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Transplantation of adipose derived stem cells in diabetes mellitus; limitations and achievements

  • Review article
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Journal of Diabetes & Metabolic Disorders Aims and scope Submit manuscript

Abstract

Objectives

Diabetes mellitus (DM) is a complex metabolic disease that results from impaired insulin secreting pancreatic β-cells or insulin resistance. Although available medications help control the disease, patients suffer from its complications. Therefore, finding effective therapeutic approaches to treat DM is a priority. Adipose Derived Stem Cells (ADSCs) based therapy is a promising strategy in various regenerative medicine applications, but its systematic translational use is still somewhat out of reach. This review is aimed at clarifying achievements as well as challenges facing the application of ADSCs for the treatment of DM, with a special focus on the mechanisms involved.

Methods

Literature searches were carried out on “Scopus”, “PubMed” and “Google Scholar” up to September 2022 to find relevant articles in the English language for the scope of this review.

Results

Recent evidence showed a significant role of ADSC therapies in DM by ameliorating insulin resistance and hyperglycemia, regulating hepatic glucose metabolism, promoting β cell function and regeneration, and functioning as a gene delivery tool. In addition, ADSCs could improve diabetic wound healing by promoting collagen deposition, inhibiting inflammation, and enhancing angiogenesis.

Conclusion

Overall, this literature review revealed the great clinical implications of ADSCs for translating into the clinical setting for the treatment of diabetes. However, further large-scale and controlled studies are needed to overcome challenges and confirm the safety and optimal therapeutic scheme before daily clinical application.

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References

  1. Khan MAB, et al. Epidemiology of type 2 diabetes–global burden of disease and forecasted trends. J Epidemiol global health. 2020;10(1):107. https://doi.org/10.2991/jegh.k.191028.001.

    Article  Google Scholar 

  2. Ozougwu J, et al. The pathogenesis and pathophysiology of type 1 and type 2 diabetes mellitus. J Physiol Pathophysiol. 2013;4(4):46–57. https://doi.org/10.5897/JPAP2013.0001.

    Article  CAS  Google Scholar 

  3. Leitner DR, et al. Obesity and type 2 diabetes: two diseases with a need for combined treatment strategies-EASO can lead the way. Obes Facts. 2017;10(5):483–92. https://doi.org/10.1159/000480525.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Cho NH, et al. IDF Diabetes Atlas: global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res Clin Pract. 2018;138:271–81. https://doi.org/10.1016/j.diabres.2018.02.023.

    Article  CAS  PubMed  Google Scholar 

  5. Huang Q, Huang Y, Liu J. Mesenchymal Stem Cells: An Excellent Candidate for the Treatment of Diabetes Mellitus International Journal of Endocrinology, 2021. 2021. DOI: https://doi.org/10.1155/2021/9938658.

  6. Sutherland D. Pancreas and islet transplantation. Diabetologia. 1981;20(4):435–50. https://doi.org/10.1007/BF00253405.

    Article  CAS  PubMed  Google Scholar 

  7. Khosravi-Maharlooei M et al. Islet transplantation for type 1 diabetes: so close and yet so far away. Eur J Endocrinol, 2015.

  8. Bruni A, et al. Islet cell transplantation for the treatment of type 1 diabetes: recent advances and future challenges. Diabetes metabolic syndrome and obesity: targets and therapy. 2014;7:211. https://doi.org/10.2147/DMSO.S50789.

    Article  CAS  PubMed  Google Scholar 

  9. O’Brien T, Barry FP. Stem cell therapy and regenerative medicine. in Mayo Clinic Proceedings. 2009. Elsevier. DOI: https://doi.org/10.4065/84.10.859.

  10. Han Y, et al. Mesenchymal stem cells for regenerative medicine. Cells. 2019;8(8):886. https://doi.org/10.3390/cells8080886.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Si Z, et al. Adipose-derived stem cells: sources, potency, and implications for regenerative therapies. Biomed Pharmacother. 2019;114:108765. https://doi.org/10.1016/j.biopha.2019.108765.

