Volume 11, Issue 1 (3-2022)                   WJPS 2022, 11(1): 12-22 | Back to browse issues page

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1. Department of Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Abstract:   (1168 Views)
Background: Diabetes is one of the metabolic diseases characterized by hyperglycemia, with many complications. Diabetic foot ulcer (DFU) is a significant complication of diabetes. Various therapy procedures have been recently described for DFU improvement.
Methods: Using PubMed, Scopus, Science Direct, and Google Scholar to discover the therapeutic effects of bee products, this review study was conducted in 2018-2019 by searching PubMed, Scopus, Science Direct, and Google Scholar databases.
Results: Cell therapies with various cell candidates such as mesenchymal stem cells (MSCs) are increasingly introduced into routine medical care to manage skin wounds. The applying of these cells for tissue regeneration was initially based on the capability of MSCs to differentiate into specialized cells within the injured tissue. Paracrine signaling and differentiation mechanisms have both been contributed to improving tissue repair by MCSs. However, the role of MSCs differentiation is less due to the poor survival of these cells at the site of injury.
Conclusion: At the same time, paracrine signaling or their secretome is the primary mechanism of MSCs that stimulate neovascularization and re-epithelialization and mobilization of inhabitant stem cells. In this review study, we discuss the role of MSCs and their secretome that can improve the use of this new approach in treating ulcers and DFU.
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Type of Study: Original Article | Subject: Special
Received: 2021/12/30 | Accepted: 2021/10/26 | Published: 2022/03/4

1. 1 Khadem Hh, Farsad Na, Pourghassem Gb, Ali Aa, Nemati A. Effect Of Cinnamon supplementation on blood glucose and lipid levels in type2 diabetic patients. Archives of Advances In Biosciences 2011;2(1):2-6. 2 Khamaisi M, Balanson SE. Stem Cells for Diabetes Complications: A Future Potential Cure. Rambam Maimonides Med J 2017;8(1): e0008. doi: 10.5041/RMMJ.10283 3 Choby B. Diabetes Update: Prevention and Management of Diabetes Complications. FP Essentials 2017;456:36-40. PMID: 28530383 4 Yazdanpanah L, Nasiri M, Adarvishi S. Literature review on the management of diabetic foot ulcer. World J Diabetes 2015;6(1): 37–53. doi: 10.4239/wjd.v6.i1.37 5 Jhamb S, Vangaveti VN, Malabu UH. Genetic and molecular basis of diabetic foot ulcers: clinical review. J Tissue Viability 2016;25(4): 229-236. doi: 10.1016/j.jtv.2016.06.005 6 Domínguez-Bendala J, Lanzoni G, Inverardi L, Ricordi C. Concise review: mesenchymal stem cells for diabetes. Stem cells translational medicine. Stem Cells Transl Med 2012 Jan;1(1):59-63. doi: 10.5966/sctm.2011-0017 7 Alexiadou K, Doupis J. Management of diabetic foot ulcers. Diabetes Ther 2012;3(1):4.doi:10.1007/s13300-012-0004-9 8 Falanga V. Wound healing and its impairment in the diabetic foot. Lancet 2005 2005/11/12/;366(9498):1736-43. doi: 10.1016/S0140-6736(05)67700-8 9 Yeboah A, Maguire T, Schloss R, Berthiaume F, Yarmush ML. Stromal Cell-Derived Growth Factor-1 Alpha-Elastin Like Peptide Fusion Protein Promotes Cell Migration and Revascularization of Experimental Wounds in Diabetic Mice. Adv Wound Care 2017;6(1):10-22. doi: 10.1089/wound.2016.0694 10 Valero C, Javierre E, García-Aznar J, Menzel A, Gomez-Benito M. Challenges in the modeling of wound healing mechanisms in soft biological tissues. Ann Biomed Eng 2015;43(7):1654-65. doi: 10.1007/s10439-014-1200-8 11 Marfia G, Navone SE, Di Vito C, et al. Mesenchymal stem cells: potential for therapy and treatment of chronic non-healing skin wounds. Organogenesis 2015;11(4):183-206. doi: 10.1080/15476278.2015.1126018 12 Wu Y, Chen L, Scott PG, Tredget EE. Mesenchymal stem cells enhance wound healing through differentiation and angiogenesis. Stem Cells 2007;25(10):2648-59. doi: 10.1634/stemcells.2007-0226 13 Dash NR, Dash SN, Routray P, Mohapatra S, Mohapatra PC. Targeting non-healing ulcers of lower extremity in human through autologous bone marrow-derived mesenchymal stem cells. Rejuvenation Res 2009;12(5):359-66. doi: 10.1089/rej.2009.0872. 