Human Umbilical Cord Blood Therapy for Diabetes Mellitus : A Review

Main Article Content

Harshad Chaudhari, MD Smita Mahendrakar, MD Alluru S. Reddi

Abstract

Stem cell therapy for patients with diabetes mellitus is receiving great attention among scientists and clinicians. Although bone marrow is considered one of the rich sources of stem cells, its limited availability of donors precludes its use for all the suitable patients. Human umbilical cord blood mononuclear cells or its-derived mesenchymal cells are being increasingly used as an alternative source of stem cells for cell-based therapy for malignant and nonmalignant diseases. Human umbilical cord blood cells have low potential for graft-versus-host disease and tumorigenicity. Also, no immunosuppression is required. Experimental evidence has shown that human umbilical cord blood -derived stem cells can differentiate into insulin-secreting β-cells. Transplantation of Human umbilical cord blood cells has been shown to improve blood glucose levels, and ameliorate kidney as well as neuropathic complications in diabetic animal models. Although the first use of autologous Human umbilical cord blood transfusion in type 1 diabetic children had a short-term beneficial effect in reducing the daily requirement of insulin dose and the maintenance of near normoglycemia, subsequent studies have failed to show this beneficial effect. In this review, we will provide both experimental and clinical evidence in favor and against the beneficial effect of human umbilical cord blood cells and cord blood-derived mesenchymal cells in the management of diabetes mellitus.

Keywords: Diabetes mellitus, human umbilical cord blood, mesenchymal cells, stem cells, Tregs, blood glucose, C-peptide

Article Details

How to Cite
CHAUDHARI, Harshad; MAHENDRAKAR, Smita; REDDI, Alluru S.. Human Umbilical Cord Blood Therapy for Diabetes Mellitus : A Review. Medical Research Archives, [S.l.], v. 10, n. 12, dec. 2022. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/3382>. Date accessed: 29 jan. 2023. doi: https://doi.org/10.18103/mra.v10i12.3382.
Section
Review Articles