    Article  CAS  PubMed  Google Scholar 

  12. Bourin P, et al. Stromal cells from the adipose tissue-derived stromal vascular fraction and culture expanded adipose tissue-derived stromal/stem cells: a joint statement of the International Federation for Adipose therapeutics and Science (IFATS) and the International Society for Cellular Therapy (ISCT). Cytotherapy. 2013;15(6):641–8. https://doi.org/10.1016/j.jcyt.2013.02.006.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Zuk PA, et al. Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng. 2001;7(2):211–28. https://doi.org/10.1089/107632701300062859.

    Article  CAS  PubMed  Google Scholar 

  14. Trzyna A, Banaś-Ząbczyk A. Adipose-derived stem cells secretome and its potential application in “stem cell-free therapy. Biomolecules. 2021;11(6):878. https://doi.org/10.3390/biom11060878.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Barba M, Taranto GD, Lattanzi W. Adipose-derived stem cell therapies for bone regeneration. Expert Opin Biol Ther. 2017;17(6):677–89. https://doi.org/10.1080/14712598.2017.1315403.

    Article  PubMed  Google Scholar 

  16. Im G-I, Shin Y-W, Lee K-B. Do adipose tissue-derived mesenchymal stem cells have the same osteogenic and chondrogenic potential as bone marrow-derived cells? Osteoarthr Cartil. 2005;13(10):845–53. https://doi.org/10.1016/j.joca.2005.05.005.

    Article  Google Scholar 

  17. Dominici M, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8(4):315–7. https://doi.org/10.1080/14653240600855905.

    Article  CAS  PubMed  Google Scholar 

  18. Mildmay-White A, Khan W. Cell surface markers on adipose-derived stem cells: a systematic review. Curr Stem Cell Res Therapy. 2017;12(6):484–92. https://doi.org/10.2174/1574888X11666160429122133.

    Article  CAS  Google Scholar 

  19. Baer PC. Adipose-derived mesenchymal stromal/stem cells: an update on their phenotype in vivo and in vitro. World J stem cells. 2014;6(3):256. https://doi.org/10.4252/wjsc.v6.i3.256.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Viswanathan S, et al. Mesenchymal stem versus stromal cells: International Society for Cell & Gene Therapy (ISCT®) mesenchymal stromal cell committee position statement on nomenclature. Cytotherapy. 2019;21(10):1019–24. https://doi.org/10.1016/j.jcyt.2019.08.002.

    Article  CAS  PubMed  Google Scholar 

  21. Li P, Guo X. A review: therapeutic potential of adipose-derived stem cells in cutaneous wound healing and regeneration. Stem Cell Res Ther. 2018;9(1):1–7. https://doi.org/10.1186/s13287-018-1044-5.

    Article  Google Scholar 

  22. Huang JI, et al. Chondrogenic potential of progenitor cells derived from human bone marrow and adipose tissue: a patient-matched comparison. J Orthop Res. 2005;23(6):1383–9. https://doi.org/10.1016/j.orthres.2005.03.018.

    Article  CAS  PubMed  Google Scholar 

  23. Choi YS, et al. Mechanical derivation of functional myotubes from adipose-derived stem cells. Biomaterials. 2012;33(8):2482–91. https://doi.org/10.1016/j.biomaterials.2011.12.004.

    Article  CAS  PubMed  Google Scholar 

  24. Miyagi-Shiohira C, et al. Cryopreservation of adipose-derived mesenchymal stem cells. Cell Med. 2015;8(1–2):3–7. https://doi.org/10.3727/215517915X689100.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Ceccarelli S, et al. Immunomodulatory effect of adipose-derived stem cells: the cutting edge of clinical application. Front cell Dev biology. 2020;8:236. https://doi.org/10.3389/fcell.2020.00236.

    Article  Google Scholar 

  26. Fu Y, et al. Trophic effects of mesenchymal stem cells in tissue regeneration. Tissue Eng Part B: Reviews. 2017;23(6):515–28. https://doi.org/10.1089/ten.teb.2016.0365.

    Article  CAS  Google Scholar 

  27. Chandra V, et al. Generation of pancreatic hormone-expressing islet-like cell aggregates from murine adipose tissue-derived stem cells. Stem Cells. 2009;27(8):1941–53. https://doi.org/10.1002/stem.117.

    Article  CAS  PubMed  Google Scholar 

  28. Nam JS, et al. Transplantation of insulin-secreting cells differentiated from human adipose tissue-derived stem cells into type 2 diabetes mice. Biochem Biophys Res Commun. 2014;443(2):775–81. https://doi.org/10.1016/j.bbrc.2013.10.059.