14 Vojtaššák J, Danišovič L, Kubeš M, et al. Autologous biograft and mesenchymal stem cells in treatment of the diabetic foot. Neuro Endocrinol. Lett 2006;27(supplement 2):134-7. PMID: 17159798 15 Liu ZJ, Zhuge Y, Velazquez OC. Trafficking and differentiation of mesenchymal stem cells. J Cell Biochem 2009;106(6):984-91. doi: 10.1002/jcb.22091 16 Sasaki M, Abe R, Fujita Y, Ando S, Inokuma D, Shimizu H. Mesenchymal stem cells are recruited into wounded skin and contribute to wound repair by transdifferentiation into multiple skin cell type. J Immunol 2008;180(4):2581-7. doi: 10.4049/jimmunol.180.4.2581 17 Amann B, Luedemann C, Ratei R, Schmidt-Lucke JA. Autologous bone marrow cell transplantation increases leg perfusion and reduces amputations in patients with advanced critical limb ischemia due to peripheral artery disease. Cell Transplant 2009;18(3):371-80. doi: 10.3727/096368909788534942 18 Rigato M, Monami M, Fadini GP. Autologous Cell Therapy for Peripheral Arterial DiseaseNovelty and Significance: Systematic Review and Meta-Analysis of Randomized, Nonrandomized, and Noncontrolled Studies. Circ Res 2017;120(8):1326-40. doi: 10.1161/CIRCRESAHA.116.309045 19 Rashtbar M, Hadjati J, Ai J, et al. Characterization of decellularized ovine small intestine submucosal layer as extracellular matrix‐based scaffold for tissue engineering. J Biomed Mater Res B Appl Biomater 2017; 106(3):933-944.. doi: 10.1002/jbm.b.33899 20 Casado JG, Tarazona R, Sanchez-Margallo F. NK and MSCs crosstalk: the sense of immunomodulation and their sensitivity. Stem Cell Rev 2013;9(2):184-9. doi: 10.1007/s12015-013-9430-y 21 Shetty P, Cooper K, Viswanathan C. Comparison of proliferative and multilineage differentiation potentials of cord matrix, cord blood, and bone marrow mesenchymal stem cells. Asian J Transfus Sci 2010;4(1):14. doi: 10.4103/0973-6247.59386 22 Arno AI, Amini-Nik S, Blit PH, et al. Human Wharton's jelly mesenchymal stem cells promote skin wound healing through paracrine signaling. Stem Cell Res Ther 2014;5(1):28. doi: 10.1186/scrt417 23 Shi S, Gronthos S. Perivascular niche of postnatal mesenchymal stem cells in human bone marrow and dental pulp. J Bone Miner Res 2003;18(4):696-704. doi: 10.1359/jbmr.2003.18.4.696 24 Jeon YJ, Kim J, Cho JH, Chung HM, Chae JI. Comparative analysis of human mesenchymal stem cells derived from bone marrow, placenta, and adipose tissue as sources of cell therapy. J Cell Biochem 2016;117(5):1112-25. doi: 10.1002/jcb.25395 25 Parikh PP, Liu Z-J, Velazquez OC. A Molecular and Clinical Review of Stem Cell Therapy in Critical Limb Ischemia. Stem Cells Int 2017;2017:3750829. doi: 10.1155/2017/3750829 26 Zeng X, Tang Y, Hu K, et al. Three-week topical treatment with placenta-derived mesenchymal stem cells hydrogel in a patient with diabetic foot ulcer: A case report. Medicine 2017;96(51):e9212. doi: 10.1097/MD.0000000000009212 27 Flegg JA, Menon SN, Maini PK, McElwain DS. On the mathematical modeling of wound healing angiogenesis in skin as a reaction-transport process. Front Physiol 2015;6; 262. doi: 10.3389/fphys.2015.00262 28 Gu C, Huang S, Gao D, et al. Angiogenic effect of mesenchymal stem cells as a therapeutic target for enhancing diabetic wound healing. Int