References

1. The IDF Diabetes Atlas 10th edition. 2021.
2. Calne RY, Gan SU, Lee KO. Stem cell and gene therapies for diabetes mellitus. Nat Rev Endocrinol. 2010;6:173-7.
3. El-Badri N, Ghoneim MA. Mesenchymal stem cell therapy in diabetes mellitus: Progress and challenges. J Nucleic Acids. Volume 2013, Article ID 194858, 7 pages.
4. Abdelalim EM, Bonnefond A, Bennaceur-Griscelli A, et al. Pluripotent stem cells as a potential tool for disease modelling and cell therapy in diabetes. Stem Cell Rev. Rep. 2014, 10, 327–337.
5. El-Badawy A, El-Badri N. Clinical efficacy of stem cell therapy for diabetes mellitus: A meta-analysis. PLoS One. 2016; 11(4): e0151938.
6. Rahim F, Arjmand B, Shirbandi K, et al. Stem cell therapy for patients with diabetes: a systematic review and meta-analysis of metabolomics-based risks and benefits. Stem Cell Investig. 2018; 5:40
7. Stiner R, Alexander M, Liu G, et al. Transplantation of stem cells from umbilical cord blood as therapy for type I diabetes. Cell Tissue Res. 2019; 378: 155-162.
8. Kassem DH, Kamal MM. Therapeutic efficacy of umbilical cord derived stem cells for diabetes mellitus: a meta-analysis study. Stem Cell Res Ther. 2020; 11:484
https://doi.org/10.1186/s13287-020-01996-x
9. Memon B, Abdelalim EM. Stem cell therapy for diabetes: Beta cells versus pancreatic progenitors. Cells. 2020; 9: 283; doi:10.3390/cells9020283.
10. Zhang Y, Chen W, Feng B, et al. The clinical efficacy and safety of stem cell therapy for diabetes mellitus: A systematic review and metaanalysis. Aging Dis. 2020; 11:141-153.
11. Goncharova AG, Yurovaa KA, Shupletsova VV, et al. Characteristics of umbilical-cord blood and its use in clinical practice. Cell Tissue Biol. 2022, 16: 15–31.
12. Ende N. The Berashis cell: A review-is it similar to the embryonic stem cell? J Med. 2000; 31: 113-130.
13. Koblas T, Harman SM, Saudek F. The application of umbilical cord blood cells in the treatment of diabetes mellitus. Rev Diabet Stud. 2005; 2: 228-234 [PMID: 1783567 DOI: 10.1900/RDS.2005.2.228].
14. Harris DT, Rogers I. Umbilical cord blood: A unique source of pluripotent stem cells for regenerative medicine. Curr Stem Cell Res Ther. 2007; 2: 301-309.
15. Bieback K, Kluter H. Mesenchymal stromal cells from umbilical cord blood. Curr Stem Cell Res Ther. 2007; 2: 310-323.
16. Haylock DN, Nilsson SK. Expansion of umbilical cord blood for clinical transplantation. Curr Stem Cell Res Ther. 2007; 2: 324-335.
17. Riordan NH, Chan K, Marleau AM, et al. Cord blood in regenerative medicine: Do we need immune suppression? J Transl Med. 2007; 5: 8 [PMID: 1796850 DOI: 1479-5876-5-8 [pii]10.1186/1479-5876-5-8].
18. Sullivan MJ. Banking on cord blood stem cells. Nat Rev Cancer. 2008; 8: 555-563 [DOI: nrc2418 [pii]10.1038/nrc2418].
19. Kogler G, Sensken S, Airey JA, et al. A new human somatic stem cell from placental cord blood with intrinsic pluripotent differentiation potential. J Exp Med. 2004; 200: 123-135 [PMID: 2212008 DOI: 10.1084/jem.20040440jem.20040440 [pii].
20. Zhao Y, Wang H, Mazzone T. Identification of stem cells from human umbilical cord blood with embryonic and hematopoietic characteristics. Exp Cell Res. 2006; 312: 2454-2464 [DOI: S0014-4827(06)00155-8 [pii]10.1016/j.yexcr.2006.04.008].
21. Murohara T. Therapeutic vasculogenesis using human cord blood-derived endothelial progenitors. Trends Cardiovasc Med. 2001; 11: 303-307 [DOI: S1050173801001281 [pii]
22. Brusko T, Atkinson M. Treg in type 1 diabetes. Cell Biochem Biophys. 2007; 48: 165-175 [DOI: CBB:48:2-3:165 [pii].
22a.Marek-Trzonkowska N, Mysliwec M, Siebert J, et al. Clinical ´ application of regulatory T cells in type 1 diabetes. Pediatr Diabetes. 2013: 14:322–332.
23. Romanov YA, Svintsitskaya VA, Smirnov VN. Searching for alternative sources of postnatal human mesenchymal stem cells: Candidate msc-like cells from umbilical cord. Stem Cells. 2003; 21: 105-110 [DOI: 10.1634/stem cells.21-1-105].
24. Li XY, Zheng ZH, Guo J, et al. Treatment of foot disease in patients with type 2 diabetes mellitus using human umbilical cord blood mesenchymal stem cells: Response and correction of immunological anomalies. Curr Pharm Des. 2013; 19: 4893-4899 [DOI: CPD-EPUB-20130122-1 [pii].
