Emerging Strategies in Stem Cell Therapy of Type 1 Diabetes Mellitus
Main Article Content
Abstract
The Stem Cell Science promise to cure diabetes remains many years away. There are, however, several advances in the field stemming from new approaches that bring us closer to this target. Early clinical trials demonstrate encouraging outcomes, such as improved glycemic control, insulin independence, and enhanced beta-cell survival. With continued advancements and multidisciplinary collaborations, stem cell therapies could redefine the treatment landscape of T1DM, addressing its root causes and long-term complications. Embryonic stem cells, induced pluripotent stem cells, mesenchymal stem cells and marrow derived stem cells are being differentiated or reprogrammed into islet beta cells. This review focuses on key developments in stem cell differentiation and their impact on diabetic complications such as nephropathy, neuropathy, retinopathy, and cardiovascular diseases. It also examines challenges like scalability, safety, and regulatory hurdles. Additionally, it discusses gene editing with CRISPR-Cas9 and 3D bioprinting for pancreatic tissue synthesis. Direct differentiation into beta cells, immune modulation, tissue repair, and paracrine effects are among the mechanisms being explored.
Keywords:
Type 1 diabetes mellitus, stem cell therapy, embryonic stem cells, iPSCs, MSCs, CRISPR-Cas9, 3D bioprinting, clinical trials, diabetic complications
Article Details
How to Cite
BTERRANI, Elie; SALEH, Gilles; WEHBE, Tarek.
Emerging Strategies in Stem Cell Therapy of Type 1 Diabetes Mellitus.
Medical Research Archives, [S.l.], v. 12, n. 12, jan. 2025.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/6174>. Date accessed: 06 jan. 2025.
doi: https://doi.org/10.18103/mra.v12i12.6174.
Section
Review Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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15- Liu, Q., Zhang, X., Tang, Y., & Zhou, X. (2023). Mesenchymal stem cells repair renal damage in diabetic nephropathy models through paracrine signaling. Journal of Nephrology, 35(5), 1123-1132.
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18- Rezania, A., Bruin, J. E., Arora, P., Rubin, A., et al. (2019). Reversal of diabetes with insulin-producing cells derived in vitro from human pluripotent stem cells. Nature Biotechnology, 37(4), 490-500.
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22- Agulnick AD, Ambruzs DM, Moorman MA, Bhoumik A, et al. 2015. Insulin-producing endocrine cells differentiated in vitro from human embryonic stem cells function in macroencapsulation devices in vivo. Stem Cells Transl Med 4: 1214–1222.
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25- Mansour RN, Barati G, Soleimani M, Ghoraeian P, et al. Generation of high-yield insulin producing cells from human-induced pluripotent stem cells on polyethersulfone nanofibrous scaffold. Artif Cells Nanomed Biotechnol. 2018;46(sup1): 733-739.
26- Abazari MF, Soleimanifar F, Nouri Aleagha M, Torabinejad S, et al. PCL/PVA nanofibrous scaffold improve insulin-producing cells generation from human induced pluripotent stem cells. Gene. 2018 Sep 10;671:50-57.
27- Shen Z, Huang W, Liu J, Tian J, Wang S, Rui K. Effects of Mesenchymal Stem Cell-Derived Exosomes on Autoimmune Diseases.Front Immunol. 2021 Sep 27;12:749192.
28- Madani S, Larijani B, Keshtkar AA, Tootee A. Safety and efficacy of hematopoietic and mesanchymal stem cell therapy for treatment of T1DM: a systematic review and meta-analysis protocol. Syst Rev. 2018 Jan 26;7(1):23.
29- Madani S, Amanzadi M, Aghayan HR, Setudeh A, et al. Investigating the safety and efficacy of hematopoietic and mesenchymal stem cell transplantation for treatment of T1DM: a systematic review and meta-analysis. Syst Rev. 2022 May 2;11(1):82.
30- Hong TW, Caxaria S, Daniels Gatward LF, Hussain S, et al. Mesenchymal stromal cell secretory molecules improve the functional survival of human islets. Diabet Med. 2023 Dec;40 (12):e15227.
31- Salama RAA, Patni MAMF, Ba-Hutair SNM, Wadid NA Exploring Novel Treatment Modalities for Type 1 Diabetes Mellitus: Potential and Prospects. Healthcare (Basel). 2024 Jul 26;12(15):1485.
32- Ahmed OM, Saleh AS, Ahmed EA, Ghoneim MM, et al. Efficiency of Bone Marrow-Derived Mesenchymal Stem Cells and Hesperetin in the Treatment of Streptozotocin-Induced Type 1 Diabetes in Wistar Rats. Pharmaceuticals (Basel). 2023 Jun 8;16(6):859.