J Low Extrem Wounds 2014;13(2):88-93. doi: 10.1177/1534734614534977 29 Zou J-P, Huang S, Peng Y, et al. Mesenchymal Stem Cells/Multipotent Mesenchymal Stromal Cells (MSCs) Potential Role in Healing Cutaneous Chronic Wounds. Int J Low Extrem Wounds 2012;11(4):244-53. doi: 10.1177/1534734612463935 30 de Mayo T, Conget P, Becerra-Bayona S, Sossa CL, Galvis V, Arango-Rodríguez ML. The role of bone marrow mesenchymal stromal cell derivatives in skin wound healing in diabetic mice. Plos One 2017;12(6):e0177533. doi: 10.1371/journal.pone.0177533 31 Xu X, Zhu F, Zhang M, et al. Stromal cell-derived factor-1 enhances wound healing through recruiting bone marrow-derived mesenchymal stem cells to the wound area and promoting neovascularization. Cells Tissues Organs 2013;197(2):103-13. doi: 10.1159/000342921 32 Yildirimer L, Thanh NTK, Seifalian AM. Skin regeneration scaffolds: a multimodal bottom-up approach. Trends Biotechnol 2012 2012/12/01/;30(12):638-48. doi: 10.1016/j.tibtech.2012.08.004 33 Aguilera V, Briceño L, Contreras H, et al. Endothelium trans differentiated from Wharton's jelly mesenchymal cells promote tissue regeneration: potential role of soluble pro-angiogenic factors. PLoS One 2014;9(11):e111025. doi: 10.1371/journal.pone.0111025 34 Li M, Zhao Y, Hao H, et al. Mesenchymal Stem Cell–Conditioned Medium Improves the Proliferation and Migration of Keratinocytes in a Diabetes-Like Microenvironment. Int J Low Extrem Wounds 2015;14(1):73-86. doi: 10.1177/1534734615569053 35 Liang X, Ding Y, Zhang Y, Tse H-F, Lian Q. Paracrine mechanisms of mesenchymal stem cell-based therapy: current status and perspectives. Cell Transplant 2014;23(9):1045-59. doi: 10.3727/096368913X667709 36 Fan C-G, Zhang Q-j, Zhou J-r. Therapeutic potentials of mesenchymal stem cells derived from human umbilical cord. Stem Cell Rev 2011;7(1):195-207. doi: 10.1007/s12015-010-9168-8 37 Pereira T, Ivanova G, Caseiro AR, et al. MSCs conditioned media and umbilical cord blood plasma metabolomics and composition. PLoS One 2014;9(11):e113769. doi: 10.1371/journal.pone.0113769 38 Ranganath SH, Levy O, Inamdar MS, Karp JM. Harnessing the mesenchymal stem cell secretome for the treatment of cardiovascular disease. Cell Stem Cell 2012;10(3):244-58. doi: 10.1016/j.stem.2012.02.005 39 Joensuu K, Uusitalo‐Kylmälä L, Hentunen TA, Heino TJ. Angiogenic potential of human mesenchymal stromal cell and circulating mononuclear cell co‐cultures is reflected in the expression profiles of pro-angiogenic factors leading to endothelial cell and pericyte differentiation. J Tissue Eng Regen Med 2018;12(3):775-83. doi: 10.1002/term.2496 40 Chen L, Xu Y, Zhao J, et al. Conditioned medium from hypoxic bone marrow-derived mesenchymal stem cells enhances wound healing in mice. PLoS One 2014;9(4):e96161. doi: 10.1371/journal.pone.0096161 41 Kuo Y-R, Wang C-T, Cheng J-T, Kao G-S, Chiang Y-C, Wang C-J. Adipose-derived stem cells accelerate diabetic wound healing through the induction of autocrine and paracrine effects. Cell Transplant 2016;25(1):71-81. doi: 10.3727/096368915X687921 42 Kaibuchi N, Iwata T, Yamato M, Okano T, Ando T. Multipotent mesenchymal stromal cell sheet therapy for bisphosphonate-related osteonecrosis of the jaw in a rat model. Acta Biomater 2016;42:400-10. doi: 10.1016/j.actbio.2016.06.022 43 Kato Y, Iwata T, Morikawa S, Yamato M, Okano T, Uchigata Y. Allogeneic transplantation of an adipose-derived stem cell sheet combined with artificial skin accelerates wound healing in a rat wound model of type 2 diabetes and obesity. Diabetes 2015;64(8):2723-34. doi: 10.2337/db14-1133 44 Malhotra S, Hu MS, Marshall CD, et al. Mesenchymal stromal cells as cell-based therapeutics for wound healing. Stem Cells Int 2016;2016:4157934. doi: 