    Article  CAS  PubMed  Google Scholar 

  29. Timper K, et al. Human adipose tissue-derived mesenchymal stem cells differentiate into insulin, somatostatin, and glucagon expressing cells. Biochem Biophys Res Commun. 2006;341(4):1135–40. https://doi.org/10.1016/j.bbrc.2006.01.072.

    Article  CAS  PubMed  Google Scholar 

  30. Dave SD, Vanikar AV, Trivedi HL. Ex vivo generation of glucose sensitive insulin secreting mesenchymal stem cells derived from human adipose tissue. Indian J Endocrinol Metabol. 2012;16(Suppl1):S65. https://doi.org/10.4103/2230-8210.94264.

    Article  CAS  Google Scholar 

  31. Zhang S, et al. Promoting long-term survival of insulin-producing cell grafts that differentiate from adipose tissue-derived stem cells to cure type 1 diabetes. PLoS ONE. 2011;6(12):e29706. https://doi.org/10.1371/journal.pone.0029706.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Dhanasekaran M, et al. Human omentum fat-derived mesenchymal stem cells transdifferentiates into pancreatic islet‐like cluster. Cell Biochem Funct. 2013;31(7):612–9. https://doi.org/10.1002/cbf.2948.

    Article  CAS  PubMed  Google Scholar 

  33. Amer MG, et al. Role of adipose tissue derived stem cells differentiated into insulin producing cells in the treatment of type I diabetes mellitus. Gene. 2018;654:87–94. https://doi.org/10.1016/j.gene.2018.02.008.

    Article  CAS  PubMed  Google Scholar 

  34. Paek HJ, Kim C, Williams SK. Adipose stem cell-based regenerative medicine for reversal of diabetic hyperglycemia. World J Diabetes. 2014;5(3):235. https://doi.org/10.4239/wjd.v5.i3.235.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Balistreri CR, et al. Stem cell therapy: old challenges and new solutions. Mol Biol Rep. 2020;47(4):3117–31. https://doi.org/10.1007/s11033-020-05353-2.

    Article  CAS  PubMed  Google Scholar 

  36. Kahn SE, Cooper ME, Prato SD. Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future. The Lancet. 2014;383(9922):1068–83. https://doi.org/10.1016/S0140-6736(13)62154-6.

    Article  CAS  Google Scholar 

  37. Si Y, et al. Infusion of mesenchymal stem cells ameliorates hyperglycemia in type 2 diabetic rats: identification of a novel role in improving insulin sensitivity. Diabetes. 2012;61(6):1616–25. https://doi.org/10.2337/db11-1141.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Estrada EJ, et al. Combined treatment of intrapancreatic autologous bone marrow stem cells and hyperbaric oxygen in type 2 diabetes mellitus. Cell Transplant. 2008;17(12):1295–304. https://doi.org/10.3727/096368908787648119.

    Article  PubMed  Google Scholar 

  39. Xie Z, et al. Human umbilical cord-derived mesenchymal stem cells elicit macrophages into an anti-inflammatory phenotype to alleviate insulin resistance in type 2 diabetic rats. Stem Cells. 2016;34(3):627–39. https://doi.org/10.1002/stem.2238.

    Article  CAS  PubMed  Google Scholar 

  40. Blaber SP, et al. Analysis of in vitro secretion profiles from adipose-derived cell populations. J translational Med. 2012;10(1):1–16. https://doi.org/10.1186/1479-5876-10-172.

    Article  CAS  Google Scholar 

  41. Ruan H, et al. Tumor necrosis factor-α suppresses adipocyte-specific genes and activates expression of preadipocyte genes in 3T3-L1 adipocytes: nuclear factor-κB activation by TNF-α is obligatory. Diabetes. 2002;51(5):1319–36. https://doi.org/10.2337/diabetes.51.5.1319.

    Article  CAS  PubMed  Google Scholar 

  42. Gratas-Delamarche A, et al. Physical inactivity, insulin resistance, and the oxidative-inflammatory loop. Free Radic Res. 2014;48(1):93–108. https://doi.org/10.3109/10715762.2013.847528.

    Article  CAS  PubMed  Google Scholar 

  43. Patel PS, Buras ED, Balasubramanyam A. The role of the immune system in obesity and insulin resistance Journal of obesity, 2013. 2013. DOI: https://doi.org/10.1155/2013/616193.