25. Kamolz LP, Kolbus A, Wick N, et al. Cultured human epithelium: Human umbilical cord blood stem cells differentiate into keratinocytes under in vitro conditions. Burns. 2006; 32: 16-19 [DOI: S0305-4179(05)00243-3 [pii]10.1016/j.burns.2005.08.020].
26. Kong KY, Ren J, Kraus M, et al. Human umbilical cord blood cells differentiate into muscle in sjl muscular dystrophy mice. Stem Cells. 2004; 22: 981-993 [DOI: 22/6/981 [pii]10.1634/stemcells.22-6-981].
27. Banerjee M, Kanitkar M, Bhonde RR. Approaches towards endogenous pancreatic regeneration. Rev Diabet Stud. 2005; 2: 165-176 [PMID: 1783561 DOI: 10.1900/RDS.2005.2.165].
28. Denner L, Bodenburg Y, Zhao JG, et al. Directed engineering of umbilical cord blood stem cells to produce c-peptide and insulin. Cell Prolif. 2007; 40: 367-380 [DOI: CPR439 [pii]10.1111/j.1365-2184.2007.00439.x].
29. Sun B, Roh KH, Lee SR, et al. Induction of human umbilical cord blood-derived stem cells with embryonic stem cell phenotypes into insulin producing islet-like structure. Biochem Biophys Res Commun. 2007; 354: 919-923 [DOI: S0006-291X(07)00110-6 [pii]10.1016/j.bbrc.2007.01.069].
30. Gao F, Wu DQ, Hu YH, Jin GX, et al. In vitro cultivation of islet-like cell clusters from human umbilical cord blood-derived mesenchymal stem cells. Transl Res. 2008; 151: 293-302 [DOI: S1931-5244(08)00095-9 [pii]10.1016/j.trsl.2008.03.003].
31. Parekh VS, Joglekar MV, Hardikar AA. Differentiation of human umbilical cord blood-derived mononuclear cells to endocrine pancreatic lineage. Differentiation. 2009; 78: 232-240 [DOI: S0301-4681(09)00085-1[pii]10.1016/j.diff.2009.07.004].
32. Romanov YA, Vtorushina VV, Dugina TN, et al. N.V., Human umbilical cord blood serum/plasma: cytokine profile and prospective application in regenerative medicine, Bull Exp Biol. Med. 2019;168:173-177.
33. 33. Ende N, Chen R, Mack R. NOD/ltj type 1 diabetes in mice and the effect of stem cells (Berashis) derived from human umbilical cord blood. J Med. 2002; 33: 181-187.
34. 34 Ende N, Chen R, Reddi AS. Effect of human umbilical cord blood cells on glycemia and insulitis in type 1 diabetic mice. Biochem Biophys Res Commun. 2004; 325: 665-669 [DOI: S0006-291X(04)02429-5 [pii]10.1016/j.bbrc.2004.10.091].
35. Ende N, Chen R, Reddi AS. Transplantation of human umbilical cord blood cells improves glycemia and glomerular hypertrophy in type 2 diabetic mice. Biochem Biophys Res Commun. 2004; 321: 168-171 [DOI:
36. Zhang F-T, Wan H-J, Ye J, et al.. Therapeutic effect of human umbilical cord blood cells on diabetic mice. Cell Res. 2008; 18: 148.
37. Zhao Y, Lin B, Darflinger R, et al. Human cord blood stem cell-modulated regulatory t lymphocytes reverse the autoimmune-caused type 1 diabetes in nonobese diabetic (nod) mice. PLoS One. 2009; 4: e4226 [PMID: 2627485 DOI: 10.1371/journal.pone.0004226].
38. Hasein, M.A., Attia, F.M., Awad, M.M.E. et al. Effect of human umbilical cord blood CD34+ progenitor cells transplantation in diabetic mice. Int J Diabetes Dev Ctries. 31: 113–117 (2011).
https://doi.org/10.1007/s13410-011-0024-4.
39. 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 [PMID: 3404952 DOI: 1423-0127-19-47 [pii]10.1186/1423-0127-19-47].
40. Xiao N, Zhao X, Luo P, et al. Co-transplantation of mesenchymal stromal cells and cord blood cells in treatment of diabetes. Cytotherapy. 2013; 15: 1374-1384 [DOI: S1465-3249(13)00597-5 [pii]10.1016/j.jcyt.2013.06.013].
41. El-Mesallamy HO, Diab MR, Hamdy NM, et al. Cell-based regenerative strategies for treatment of diabetic skin wounds, a comparative study between human umbilical cord blood-mononuclear cells and calves' blood haemodialysate. PLoS One. 2014; 9: e89853 [PMID: 3958350 DOI:
42. Haller MJ, Viener H-L, Brusko T, et al. Insulin requirements, HbA1c, and stimulated c-peptide following autologous umbilical cord blood transfusion in children with T1D. Diabetes. 2007; 56: Suppl 1:A82.
43. Haller MJ, Viener HL, Wasserfall C, et al. Autologous umbilical cord blood infusion for type 1 diabetes. Exp Hematol. 2008; 36: 710-715 [PMID: 2444031 DOI: S0301-472X(08)00045-3
[pii] 10.1016/j.exphem.2008.01.009.
44. Haller MJ, Wasserfall CH, McGrail KM, et al. Autologous umbilical cord blood transfusion in very young children with type 1 diabetes. Diabetes Care. 2009; 32: 2041-2046 [PMID: 2768209 DOI: dc09-0967 [pii]10.2337/dc09-0967].