33- Zhang Y, Zhang YY, Pan ZW, Li QQ, et al. GDF11 promotes wound healing in diabetic mice via stimulating HIF-1ɑ-VEGF/SDF-1ɑ-mediated endothelial progenitor cell mobilization and neovascularization. Acta Pharmacol Sin. 2023 May;44(5):999-1013.
34- Chellappan DK, Sivam NS, Teoh KX, Leong WP, et al. Gene therapy and type 1 diabetes mellitus. Biomed Pharmacother. 2018 Dec;108:1188-1200.
35- Mohammadi V, Maleki AJ, Nazari M, Siahmansouri A, et al. Chimeric Antigen Receptor (CAR)-Based Cell Therapy for Type 1 Diabetes Mellitus (T1DM); Current Progress and Future Approaches. Stem Cell Rev Rep. 2024 Apr;20 (3):585-600.
36- Gurlin RE, Giraldo JA, Latres E.. 3D Bioprinting and Translation of Beta Cell Replacement Therapies for Type 1 Diabetes. Tissue Eng Part B Rev. 2021 Jun;27(3):238-252.
37- Xu Y, Wang Y, Song Y, Deng J, et al. Generation and Phenotype Identification of PAX4 Gene Knockout Rabbit by CRISPR/Cas9 System. G3 (Bethesda). 2018 Jul 31;8(8):2833-2840.
38- Coombe L, Kadri A, Martinez JF, Tatachar V, et al. Current approaches in regenerative medicine for the treatment of diabetes: introducing CRISPR/CAS9 technology and the case for non-embryonic stem cell therapy. Am J Stem Cells. 2018 Dec 1;7(5):104-113.
39- Ravnic DJ, Leberfinger AN, Ozbolat IT. Bioprinting and Cellular Therapies for Type 1 Diabetes. Trends Biotechnol. 2017 Nov;35 (11):1025-1034.
40- Kumar SA, Delgado M, Mendez VE, Joddar B. Applications of stem cells and bioprinting for potential treatment of diabetes. World J Stem Cells. 2019 Jan 26;11(1):13-32.
41- Salama RAA, Patni MAMF, Ba-Hutair SNM, Wadid NA, et al. Exploring Novel Treatment Modalities for Type 1 Diabetes Mellitus: Potential and Prospects. Healthcare (Basel). 2024 Jul 26;12(15):1485.
42- Izadi M, Sadr Hashemi Nejad A, Moazenchi M, Masoumi S, et al. Mesenchymal stem cell transplantation in newly diagnosed type-1 diabetes patients: a phase I/II randomized placebo-controlled clinical trial. Stem Cell Res Ther. 2022 Jun 20;13(1):264.
43- Al Madhoun A, Koti L, Carrió N, Atari M, et al. Clinical Application of Umbilical Cord Mesenchymal Stem Cells Preserves beta-cells in Type 1 Diabetes. Stem Cells Transl Med. 2024 Feb 14;13(2):101-106.
44- Calafiore R, Basta G. Stem cells for the cell and molecular therapy of type 1 diabetes mellitus (T1D): the gap between dream and reality. Am J Stem Cells. 2015 Mar 15;4(1):22-31.
45- Wszoła M, Nitarska D, Cywoniuk P, Gomółka M, et al. Stem Cells as a Source of Pancreatic Cells for Production of 3D Bioprinted Bionic Pancreas in the Treatment of Type 1 Diabetes. Cells. 2021 Jun 18;10(6):1544.
2. Edelman D, Olsen MK, Dudley TK, Harris AC, Oddone EZ. Utility of hemoglobin A1c in predicting diabetes risk. J Gen Intern Med 2004; 19(12): 1175–1180.
3. Pradhan AD, Rifai N, Buring JE, Ridker PM. Hemoglobin A1c predicts diabetes but not cardiovascular disease in nondiabetic women. Am J Med 2007; 120(8): 720–727.
4. Sylva P. Type 1 Diabetes and its Complications. Global Journal of Life Sciences and Biological Research. Commentary - (2022) Volume 8, Issue 2
5. DCCT Research Group: Effect of intensive diabetes treatment on the development and progression of long-term complications in adolescents with insulin-dependent diabetes mellitus: Diabetes Control and Complications Trial: Diabetes Control and Complications Trial Research Group. J Pediatr 1994, 125:177–188.
6. Ahern JA, Wesche J, Strand T, et al.: The impact of the trial coordinator in the Diabetes Control and Complications Trial (DCCT): The DCCT Research Group. Diabetes Educ 1993, 19:509–512.
7. Brink SJ: How to apply the experience from the diabetes control and complications trial to children and adolescents? Ann Med 1997, 29:425–438.
8- Wan XX, Zhang DY, Khan MA, Zheng SY, et al. Stem Cell Transplantation in the Treatment of Type 1 Diabetes Mellitus: From Insulin Replacement to Beta-Cell Replacement. Front Endocrinol (Lausanne). 2022 Mar 18;13:859638.