  44. Mahmoud F, Al-Ozairi E. Inflammatory cytokines and the risk of cardiovascular complications in type 2 diabetes. Dis Markers. 2013;35(4):235–41. https://doi.org/10.1155/2013/931915.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Hu J, et al. Effects of autologous adipose-derived stem cell infusion on type 2 diabetic rats. Endocr J. 2015;EJ14–0584. https://doi.org/10.1507/endocrj.EJ14-0584.

  46. Hu W, et al. Therapeutic potentials of extracellular vesicles for the treatment of diabetes and diabetic complications. Int J Mol Sci. 2020;21(14):5163. https://doi.org/10.3390/ijms21145163.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Shree N, Bhonde RR. Conditioned media from adipose tissue derived mesenchymal stem cells reverse insulin resistance in cellular models. J Cell Biochem. 2017;118(8):2037–43. https://doi.org/10.1002/jcb.25777.

    Article  CAS  PubMed  Google Scholar 

  48. Sanap A, Bhonde R, Joshi K. Conditioned medium of adipose derived mesenchymal stem cells reverse insulin resistance through downregulation of stress induced serine kinases. Eur J Pharmacol. 2020;881:173215. https://doi.org/10.1016/j.ejphar.2020.173215.

    Article  CAS  PubMed  Google Scholar 

  49. Liu J, et al. Clinical potential of extracellular vesicles in type 2 diabetes. Front Endocrinol. 2021;11:596811. https://doi.org/10.3389/fendo.2020.59681.

    Article  Google Scholar 

  50. Zhao H, et al. Exosomes from adipose-derived stem cells attenuate adipose inflammation and obesity through polarizing M2 macrophages and beiging in white adipose tissue. Diabetes. 2018;67(2):235–47. https://doi.org/10.2337/db17-0356.

    Article  CAS  PubMed  Google Scholar 

  51. Xie M, et al. Adipose-derived mesenchymal stem cells ameliorate hyperglycemia through regulating hepatic glucose metabolism in type 2 diabetic rats. Biochem Biophys Res Commun. 2017;483(1):435–41. https://doi.org/10.1016/j.bbrc.2016.12.125.

    Article  CAS  PubMed  Google Scholar 

  52. Abu-Abeeleh M, et al. A preliminary study of the use of human adipose tissue-derived stem cells for the treatment of streptozotocin-induced diabetes mellitus in a rat model. Comp Clin Pathol. 2010;19(1):1–4. https://doi.org/10.1007/s00580-009-0912-x.

    Article  Google Scholar 

  53. Li Y-Y, et al. Adipose-derived mesenchymal stem cells ameliorate STZ-induced pancreas damage in type 1 diabetes. Biomed Mater Eng. 2012;22(1–3):97–103. https://doi.org/10.3233/BME-2012-0694.

    Article  CAS  PubMed  Google Scholar 

  54. Khatri R, Petry SF, Linn T. Intrapancreatic MSC transplantation facilitates pancreatic islet regeneration. Stem Cell Res Ther. 2021;12(1):1–14. https://doi.org/10.1186/s13287-021-02173-4.

    Article  CAS  Google Scholar 

  55. Saisho Y. β-cell dysfunction: its critical role in prevention and management of type 2 diabetes. World J diabetes. 2015;6(1):109. https://doi.org/10.4239/wjd.v6.i1.109.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Talchai C, et al. Pancreatic β cell dedifferentiation as a mechanism of diabetic β cell failure. Cell. 2012;150(6):1223–34. https://doi.org/10.1016/j.cell.2012.07.029.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Wang L, et al. Mesenchymal stem cells ameliorate β cell dysfunction of human type 2 diabetic islets by reversing β cell dedifferentiation. EBioMedicine. 2020;51:102615. https://doi.org/10.1016/j.ebiom.2019.102615.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Sun L-L, et al. Transplantation of betatrophin-expressing adipose-derived mesenchymal stem cells induces β-cell proliferation in diabetic mice. Int J Mol Med. 2017;39(4):936–48. https://doi.org/10.3892/ijmm.2017.2914.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Fang Q, et al. Adipocyte-derived stem cell-based gene therapy upon adipogenic differentiation on microcarriers attenuates type 1 diabetes in mice. Stem Cell Res Ther. 2019;10(1):1–11. https://doi.org/10.1186/s13287-019-1135-y.

