diaendoСахарный диабетDiabetes mellitus2072-03512072-0378Endocrinology research centre10.14341/DM13215diaendo-13215Research ArticleОбзорыReviewТерапия хронических трофических язв у больных сахарным диабетом с применением генных модификаций клеточного трансплантатаTherapy of chronic skin ulcers in patients with diabetes mellitus using gene modifications of cell transplanthttps://orcid.org/0000-0002-3881-3221АбакушинаЕ. В.AbakushinaE. V.

Абакушина Елена Вячеславовна - д.м.н.; ResearcherID: O-6947-2014; Scopus Author ID: 15844847700.

117292, Москва, ул. Дмитрия Ульянова, д. 11

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

11 Dm. Ulyanov street, 117292 Moscow

abakushina@mail.ruhttps://orcid.org/0000-0003-3068-3351ВоробьеваИ. Г.VorobyovaI. G.

Воробьева Ива Глебовна - к.б.н., ст.н.с.

Москва

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

Moscow

vorobieva@tecon.ruhttps://orcid.org/0000-0002-1316-398XСтепановаИ. А.StepanovaI. A.

Степанова Ирина Анатольевна - к.б.н., н.с.; ResearcherID: U-5075-2018; Scopus Author ID: 56086276200.

Москва

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

Moscow

IrinkaStepanova@yandex.ruhttps://orcid.org/0000-0002-7418-0222РумянцевС. А.RoumiantsevS. A.

Румянцев Сергей Александрович - д.м.н., профессор; ResearcherID: L-1428-2018; Scopus Author ID: 6506470384.

Москва

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

Moscow

s_roumiantsev@mail.ruООО «Текон Медицинские приборы»; ГНЦ РФ ФГБУ «Национальный медицинский исследовательский центр эндокринологии»РоссияTecon MP LLC; Endocrinology Research CentreRussian FederationООО «Текон Медицинские приборы»РоссияTecon MP LLCRussian FederationГНЦ РФ ФГБУ «Национальный медицинский исследовательский центр эндокринологии»РоссияEndocrinology Research CentreRussian Federation202418012025276611619Copyright © Абакушина Е.В., Воробьева И.Г., Степанова И.А., Румянцев С.А., 20252025Абакушина Е.В., Воробьева И.Г., Степанова И.А., Румянцев С.А.Abakushina E.V., Vorobyova I.G., Stepanova I.A., Roumiantsev S.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.dia-endojournals.ru/jour/article/view/13215

У пациентов с сахарным диабетом (СД) системные нарушения в организме могут вызывать целый ряд осложнений. Одним из основных осложнений является нарушение процессов заживления ран, что может привести к развитию диабетической язвы стопы (ДЯС) и последующей ампутации конечности. Модифицированные мезенхимальные стволовые клетки (ГМ-МСК) как средство терапии хронических ран позволяют снизить homing (хоуминг), обладают повышенным пролиферативным потенциалом, терапевтическими противоопухолевыми и поддерживающими функции поджелудочной железы свойствами. Для терапии ДЯС изучают нативные и генно-модифицированные клетки из аллогенных или аутологичных источников. В обзоре представлен мировой опыт применения стволовых клеток в терапии в доклинических и клинических исследованиях, собраны данные о предложенных технологиях терапии диабетических язв с применением ГМ-МСК: совместная трансплантация ГМ-МСК с островками поджелудочной железы, регуляция процессов миграции при помощи изменения экспрессии интегринов, блокирование сигналов эстрогена, повышенная экспрессия ряда генов, таких как SDF-1α, c-JUN, MALAT1, для повышения жизнеспособности и стимуляции пролиферации мезенхимальных стволовых клеток. Клетки, временно несущие терапевтические генно-инженерные конструкции, в доклинических испытаниях показывают высокую эффективность их применения.

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.