10.1155/2016/4157934 45 Gomathysankar S, Halim AS, Yaacob NS. Proliferation of keratinocytes induced by adipose-derived stem cells on a chitosan scaffold and its role in wound healing, a review. Arch. Plast. Surg 2014;41(5):452-7. doi: 10.5999/aps.2014.41.5.452 46 Martin P, Nunan R. Cellular and molecular mechanisms of repair in acute and chronic wound healing. Br J Dermatol 2015;173(2):370-8. doi: 10.1111/bjd.13954 47 Al‐Shaibani MB, Wang Xn, Lovat PE, Dickinson AM. Cellular Therapy for Wounds: Applications of Mesenchymal Stem Cells in Wound Healing. Wound healing–new insights into ancient challenges. London: InTech (2016): 99-131. 48 Wang L-T, Ting C-H, Yen M-L, et al. Human mesenchymal stem cells (MSCs) for treatment towards immune-and inflammation-mediated diseases: review of current clinical trials. J Biomed Sci 2016;23(1):76. doi: 10.1186/s12929-016-0289-5 49 Walter MNM, Wright KT, Fuller HR, MacNeil S, Johnson WEB. Mesenchymal stem cell-conditioned medium accelerates skin wound healing: An in vitro study of fibroblast and keratinocyte scratch assays. Exp Cell Res 2010 2010/04/15/;316(7):1271-81. doi: 10.1016/j.yexcr.2010.02.026 50 Cao Y, Gang X, Sun C, Wang G. Mesenchymal Stem Cells Improve Healing of Diabetic Foot Ulcer. J. Diabetes Res 2017;2017:9328347. doi: 10.1155/2017/9328347 51 Gupta GJ, Karki K, Jain P, Saxena AK. Autologous Bone Marrow Aspirate Therapy for Skin Tissue Engineering and Tissue Regeneration. Adv Wound Care 2017;6(4):135-142. doi: 10.1089/wound.2016.0704 52 Javazon EH, Keswani SG, Badillo AT, et al. Enhanced epithelial gap closure and increased angiogenesis in wounds of diabetic mice treated with adult murine bone marrow stromal progenitor cells. Wound Repair Regen 2007;15(3):350-9. doi: 10.1111/j.1524-475X.2007.00237.x. 53 Kim W-S, Park B-S, Sung J-H, et al. Wound healing effect of adipose-derived stem cells: a critical role of secretory factors on human dermal fibroblasts. J Dermatol Sci 2007;48(1):15-24. doi: 10.1016/j.jdermsci.2007.05.018 54 Lee EY, Xia Y, Kim WS, et al. Hypoxia‐enhanced wound‐healing function of adipose‐derived stem cells: Increase in stem cell proliferation and up‐regulation of VEGF and bFGF. Wound Repair Regen 2009;17(4):540-7. doi: 10.1111/j.1524-475X.2009.00499.x. 55 Smith AN, Willis E, Chan VT, et al. Mesenchymal stem cells induce dermal fibroblast responses to injury. Exp Cell Res 2010;316(1):48-54. doi: 10.1016/j.yexcr.2009.08.001 56 Park S-R, Kim J-W, Jun H-S, Roh JY, Lee H-Y, Hong I-S. Stem Cell Secretome and Its Effect on Cellular Mechanisms Relevant to Wound Healing. Mol Ther 2018 2018/02/07/;26(2):606-17. doi: 10.1016/j.ymthe.2017.09.023 57 Ong HT, Redmond SL, Marano RJ, et al. Paracrine Activity from Adipose-Derived Stem Cells on In Vitro Wound Healing in Human Tympanic Membrane Keratinocytes. Stem Cells Dev 2017;26(6):405-18. doi: 10.1089/scd.2016.0204 58 Sah SK, Kim HY, Lee JH, et al. Effects of Human Mesenchymal Stem Cells Coculture on Calcium-Induced Differentiation of Normal Human Keratinocytes. Stem Cells 2017;35(6):1592-602. doi: 10.1002/stem.2593 59 Hocking AM, Gibran NS. Mesenchymal stem cells: paracrine signaling and differentiation during cutaneous wound repair. Exp Cell Res 2010;316(14):2213-9. doi: 10.1016/j.yexcr.2010.05.009 60 Boulton AJ, Vileikyte L, Ragnarson-Tennvall G, Apelqvist J. The global burden of diabetic foot disease. The Lancet 2005;366(9498):1719-24. doi: 10.1016/S0140-6736(05)67698-2 61 Vija L, Farge D, Gautier J-F, et al. Mesenchymal stem cells: Stem cell therapy perspectives for type 1 diabetes. Diabetes Metab 2009;35(2):85-93. doi: 10.1016/j.diabet.2008.10.003 62 Anzalone R, Iacono ML, Loria T, et al. Wharton's jelly mesenchymal stem cells as candidates for beta cells regeneration: extending the differentiative and immunomodulatory benefits of adult mesenchymal stem cells for the treatment of type 1 diabetes. Stem Cell Rev 2011;7(2):342-63. doi: 10.1007/s12015-010-9196-4 63 Kočí Z, Turnovcová K, Dubský M, et al. Characterization of human adipose tissue‐derived stromal cells isolated from diabetic patient's distal limbs with critical ischemia. Cell Biochem Funct 2014;32(7):597-604. doi: 10.1002/cbf.3056. 