    Article  CAS  Google Scholar 

  60. Burgess JL, et al. Diabetic wound-healing science. Medicina. 2021;57(10):1072. https://doi.org/10.3390/medicina57101072.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Lee DE, Ayoub N, Agrawal DK. Mesenchymal stem cells and cutaneous wound healing: novel methods to increase cell delivery and therapeutic efficacy. Stem Cell Res Ther. 2016;7(1):1–8. https://doi.org/10.1186/s13287-016-0303-6.

    Article  CAS  Google Scholar 

  62. Patel S, et al. Mechanistic insight into diabetic wounds: Pathogenesis, molecular targets and treatment strategies to pace wound healing. Biomed Pharmacother. 2019;112:108615. https://doi.org/10.1016/j.biopha.2019.108615.

    Article  CAS  PubMed  Google Scholar 

  63. Rea IM, et al. Age and age-related diseases: role of inflammation triggers and cytokines. Front Immunol. 2018;586. https://doi.org/10.3389/fimmu.2018.00586.

  64. Maxson S, et al. Concise review: role of mesenchymal stem cells in wound repair. Stem cells translational medicine. 2012;1(2):142–9. https://doi.org/10.5966/sctm.2011-0018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Nambu M, et al. Accelerated wound healing in healing-impaired db/db mice by autologous adipose tissue-derived stromal cells combined with atelocollagen matrix. Ann Plast Surg. 2009;62(3):317–21. https://doi.org/10.1097/SAP.0b013e31817f01b6.

    Article  CAS  PubMed  Google Scholar 

  66. Liu K, et al. Adipose stem cell-derived exosomes in combination with hyaluronic acid accelerate wound healing through enhancing re‐epithelialization and vascularization. Br J Dermatol. 2019;181(4):854–6. https://doi.org/10.1111/bjd.17984.

    Article  CAS  PubMed  Google Scholar 

  67. Wang L et al. Exosomes secreted by human adipose mesenchymal stem cells promote scarless cutaneous repair by regulating extracellular matrix remodelling (vol 7, 13321, 2017). SCIENTIFIC REPORTS, 2021. 11(1). DOI: https://doi.org/10.1038/s41598-017-12919-x.

  68. Shen T, et al. Accelerated healing of diabetic wound using artificial dermis constructed with adipose stem cells and poly (L-glutamic acid)/chitosan scaffold. Chin Med J. 2013;126(08):1498–503.

    CAS  PubMed  Google Scholar 

  69. Zografou A, et al. Autologous transplantation of adipose-derived stem cells enhances skin graft survival and wound healing in diabetic rats. Ann Plast Surg. 2013;71(2):225–32. https://doi.org/10.1097/SAP.0b013e31826af01a.

    Article  CAS  PubMed  Google Scholar 

  70. Li C, et al. Adipose mesenchymal stem cell-derived Exosomes Promote Wound Healing through the WNT/β-catenin signaling pathway in dermal fibroblasts. Stem Cell Reviews and Reports. 2022;1–15. https://doi.org/10.1007/s12015-022-10378-0.

  71. Moon KM, et al. The effect of secretory factors of adipose-derived stem cells on human keratinocytes. Int J Mol Sci. 2012;13(1):1239–57. https://doi.org/10.3390/ijms13011239.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Ebrahimian T et al. Cell therapy based on adipose tissue-derived stromal cells promotes physiological and pathological wound healing Arteriosclerosis, thrombosis, and vascular biology, 2009. 29(4): p. 503–10. DOI: https://doi.org/10.1161/ATVBAHA.108.17896.

  73. Tutuianu R, et al. Human mesenchymal stromal cell-derived exosomes promote in vitro wound healing by modulating the biological properties of skin keratinocytes and fibroblasts and stimulating angiogenesis. Int J Mol Sci. 2021;22(12):6239. https://doi.org/10.3390/ijms22126239.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Hong SJ, et al. Topically delivered adipose derived stem cells show an activated-fibroblast phenotype and enhance granulation tissue formation in skin wounds. PLoS ONE. 2013;8(1):e55640. https://doi.org/10.1371/journal.pone.0055640.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Poliwoda S, et al. Stem cells: a comprehensive review of origins and emerging clinical roles in medical practice. Orthop Rev. 2022;14(3). https://doi.org/10.52965/001c.37498.