45. Bleich D. Umbilical cord blood and type 1 diabetes: A road ahead or dead end? Diabetes Care. 2009; 32: 2138-2139 [PMID: 2768207 DOI: 32/11/2138 [pii]10.2337/dc09-1456].
46. Haller MJ, Wasserfall CH, Hulme MA, et al. Autologous umbilical cord blood transfusion in young children with type 1 diabetes fails to preserve C-peptide. Diabetes Care. 2011 Dec;34(12):2567-2569. DOI: 10.2337/dc11-1406. PMID: 22011412; PMCID: PMC3220832.
47. Haller MJ, Wasserfall CH, Hulme MA, et al. Autologous umbilical cord blood infusion followed by oral docosahexaenoic acid and vitamin D supplementation for C-peptide preservation in children with type 1 diabetes. Biol Blood Marrow Transplant. 2013; 19: 1126-1129 [PMID: 3852705
DOI: S1083-8791(13)00165-1
[pii]10.1016/j.bbmt.2013.04.011].
48. Giannopoulou EZ, Puff R, Beyerlein A, et al. Effect of a single autologous cord blood infusion on beta-cell and immune function in children with new onset type 1 diabetes: a non-randomized, controlled trial. Pediatr Diabetes. 2014: 15:100–109.
49. Zhao Y, Jiang Z, Zhao T, et al. Reversal of type 1 diabetes via islet beta cell regeneration following immune modulation by cord blood-derived multipotent stem cells. BMC Med. 2012; 10: 3 [PMID: 3322343 DOI: 1741-7015-10-3 [pii]10.1186/1741-7015-10-3].
50. Zhao Y, Jiang Z, Zhao T, et al. Targeting insulin resistance in type 2 diabetes via immune modulation of cord blood-derived multipotent stem cells (CB-SCs) in stem cell educator therapy: Phase I/II clinical trial. BMC Med. 2013; 11: 160 [PMID: 3716981 DOI: 1741-7015-11-160 [pii]10.1186/1741-7015-11-160].
51. Tong Q, Duan L, Xu Z, et al. Improved insulin secretion following intrapancreatic UCB transplantation in patients with T2DM. J Clin Endocrinol Metab. 2013; 98: E1501-1504 [DOI: jc.2013-1451
[pii]10.1210/jc.2013-1451].
52. Masoad RE, Ewais MM, Tawfik MK, et al. Effect of mononuclear cells versus pioglitazone on streptozotocin-induced diabetic nephropathy in rats. Pharmacol. Rep. 2012; 64, 1223–1233.
53. Park JH, Hwang I, Hwang SH, et al. Human umbilical cord blood-derived mesenchymal stem cells prevent diabetic renal injury through paracrine action. Diabetes Res Clin Pract. 2012; 98: 465-473
[DOI: S0168-8227(12)00339-7
[pii]10.1016/j.diabres.2012.09.034].
54. Park JH, Park J, Hwang SH, et al. Delayed treatment with human umbilical cord blood-derived stem cells attenuates diabetic renal injury. Transplant Proc. 2012; 44: 1123-1126 [DOI: S0041-1345 (12)00295-3 [pii]
10.1016/j.transproceed.2012.03.044].
55. Chen L, Xiang E, Li C, et al. Umbilical cord-derived mesenchymal stem cells ameliorate nephrocyte injury and proteinuria in a diabetic nephropathy rat model. J Diabetes Res. 2020 Apr 29;2020:8035853. doi: 10.1155/2020/8035853. PMID: 32405507;
56. Xiang E, Han B, Zhang Q, et al. Human umbilical cord-derived mesenchymal stem cells prevent the progression of early diabetic nephropathy through inhibiting inflammation and fibrosis. Stem Cell Res Ther. 2020;11(1):336.
doi: 10.1186/s13287-020-01852-
57. Bhattacharya N. Placental umbilical cord blood transfusion: A new method of treatment of patients with diabetes and microalbuminuria in the background of anemia. Clin Exp Obstet Gynecol. 2006; 33:164-168.
58. Naruse K, Hamada Y, Nakashima E, et al. Therapeutic neovascularization using cord blood-derived endothelial progenitor cells for diabetic neuropathy. Diabetes. 2005;54:1823-1828 [DOI: 54/6/1823 [pii].
59. Kang KS, Kim SW, Oh YH, et al. A 37-year-old spinal cord-injured female patient, transplanted of multipotent stem cells from human uc blood, with improved sensory perception and mobility, both functionally and morphologically: A case study. Cytotherapy. 2005; 7:368-373
[DOI: Q77706775451QH1L
[pii]10.1080/14653240500238160].
60. Park DH, Eve DJ, Chung YG, et al. Regenerative medicine for neurological disorders. Scientific World J. 2010; 10: 470-489 [DOI: 10.1100/tsw.2010.39].
61. Mayer E, Bannert C, Gruber S, et al. Cord blood derived CD4+ CD25 (high) T cells become functional regulatory T cells upon antigen encounter. PLoS One. 2012;7: e29355 [PMID: 3260151
DOI: 10.1371/journal.pone.0029355PONE-D-11-14178 [pii].