64 Shin L, Peterson DA. Impaired therapeutic capacity of autologous stem cells in a model of type 2 diabetes. Stem Cells Transl. Med 2012;1(2):125-35. doi: 10.5966/sctm.2012-0031 65 Seo E, Lim JS, Jun J-B, Choi W, Hong I-S, Jun H-S. Exendin-4 in combination with adipose-derived stem cells promotes angiogenesis and improves diabetic wound healing. J Transl Med 2017;15(1):35. doi: 10.1186/s12967-017-1145-4 66 Liang L, Li Z, Ma T, et al. Transplantation of human placenta-derived mesenchymal stem cells alleviates critical limb ischemia in diabetic nude rats. Cell Transplant 2017;26(1):45-61. doi: 10.3727/096368916X692726 67 Brini AT, Amodeo G, Ferreira LM, et al. Therapeutic effect of human adipose-derived stem cells and their secretome in experimental diabetic pain. Sci Rep 2017;7(1):9904. doi: 10.1038/s41598-017-09487-5 68 Wu SC, Pollak R, Frykberg RG, et al. Safety and efficacy of intramuscular human placenta‐derived mesenchymal stromal‐like cells (cenplacel [PDA‐002]) in patients who have a diabetic foot ulcer with peripheral arterial disease. Int. Wound J 2017;14(5):823-9.doi: 10.1111/iwj.12715 69 Edwards SS, Zavala G, Prieto CP, et al. Functional analysis reveals angiogenic potential of human mesenchymal stem cells from Wharton's jelly in dermal regeneration. Angiogenesis 2014;17(4):851-66. doi: 10.1007/s10456-014-9432-7 70 O'Loughlin A, Kulkarni M, Creane M, et al. Topical administration of allogeneic mesenchymal stromal cells seeded in a collagen scaffold augments wound healing and increases angiogenesis in the diabetic rabbit ulcer. Diabetes 2013;62(7):2588-94. doi: 10.2337/db12-1822 71 Kim S-W, Zhang H-Z, Guo L, Kim J-M, Kim MH. Amniotic mesenchymal stem cells enhance wound healing in diabetic NOD/SCID mice through high angiogenic and engraftment capabilities. PLoS One 2012;7(7):e41105. doi: 10.1371/journal.pone.0041105 72 Kirana S, Stratmann B, Prante C, et al. Autologous stem cell therapy in the treatment of limb ischaemia induced chronic tissue ulcers of diabetic foot patients. Int J Clin Pract 2012;66(4):384-93. doi: 10.1111/j.1742-1241.2011.02886.x 73 Amann B, Lüdemann C, Ratei R, Schmidt-Lucke J. Autologous bone-marrow stem-cell transplantation for induction of arteriogenesis for limb salvage in critical limb ischaemia. Zentralbl Chir 2009;134(4):298-304. doi: 10.1055/s-0029-1224532 74 Falanga V, Iwamoto S, Chartier M, et al. Autologous bone marrow–derived cultured mesenchymal stem cells delivered in a fibrin spray accelerate healing in murine and human cutaneous wounds. Tissue Eng 2007;13(6):1299-312. doi: 10.1089/ten.2006.0278 75 Chen L, Tredget EE, Wu PY, Wu Y. Paracrine factors of mesenchymal stem cells recruit macrophages and endothelial lineage cells and enhance wound healing. PLoS One 2008;3(4):e1886. doi: 10.1371/journal.pone.0001886 76 Kato J, Kamiya H, Himeno T, et al. Mesenchymal stem cells ameliorate impaired wound healing through enhancing keratinocyte functions in diabetic foot ulcerations on the plantar skin of rats. J Diabetes Complications 2014;28(5):588-95. doi: 10.1016/j.jdiacomp.2014.05.003 77 Li H, Fu X, Ouyang Y, Cai C, Wang J, Sun T. Adult bone-marrow-derived mesenchymal stem cells contribute to wound healing of skin appendages. Cell Tissue Res 2006;326(3):725-36. doi: 10.1007/s00441-006-0270-9

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