Islet Like Cells Induced from Umbilical Cord Mesenchymal Stem Cells with Neonatal Bovine Pancreatic Mesenchymal Exosomes for Treatment of Diabetes Mellitus

Abstract

To investigate the safety and efficacy of the islet-like cell (cell) induced from human umbilical cord mesenchymal stem cell (UCMSC) with different methods for the treatment of diabetic animal model. UCMSCs were induced to βcells with cytokines (CY) and neonatal bovine pancreatic mesenchymal cell exosomes (Ex) combined with CY (EX+CY). The insulin secretion of UCMSC and βcell was measured with ELISA when the cells were growing in different concentrations of glucose media for different times. UCMSCs (4×105) and the same number of cells prepared with two methods were transplanted to type I diabetic rat models. UCMSCs could be induced into islet βcells by CY or EX+CY in vitro. The insulin secretion of the prepared β cells growing in 25.0 mM glucose medium was over 5-fold of that in 6.0 mM glucose. The transplantation of the βcells to type I diabetic rat models could reduce the blood glucose and prolong the survival time. The β cells induced by EX+CY had much more significant effects on decreasing blood glucose and increasing survival time (p<0.01). The cells did not affect blood sugar level and had no serious side-effects in human health. UCMSC could be induced to islet βcells with either CY or EX+CY. The transplantation of the induced islet βcells could reduce blood glucose and prolong the survival time of diabetic animal models. Although the cells induced with EX+CY had more significant effects on diabetic rats, they did not affect blood glucose level and had no serious side-effects in human health.

Key words

diabetes mellitus - human umbilical cord mesenchymal stem cell - islet β cell - neonate bovine pancreatic mesenchymal exosomes