диабетическая язва стопымезенхимальные стволовые клеткигенные модификацииdiabetic foot ulcermesenchymal stem cellsgene modificationsCтатья подготовлена на основании результатов, полученных в ходе реализации Соглашения о предоставлении гранта в форме субсидий из федерального бюджета на осуществление государственной поддержки создания и развития научных центров мирового уровня, выполняющих исследования и разработки по приоритетам научно-технологического развития от 20 апреля 2022 года № 075-15-2022-310ReferencesArmstrong DG, Boulton AJM, Bus SA. Diabetic Foot Ulcers and Their Recurrence. N Engl J Med. 2017;376(24):2367-2375. https://doi/10.1056/NEJMra1615439Armstrong 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/NEJMra1615439Liu 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.2020.00258Liu 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.2020.00258Hanefeld M, Duetting E, Bramlage P. Cardiac implications of hypoglycemia in patients with diabetes - a systematic review. Cardiovasc Diabetol. 2013;12:135. https://doi.org/10.1186/1475-2840-12-135Hanefeld 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.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.0134914Skrepnek 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.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/s40659-015-0053-4Shao 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/s40659-015-0053-4Najar M, Melki R, Khalife F, et al. Therapeutic Mesenchymal Stem/Stromal Cells: Value, Challenges and Optimization. Front Cell Dev Biol. 2022;9:716853. https://doi.org/10.3389/fcell.2021.716853Najar 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.2021.716853ClinTrials.gov [Internet]. National Library of Medicine [cited 2024 Aug 7]. Available from: https://clinicaltrials.gov/.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.2015.0627Chinese Clinical Trial Registry [Internet]. ChiCTR. [cited 2024 Aug 7]. Available from: https://www.chictr.org.cn.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.2011.09.013Otero-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.2015.0627Rahavi 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/10.1155/2015/878535Rivas-Santiago B, Trujillo V, Montoya A, et al. Expression of antimicrobial peptides in diabetic foot ulcer. J Dermatol Sci. 2012;65(1):19-26. https://doi.org/10.1016/j.jdermsci.2011.09.013Sriram 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.2015.08.001Rahavi H, Hashemi SM, Soleimani M, et al. 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/10.1155/2015/878535Warsinske 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/s11538-015-0096-2Sriram 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.2015.08.001Tang 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.2014.1921Warsinske HC, Ashley SL, Linderman JJ, et al. Identifying Mechanisms of Homeostatic Signaling in Fibroblast Differentiation. Bull Math Biol. 2015;77(8):1556-82. https://doi.org/10.1007/s11538-015-0096-2Gentile P., Casella D., Palma E., Calabrese C., J. Clin. Med. 2019;12(8). doi:10.3390/jcm8040504Tang QL, Han SS, Feng J, et al. 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.2014.1921Cassidy 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/ijms21072476Gentile P, Casella D, Palma E, Calabrese C. Engineered Fat Graft Enhanced with Adipose-Derived Stromal Vascular Fraction Cells for Regenerative Medicine: Clinical, Histological and Instrumental Evaluation in Breast Reconstruction. J Clin Med. 2019;8(4):504. https://doi.org/10.3390/jcm8040504Moll 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.1729Cassidy FC, Shortiss C, Murphy CG, et al. 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/ijms21072476López-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/ijms22179531Moll G, Alm JJ, Davies LC, et al. Do cryopreserved mesenchymal stromal cells display impaired immunomodulatory and therapeutic properties? Stem Cells. 2014;32(9):2430-42. https://doi.org/10.1002/stem.1729Fukumoto R. Mesenchymal stem cell therapy for acute radiation syndrome. Mil Med Res. 2016;3:17. https://doi.org/10.1186/s40779-016-0086-1López-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/ijms22179531Krampera 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.2013.02.010Fukumoto R. Mesenchymal stem cell therapy for acute radiation syndrome. Mil Med Res. 2016;3:17. https://doi.org/10.1186/s40779-016-0086-1Joswig 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/s13287-017-0503-8Krampera M, Galipeau J, Shi Y, et al. 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.2013.02.010Lourenco 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.1402097Joswig AJ, Mitchell A, Cummings KJ, et al. 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/s13287-017-0503-8Carraro 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.13415Lourenco S, Teixeira VH, Kalber T, et al. 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.1402097Segers 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.00523.2005Carraro A, Trevellin E, Fassan M, et al. Esophageal adenocarcinoma microenvironment: Peritumoral adipose tissue effects associated with chemoresistance. Cancer Sci. 2017;108(12):2393-2404. https://doi.org/10.1111/cas.13415Jabłońska-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/10.3109/14756366.2016.1161620Segers VF, Van Riet I, Andries LJ, et al. 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.00523.2005Sheng 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.2008.80Jabłońska-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/10.3109/14756366.2016.1161620Barros 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.2018.10.039Sheng H, Wang Y, Jin Y, et al. 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.2008.80Du 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/10.1155/2019/4592701Barros JF, Waclawiak I, Pecli C, et al. 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.2018.10.039Ahn 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.0074897Du J, Liu A, Zhu R, et al. 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/10.1155/2019/4592701Yang 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/10.1155/2014/318098Ahn JO, Lee HW, Seo KW, et al. 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.0074897Hörnle 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.2010.434Yang X, Du J, Xu X, et al. 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/10.1155/2014/318098Yang 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.S59227Hörnle M, Peters N, Thayaparasingham B, et al. 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.2010.434Guo 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.2016.4297Yang ZS, Tang XJ, Guo XR, et al. 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.S59227Etich 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/10.1080/03008207.2016.1210606Guo XR, Hu QY, Yuan YH, et al. 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.2016.4297Yue 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/10.1155/2020/7430968Etich 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/10.1080/03008207.2016.1210606Laiva 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/biomedicines9020160Yue C, Guo Z, Luo Y, et al. 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/10.1155/2020/7430968Sun 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/10.1080/15384101.2020.1829799Laiva 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/biomedicines9020160Zhu 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.2021.01.031Sun 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/10.1080/15384101.2020.1829799Khalid 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.12706Zhu J, Luo Y, Zhao Y, et al. 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.2021.01.031Li 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.25927Li X, Song Y, Liu F, et al. 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.25927Li X, Song Y, Liu F, et al. 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.25927Khalid RS, Khan I, Zaidi MB, et al. 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.12706Khalid RS, Khan I, Zaidi MB, et al. 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

The authors declare that there are no conflicts of interest present.