9- Plotnikoff RC, Taylor LM, Wilson PM, et al. Factors associated with physical activity in Canadian adults with diabetes. Med Sci Sports Exerc. 2006;38:1526–34.
10- Brazeau AS, Rabasa-Lhoret R, Strychar I, et al. Barriers to physical activity among patients with type 1 diabetes. Diabetes Care. 2008;31:2108–9.
11- Wallace TM, Matthews DR. Recent advances in the monitoring and management of diabetic ketoacidosis. QJM. 2004;97:773–80.
12- Bhansali, A., Kumar, V., Saikia, U. N., Sharma, R. R., Gupta, V., Jain, A., & Marwaha, R. K. (2020). Efficacy and safety of autologous bone marrow-derived stem cell transplantation in patients with type 1 diabetes mellitus. Stem Cell Research & Therapy, 11(1), 56.
13- Gao, L., Zhang, Y., Hu, L., Xu, C., Wang, L., & Zhao, Y. (2020). Mesenchymal stem cell transplantation improves β-cell function in type 1 diabetes mellitus. Stem Cells Translational Medicine, 9(8), 967-974.
14- Kim, J., Kim, H., Jo, M., & Park, S. (2023). CRISPR-Cas9-mediated gene correction in iPSCs for the treatment of type 1 diabetes. Nature Biotechnology, 41(3), 401-410.
15- Liu, Q., Zhang, X., Tang, Y., & Zhou, X. (2023). Mesenchymal stem cells repair renal damage in diabetic nephropathy models through paracrine signaling. Journal of Nephrology, 35(5), 1123-1132.
16- Pagliuca, F. W., Millman, J. R., Gürtler, M., Segel, M., et al. (2018). Generation of functional human pancreatic beta cells in vitro. Nature Biotechnology, 36(4), 359-364.
17- Patel, M., Shah, S., & Bhatia, D. (2022). Therapeutic potential of MSC-derived exosomes in diabetic retinopathy. Cellular Therapy, 38(7), 554-563.
18- Rezania, A., Bruin, J. E., Arora, P., Rubin, A., et al. (2019). Reversal of diabetes with insulin-producing cells derived in vitro from human pluripotent stem cells. Nature Biotechnology, 37(4), 490-500.
19- Shaw, A. C., Joshi, S., & Krause, D. S. (2020). Correction of INS gene mutations using CRISPR/Cas9 to restore insulin production in human iPSCs. Cell Reports Medicine, 2(2), 100233.
20- Wang, W., Qian, D., & Zhang, L. (2021). Sustained C-peptide production from encapsulated human embryonic stem cell-derived beta cells in patients with type 1 diabetes. Diabetes Care, 44(6), 1416-1424.
21- Nguyen, D., Huynh, L., & Tran, P. (2022). Application of 3D bioprinted pancreatic tissue constructs in treating Type 1 Diabetes Mellitus. Bioengineering & Translational Medicine, 7(3), e10245.
22- Agulnick AD, Ambruzs DM, Moorman MA, Bhoumik A, et al. 2015. Insulin-producing endocrine cells differentiated in vitro from human embryonic stem cells function in macroencapsulation devices in vivo. Stem Cells Transl Med 4: 1214–1222.
23- Alagpulinsa DA, Cao JJL, Driscoll RK, Sirbulescu RF, et al. 2019. Alginate-microencapsulation of human stem cell-derived β cells with CXCL12 prolongs their survival and function in immunocompetent mice without systemic immunosuppression. Am J Transplant 19: 1930–1940.
24- Bai C, Ren Q, Liu H, Li X, Guan W, Gao Y. miR-212/132-Enriched Extracellular Vesicles Promote Differentiation of Induced Pluripotent Stem Cells Into Pancreatic Beta Cells. Front Cell Dev Biol. 2021 May 13;9:673231.
25- Mansour RN, Barati G, Soleimani M, Ghoraeian P, et al. Generation of high-yield insulin producing cells from human-induced pluripotent stem cells on polyethersulfone nanofibrous scaffold. Artif Cells Nanomed Biotechnol. 2018;46(sup1): 733-739.
26- Abazari MF, Soleimanifar F, Nouri Aleagha M, Torabinejad S, et al. PCL/PVA nanofibrous scaffold improve insulin-producing cells generation from human induced pluripotent stem cells. Gene. 2018 Sep 10;671:50-57.
27- Shen Z, Huang W, Liu J, Tian J, Wang S, Rui K. Effects of Mesenchymal Stem Cell-Derived Exosomes on Autoimmune Diseases.Front Immunol. 2021 Sep 27;12:749192.
28- Madani S, Larijani B, Keshtkar AA, Tootee A. Safety and efficacy of hematopoietic and mesanchymal stem cell therapy for treatment of T1DM: a systematic review and meta-analysis protocol. Syst Rev. 2018 Jan 26;7(1):23.
29- Madani S, Amanzadi M, Aghayan HR, Setudeh A, et al. Investigating the safety and efficacy of hematopoietic and mesenchymal stem cell transplantation for treatment of T1DM: a systematic review and meta-analysis. Syst Rev. 2022 May 2;11(1):82.
30- Hong TW, Caxaria S, Daniels Gatward LF, Hussain S, et al. Mesenchymal stromal cell secretory molecules improve the functional survival of human islets. Diabet Med. 2023 Dec;40 (12):e15227.
31- Salama RAA, Patni MAMF, Ba-Hutair SNM, Wadid NA Exploring Novel Treatment Modalities for Type 1 Diabetes Mellitus: Potential and Prospects. Healthcare (Basel). 2024 Jul 26;12(15):1485.
32- Ahmed OM, Saleh AS, Ahmed EA, Ghoneim MM, et al. Efficiency of Bone Marrow-Derived Mesenchymal Stem Cells and Hesperetin in the Treatment of Streptozotocin-Induced Type 1 Diabetes in Wistar Rats. Pharmaceuticals (Basel). 2023 Jun 8;16(6):859.
33- Zhang Y, Zhang YY, Pan ZW, Li QQ, et al. GDF11 promotes wound healing in diabetic mice via stimulating HIF-1ɑ-VEGF/SDF-1ɑ-mediated endothelial progenitor cell mobilization and neovascularization. Acta Pharmacol Sin. 2023 May;44(5):999-1013.
34- Chellappan DK, Sivam NS, Teoh KX, Leong WP, et al. Gene therapy and type 1 diabetes mellitus. Biomed Pharmacother. 2018 Dec;108:1188-1200.
35- Mohammadi V, Maleki AJ, Nazari M, Siahmansouri A, et al. Chimeric Antigen Receptor (CAR)-Based Cell Therapy for Type 1 Diabetes Mellitus (T1DM); Current Progress and Future Approaches. Stem Cell Rev Rep. 2024 Apr;20 (3):585-600.
36- Gurlin RE, Giraldo JA, Latres E.. 3D Bioprinting and Translation of Beta Cell Replacement Therapies for Type 1 Diabetes. Tissue Eng Part B Rev. 2021 Jun;27(3):238-252.
37- Xu Y, Wang Y, Song Y, Deng J, et al. Generation and Phenotype Identification of PAX4 Gene Knockout Rabbit by CRISPR/Cas9 System. G3 (Bethesda). 2018 Jul 31;8(8):2833-2840.
38- Coombe L, Kadri A, Martinez JF, Tatachar V, et al. Current approaches in regenerative medicine for the treatment of diabetes: introducing CRISPR/CAS9 technology and the case for non-embryonic stem cell therapy. Am J Stem Cells. 2018 Dec 1;7(5):104-113.
39- Ravnic DJ, Leberfinger AN, Ozbolat IT. Bioprinting and Cellular Therapies for Type 1 Diabetes. Trends Biotechnol. 2017 Nov;35 (11):1025-1034.
40- Kumar SA, Delgado M, Mendez VE, Joddar B. Applications of stem cells and bioprinting for potential treatment of diabetes. World J Stem Cells. 2019 Jan 26;11(1):13-32.
41- Salama RAA, Patni MAMF, Ba-Hutair SNM, Wadid NA, et al. Exploring Novel Treatment Modalities for Type 1 Diabetes Mellitus: Potential and Prospects. Healthcare (Basel). 2024 Jul 26;12(15):1485.
42- Izadi M, Sadr Hashemi Nejad A, Moazenchi M, Masoumi S, et al. Mesenchymal stem cell transplantation in newly diagnosed type-1 diabetes patients: a phase I/II randomized placebo-controlled clinical trial. Stem Cell Res Ther. 2022 Jun 20;13(1):264.
43- Al Madhoun A, Koti L, Carrió N, Atari M, et al. Clinical Application of Umbilical Cord Mesenchymal Stem Cells Preserves beta-cells in Type 1 Diabetes. Stem Cells Transl Med. 2024 Feb 14;13(2):101-106.
44- Calafiore R, Basta G. Stem cells for the cell and molecular therapy of type 1 diabetes mellitus (T1D): the gap between dream and reality. Am J Stem Cells. 2015 Mar 15;4(1):22-31.
45- Wszoła M, Nitarska D, Cywoniuk P, Gomółka M, et al. Stem Cells as a Source of Pancreatic Cells for Production of 3D Bioprinted Bionic Pancreas in the Treatment of Type 1 Diabetes. Cells. 2021 Jun 18;10(6):1544.