Publication History

Received: 23 July 2023

Accepted after revision: 28 August 2023

Article published online:
13 October 2023

• References

• 1 Zheng Y, Ley SH, Hu FB. Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat Rev Endocrinol 2018; 4: 88-98
• 2 Li Y, He C, Liu R, Xiao Z. et al. Stem cells therapy for diabetes: from past to future. Cytotherapy 2023; 29: S1465-S3249
• 3 Ghoneim MA, Refaie AF, Elbassiouny BL. et al. From mesenchymal stromal/stem cells to insulin-producing cells: progress and challenges. Stem Cell Rev Rep 2020; 16: 1156-1172
• 4 Carlsson PO, Espes D, Sisay S. et al. Umbilical cord-derived mesenchymal stromal cells preserve endogenous insulin production in type 1 diabetes: a Phase I/II randomised double-blind placebo-controlled trial. Diabetologia 2023; 66: 1431-1441
• 5 Jiang H, Jiang FX. Human pluripotent stem cell-derived β cells: Truly immature islet β cells for type 1 diabetes therapy?. World J Stem Cells 2023; 26: 182-195
• 6 Zhoujun Z, Bingzheng F, Yuwei Y. et al. Transplantation of insulin-producing cells derived from human MSCs to treat diabetes in a non-human primate model. Artif Organs 2023;
• 7 Gomes A, Coelho P, Soares R. et al. Human umbilical cord mesenchymal stem cells in type 2 diabetes mellitus: the emerging therapeutic approach. Cell Tissue Res 2021; 385: 497-518
• 8 Markov A, Thangavelu L, Aravindhan S. et al. Mesenchymal stem/stromal cells as a valuable source for the treatment of immune-mediated disorders. Stem Cell Res Ther 2021; 12: 192
• 9 Brown C, McKee C, Bakshi S. et al. Mesenchymal stem cells: Cell therapy and regeneration potential. J Tissue Eng Regen Med 2019; 13: 1738-1755
• 10 Gerace D, Ren B, Martiniello-Wilks R, Simpson AM. High-efficiency lentiviral gene modification of primary murine bone-marrow mesenchymal stem cells. Methods Mol Biol 2019; 197-214
• 11 van Gurp L, Fodoulian L, Oropeza D. et al. Generation of human islet cell type-specific identity genesets. Nat Commun 2022; 13: 2020
• 12 Maxwell KG, Millman JR. Applications of iPSC-derived beta cells from patients with diabetes. Cell Rep Med 2021; 2: 100238
• 13 Melton D. The promise of stem cell-derived islet replacement therapy. Diabetologia 2021; 64: 1030-1036
• 14 Amirruddin NS, Low BSJ, Lee KO. et al. New insights into human beta cell biology using human pluripotent stem cells. Semin Cell Dev Biol 2020; 103: 31-40
• 15 Abuarqoub D, Adwan S, Zaza R. et al. Effective generation of functional pancreatic β cells from human-derived dental stem cells of apical papilla and bone-marrow-derived stem cells: a comparative study. Pharmaceuticals (Basel) 2023; 16: 649
• 16 Hald J, Galbo T, Rescan C. et al. Pancreatic islet and progenitor cell surface markers with cell sorting potential. Diabetologia 2012; 55: 154-165
• 17 Moazenchi M, Sadr Hashemi Nejad A, Izadi M. et al. Comparative study of the effects of confounding factors on improving rat pancreatic islet isolation yield and quality. Cell J 2022; 24: 491-499
• 18 De Paep DL, Van Hulle F, Ling Z. et al. Utility of islet cell preparations from donor pancreases after euthanasia. Cell Transplant 2022; 31: 9636897221096160
• 19 Abuarqoub D, Adwan S, Zaza R. et al. Effective generation of functional pancreatic β cells from human-derived dental stem cells of apical papilla and bone-marrow-derived stem cells: a comparative study. Pharmaceuticals (Basel) 2023; 16: 649
• 20 Bhonde RR, Sheshadri P, Sharma S. et al. Making surrogate β like cells from mesenchymal stromal cells: perspectives and future endeavors. Int J Biochem Cell Biol 2014; 46: 90-102
• 21 Millman JR, Pagliuca FW. Autologous pluripotent stem cell-derived β-like cells for diabetes cellular therapy. Diabetes 2017; 66: 1111-1120
• 22 Li X, Wei Z, Wu L. et al. Efficacy of Fe₃O₄@polydopamine nanoparticle-labeled human umbilical cord Wharton’s jelly-derived mesenchymal stem cells in the treatment of streptozotocin-induced diabetes in rats. Biomater Sci 2020; 8: 5362-5375
• 23 Sarang S, Viswanathan C. Umbilical cord derived mesenchymal stem cells useful in insulin production - another opportunity in cell therapy. Int J Stem Cells 2016; 9: 60-69
• 24 Zhou Z, Zhu X, Huang H. et al. Recent progress of research regarding the applications of stem cells for treating diabetes mellitus. Stem Cells Dev 2022; 31: 102-110
• 25 Takahashi H, Sakata N, Yoshimatsu G. et al. Regenerative and transplantation medicine: cellular therapy using adipose tissue-derived mesenchymal stromal cells for type 1 diabetes mellitus. J Clin Med 2019; 8: 249
• 26 Wang Z, Li H, Fang J. et al. Comparative analysis of the therapeutic effects of amniotic membrane and umbilical cord derived mesenchymal stem cells for the treatment of type 2 diabetes. Stem Cell Rev Rep 2022; 18: 1193-1206
• 27 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
• 28 Zhao N, Gao YF, Bao L. et al. Glycemic control by umbilical cord-derived mesenchymal stem cells promotes effects of fasting-mimicking diet on type 2 diabetic mice. Stem Cell Res Ther 2021; 12: 395
• 29 Ma Y, Wang L, Yang S. et al. The tissue origin of human mesenchymal stem cells dictates their therapeutic efficacy on glucose and lipid metabolic disorders in type II diabetic mice. Stem Cell Res Ther 2021; 12: 385