, Z., Takahashi, T., Han, Z., Li, Z. (eds) Perinatal Stem Cells. Springer, Singapore. https://doi.org/10.1007/978-981-13-2703-2_9

Download citation

  • DOI: https://doi.org/10.1007/978-981-13-2703-2_9

  • Published:

  • Publisher Name: Springer, Singapore

  • Print ISBN: 978-981-13-2702-5

  • Online ISBN: 978-981-13-2703-2

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation