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Therapy of chronic skin ulcers in patients with diabetes mellitus using gene modifications of cell transplant

https://doi.org/10.14341/DM13215

Abstract

In patients with diabetes mellitus (DM), systemic disorders in the body can cause a number of complications. One of the main complications is the disruption of wound healing processes, which can lead to the development of a diabetic foot ulcer (DFU) and subsequent amputation of the limb. Modified mesenchymal stem cells (GM-MSCs) - as a means of treating chronic wounds, reduce homing, have increased proliferative potential, therapeutic antitumor and pancreas-supporting properties. Native and genetically modified cells from allogeneic or autologous sources are studied for the treatment of DFU. The review presents the world experience of using stem cells in therapy in preclinical and clinical studies, collects data on the proposed technologies for the treatment of diabetic ulcers using GM-MSCs: combined transplantation of GM-MSCs with pancreatic islets, regulation of migration processes by changing the expression of integrins, blocking estrogen signals, increased expression of a number of genes, such as SDF-1α, c-JUN, MALAT1, to increase the viability and stimulate the proliferation of mesenchymal stem cells. Cells temporarily carrying therapeutic genetically engineered constructs show high efficiency of their use in preclinical trials.

About the Authors

E. V. Abakushina
Tecon MP LLC; Endocrinology Research Centre
Russian Federation

Elena V. Abakushina - MD, PhD; ResearcherID: O-6947-2014; Scopus Author ID: 15844847700.

11 Dm. Ulyanov street, 117292 Moscow


Competing Interests:

none



I. G. Vorobyova
Tecon MP LLC
Russian Federation

Iva G. Vorobyova - PhD in Biology, senior researcher.

Moscow


Competing Interests:

none



I. A. Stepanova
Tecon MP LLC; Endocrinology Research Centre
Russian Federation

Irina A. Stepanova - PhD in Biology, researcher; ResearcherID: U-5075-2018; Scopus Author ID: 56086276200.

Moscow


Competing Interests:

none



S. A. Roumiantsev
Endocrinology Research Centre
Russian Federation

Sergey A. Roumiantsev - MD, PhD, Professor ResearcherID: L-1428-2018; Scopus Author ID: 6506470384.

Moscow


Competing Interests:

none



References

1. Armstrong DG, Boulton AJM, Bus SA. Diabetic Foot Ulcers and Their Recurrence. N Engl J Med. 2017;376(24):2367-2375. https://www.nejm.org/doi/10.1056/NEJMra1615439

2. Liu J, Ding Y, Liu Z, Liang X. Senescence in Mesenchymal Stem Cells: Functional Alterations, Molecular Mechanisms, and Rejuvenation Strategies. Front Cell Dev Biol. 2020;8:258. https://doi.org/10.3389/fcell.2020.00258

3. Hanefeld M, Duetting E, Bramlage P. Cardiac implications of hypoglycemia in patients with diabetes - a systematic review. Cardiovasc Diabetol. 2013;12:135. doi: 10.1186/1475-2840-12-135.

4. Skrepnek GH, Mills JL Sr, Armstrong DG. A Diabetic Emergency One Million Feet Long: Disparities and Burdens of Illness among Diabetic Foot Ulcer Cases within Emergency Departments in the United States, 2006-2010. PLoS One. 2015;10(8):e0134914. https://doi.org/10.1371/journal.pone.0134914.

5. Shao J, Zhang W, Yang T. Using mesenchymal stem cells as a therapy for bone regeneration and repairing. Biol Res. 2015;48:62. https://doi.org/10.1186/s40659-015-0053-4

6. Najar M, Melki R, Khalife F, Lagneaux L, Bouhtit F, Moussa Agha D, Fahmi H, Lewalle P, Fayyad-Kazan M, Merimi M. Therapeutic Mesenchymal Stem/Stromal Cells: Value, Challenges and Optimization. Front Cell Dev Biol. 2022;9:716853. https://doi.org/10.3389/fcell.2021.716853

7. Otero-Viñas M, Falanga V. Mesenchymal Stem Cells in Chronic Wounds: The Spectrum from Basic to Advanced Therapy. Adv Wound Care (New Rochelle). 2016;5(4):149-163. https://doi.org/10.1089/wound.2015.0627

8. Rivas-Santiago B, Trujillo V, Montoya A, Gonzalez-Curiel I, Castañeda-Delgado J, Cardenas A, Rincon K, Hernandez ML, Hernández-Pando R. Expression of antimicrobial peptides in diabetic foot ulcer. J Dermatol Sci. 2012;65(1):19-26. https://doi.org/10.1016/j.jdermsci.2011.09.013

9. Rahavi H, Hashemi SM, Soleimani M, Mohammadi J, Tajik N. Adipose tissue-derived mesenchymal stem cells exert in vitro immunomodulatory and beta cell protective functions in streptozotocin-induced diabetic mice model. J Diabetes Res. 2015; 2015:878535. https://doi.org/10.1155/2015/878535

10. Sriram G, Bigliardi PL, Bigliardi-Qi M. Fibroblast heterogeneity and its implications for engineering organotypic skin models in vitro. Eur J Cell Biol. 2015;94(11):483-512. https://doi.org/10.1016/j.ejcb.2015.08.001

11. Warsinske HC, Ashley SL, Linderman JJ, Moore BB, Kirschner DE. Identifying Mechanisms of Homeostatic Signaling in Fibroblast Differentiation. Bull Math Biol. 2015;77(8):1556-82. https://doi.org/10.1007/s11538-015-0096-2

12. Tang QL, Han SS, Feng J, Di JQ, Qin WX, Fu J, Jiang QY. Moist exposed burn ointment promotes cutaneous excisional wound healing in rats involving VEGF and bFGF. Mol Med Rep. 2014;9(4):1277-82. https://doi.org/10.3892/mmr.2014.1921

13. Gentile P., Casella D., Palma E., Calabrese C., J. Clin. Med. 2019;12(8). doi:10.3390/jcm8040504

14. Cassidy FC, Shortiss C, Murphy CG, Kearns SR, Curtin W, De Buitléir C, O'Brien T, Coleman CM. Impact of Type 2 Diabetes Mellitus on Human Bone Marrow Stromal Cell Number and Phenotypic Characteristics. Int J Mol Sci. 2020;21(7):2476. https://doi.org/10.3390/ijms21072476

15. Moll G, Alm JJ, Davies LC, von Bahr L, Heldring N, Stenbeck-Funke L, Hamad OA, Hinsch R, Ignatowicz L, Locke M, Lönnies H, Lambris JD, Teramura Y, Nilsson-Ekdahl K, Nilsson B, Le Blanc K. Do cryopreserved mesenchymal stromal cells display impaired immunomodulatory and therapeutic properties? Stem Cells. 2014;32(9):2430-42. https://doi.org/10.1002/stem.1729

16. López-García L, Castro-Manrreza ME. TNF-α and IFN-γ Participate in Improving the Immunoregulatory Capacity of Mesenchymal Stem/Stromal Cells: Importance of Cell-Cell Contact and Extracellular Vesicles. Int J Mol Sci. 2021;22(17):9531. https://doi.org/10.3390/ijms22179531

17. Fukumoto R. Mesenchymal stem cell therapy for acute radiation syndrome. Mil Med Res. 2016;3:17. https://doi.org/10.1186/s40779-016-0086-1

18. Krampera M, Galipeau J, Shi Y, Tarte K, Sensebe L; MSC Committee of the International Society for Cellular Therapy (ISCT). Immunological characterization of multipotent mesenchymal stromal cells--The International Society for Cellular Therapy (ISCT) working proposal. Cytotherapy. 2013;15(9):1054-61. https://doi.org/10.1016/j.jcyt.2013.02.010

19. Joswig AJ, Mitchell A, Cummings KJ, Levine GJ, Gregory CA, Smith R 3rd, Watts AE. Repeated intra-articular injection of allogeneic mesenchymal stem cells causes an adverse response compared to autologous cells in the equine model. Stem Cell Res Ther. 2017;8(1):42. https://doi.org/10.1186/s13287-017-0503-8

20. Lourenco S, Teixeira VH, Kalber T, Jose RJ, Floto RA, Janes SM. Macrophage migration inhibitory factor-CXCR4 is the dominant chemotactic axis in human mesenchymal stem cell recruitment to tumors. J Immunol. 2015;194(7):3463-74. https://doi.org/10.4049/jimmunol.1402097

21. Carraro A, Trevellin E, Fassan M, Kotsafti A, Lunardi F, Porzionato A, Dall'Olmo L, Cagol M, Alfieri R, Macchi V, Tedeschi U, Calabrese F, Rugge M, Castoro C, Vettor R, Scarpa M. Esophageal adenocarcinoma microenvironment: Peritumoral adipose tissue effects associated with chemoresistance. Cancer Sci. 2017;108(12):2393-2404. https://doi.org/10.1111/cas.13415

22. Segers VF, Van Riet I, Andries LJ, Lemmens K, Demolder MJ, De Becker AJ, Kockx MM, De Keulenaer GW. Mesenchymal stem cell adhesion to cardiac microvascular endothelium: activators and mechanisms. Am J Physiol Heart Circ Physiol. 2006;290(4):H1370-7. https://doi.org/10.1152/ajpheart.00523.2005

23. Jabłońska-Trypuć A, Matejczyk M, Rosochacki S. Matrix metalloproteinases (MMPs), the main extracellular matrix (ECM) enzymes in collagen degradation, as a target for anticancer drugs. J Enzyme Inhib Med Chem. 2016;31(sup1): 177-183. https://doi.org/10.3109/14756366.2016.1161620

24. Sheng H, Wang Y, Jin Y, Zhang Q, Zhang Y, Wang L, Shen B, Yin S, Liu W, Cui L, Li N. A critical role of IFNgamma in priming MSC-mediated suppression of T cell proliferation through up-regulation of B7-H1. Cell Res. 2008;18(8):846-57. https://doi.org/10.1038/cr.2008.80

25. Barros JF, Waclawiak I, Pecli C, Borges PA, Georgii JL, Ramos-Junior ES, Canetti C, Courau T, Klatzmann D, Kunkel SL, Penido C, Canto FB, Benjamim CF. Role of Chemokine Receptor CCR4 and Regulatory T Cells in Wound Healing of Diabetic Mice. J Invest Dermatol. 2019;139(5):1161-1170. https://doi.org/10.1016/j.jid.2018.10.039

26. Du J, Liu A, Zhu R, Zhou C, Su H, Xie G, Deng Y, Xu X. The Different Effects of IFN-β and IFN-γ on the Tumor-Suppressive Activity of Human Amniotic Fluid-Derived Mesenchymal Stem Cells. Stem Cells Int. 2019;2019: 4592701. https://doi.org/10.1155/2019/4592701

27. Ahn Jo, Lee Hw, Seo Kw, Kang Sk, Ra Jc, Youn Hy. Anti-tumor effect of adipose tissue derived-mesenchymal stem cells expressing interferon-β and treatment with cisplatin in a xenograft mouse model for canine melanoma. PLoS One. 2013;8(9): e74897. https://doi.org/10.1371/journal.pone.0074897

28. Yang X, Du J, Xu X, Xu C, Song W. IFN-γ-secreting-mesenchymal stem cells exert an antitumor effect in vivo via the TRAIL pathway. J Immunol Res. 2014;2014:318098. https://doi.org/10.1155/2014/318098

29. Hörnle M, Peters N, Thayaparasingham B, Vörsmann H, Kashkar H, Kulms D. Caspase-3 cleaves XIAP in a positive feedback loop to sensitize melanoma cells to TRAIL-induced apoptosis. Oncogene. 2011;30(5):575-87. https://doi.org/10.1038/onc.2010.434

30. Yang ZS, Tang XJ, Guo XR, Zou DD, Sun XY, Feng JB, Luo J, Dai LJ, Warnock GL. Cancer cell-oriented migration of mesenchymal stem cells engineered with an anticancer gene (PTEN): an imaging demonstration. Onco Targets Ther. 2014;7: 441-6. https://doi.org/10.2147/OTT.S59227

31. Guo XR, Hu QY, Yuan YH, Tang XJ, Yang ZS, Zou DD, Bian LJ, Dai LJ, Li DS. PTEN-mRNA engineered mesenchymal stem cell-mediated cytotoxic effects on U251 glioma cells. Oncol Lett. 2016;11(4):2733-2740. https://doi.org/10.3892/ol.2016.4297

32. Etich J, Bergmeier V, Pitzler L, Brachvogel B. Identification of a reference gene for the quantification of mRNA and miRNA expression during skin wound healing. Connect Tissue Res. 2017;58(2):196-207. https://doi.org/10.1080/03008207.2016.1210606

33. Yue C, Guo Z, Luo Y, Yuan J, Wan X, Mo Z. c-Jun Overexpression Accelerates Wound Healing in Diabetic Rats by Human Umbilical Cord-Derived Mesenchymal Stem Cells. Stem Cells Int. 2020;2020:7430968. https://doi.org/10.1155/2020/7430968

34. Laiva AL, O'Brien FJ, Keogh MB. SDF-1α Gene-Activated Collagen Scaffold Restores Pro-Angiogenic Wound Healing Features in Human Diabetic Adipose-Derived Stem Cells. Biomedicines. 2021;9(2):160. https://doi.org/10.3390/biomedicines9020160

35. Sun X., Luo L., Li J. Cell Cycle. 2020 Nov. V. 19. P. 3018. Sun X, Luo L, Li J. LncRNA MALAT1 facilitates BM-MSCs differentiation into endothelial cells via targeting miR-206/VEGFA axis. Cell Cycle. 2020;19(22):3018-3028. https://doi.org/10.1080/15384101.2020.1829799

36. Zhu J, Luo Y, Zhao Y, Kong Y, Zheng H, Li Y, Gao B, Ai L, Huang H, Huang J, Li Z, Chen C. circEHBP1 promotes lymphangiogenesis and lymphatic metastasis of bladder cancer via miR-130a-3p/TGFβR1/VEGF-D signaling. Mol Ther. 2021;29(5):1838-1852. https://doi.org/10.1016/j.ymthe.2021.01.031

37. Khalid RS, Khan I, Zaidi MB, Naeem N, Haneef K, Qazi RM, Habib R, Malick TS. IL-7 overexpression enhances therapeutic potential of rat bone marrow mesenchymal stem cells for diabetic wounds. Wound Repair and Regeneration. 2019;27(3):235-248. https://doi.org/10.1111/wrr.12706

38. Li X, Song Y, Liu F, Liu F, Liu D, Miao H, Ren J, Xu J, Ding L, Hu Y, Wang Z, Hou Y, Zhao G. Long Non-Coding RNA MALAT1 Promotes Proliferation, Angiogenesis, and Immunosuppressive Properties of Mesenchymal Stem Cells by Inducing VEGF and IDO. J. Cell. Biochem. 2017;118(9):2780-2791. https://doi.org/10.1002/jcb.25927


Supplementary files

1. Figure 1. Interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) determine the immune phenotype of mesenchymal stem cells.
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Abakushina E.V., Vorobyova I.G., Stepanova I.A., Roumiantsev S.A. Therapy of chronic skin ulcers in patients with diabetes mellitus using gene modifications of cell transplant. Diabetes mellitus. 2024;27(6):611-619. (In Russ.) https://doi.org/10.14341/DM13215

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ISSN 2072-0351 (Print)
ISSN 2072-0378 (Online)