  76. Nie C, et al. Locally administered adipose-derived stem cells accelerate wound healing through differentiation and vasculogenesis. Cell Transplant. 2011;20(2):205–16. https://doi.org/10.3727/096368910X52006.

    Article  PubMed  Google Scholar 

  77. An R, et al. Adipose stem cells isolated from diabetic mice improve cutaneous wound healing in streptozotocin-induced diabetic mice. Stem Cell Res Ther. 2020;11(1):1–11. https://doi.org/10.1186/s13287-020-01621-x.

    Article  CAS  Google Scholar 

  78. Huang S-P, et al. Promotion of wound healing using adipose-derived stem cells in radiation ulcer of a rat model. J Biomed Sci. 2013;20(1):1–10. https://doi.org/10.1186/1423-0127-20-51.

    Article  CAS  Google Scholar 

  79. Mulder GD, Berg JSV. Cellular senescence and matrix metalloproteinase activity in chronic wounds: relevance to debridement and new technologies. J Am Podiatr Med Assoc. 2002;92(1):34–7. https://doi.org/10.7547/87507315-92-1-34.

    Article  PubMed  Google Scholar 

  80. Hao Z, et al. Research progress of adipose-derived stem cells in the treatment of chronic wounds. Front Chem. 2023;11. https://doi.org/10.3389/fchem.2023.1094693.

  81. Xiong J et al. Comparison of proangiogenic effects of adipose-derived stem cells and foreskin fibroblast exosomes on artificial dermis prefabricated flaps Stem Cells International, 2020. 2020. DOI: https://doi.org/10.1155/2020/5293850.

  82. Yoo KH, et al. Comparison of immunomodulatory properties of mesenchymal stem cells derived from adult human tissues. Cell Immunol. 2009;259(2):150–6. https://doi.org/10.1016/j.cellimm.2009.06.010.

    Article  CAS  PubMed  Google Scholar 

  83. Krampera M, et al. Role for interferon-γ in the immunomodulatory activity of human bone marrow mesenchymal stem cells. Stem Cells. 2006;24(2):386–98. https://doi.org/10.1634/stemcells.2005-0008.

    Article  CAS  PubMed  Google Scholar 

  84. Stojanović S, Najman S. The effect of conditioned media of stem cells derived from lipoma and adipose tissue on macrophages’ response and wound healing in indirect co-culture system in vitro. Int J Mol Sci. 2019;20(7):1671. https://doi.org/10.3390/ijms20071671.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Fantin A, et al. Tissue macrophages act as cellular chaperones for vascular anastomosis downstream of VEGF-mediated endothelial tip cell induction. Blood The Journal of the American Society of Hematology. 2010;116(5):829–40. https://doi.org/10.1182/blood-2009-12-257832.

    Article  CAS  Google Scholar 

  86. Morey M, et al. Hyperglycemia acts in synergy with hypoxia to maintain the pro-inflammatory phenotype of macrophages. PLoS ONE. 2019;14(8):e0220577. https://doi.org/10.1371/journal.pone.0220577.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Gao F, et al. Mesenchymal stem cells and immunomodulation: current status and future prospects. Cell Death Dis. 2016;7(1):e2062–2. https://doi.org/10.1038/cddis.2015.327.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Eleuteri S, Fierabracci A. Insights into the secretome of mesenchymal stem cells and its potential applications. Int J Mol Sci. 2019;20(18):4597. https://doi.org/10.3390/ijms20184597.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Honnegowda TM, et al. Role of angiogenesis and angiogenic factors in acute and chronic wound healing. Plast Aesthetic Res. 2015;2:243–9. https://doi.org/10.4103/2347-9264.165438.

    Article  Google Scholar 

  90. Zhao L, Johnson T, Liu D. Therapeutic angiogenesis of adipose-derived stem cells for ischemic diseases. Stem Cell Res Ther. 2017;8(1):1–9. https://doi.org/10.1186/s13287-017-0578-2.

    Article  CAS  Google Scholar 

  91. Rehman J, et al. Secretion of angiogenic and antiapoptotic factors by human adipose stromal cells. Circulation. 2004;109(10):1292–8. https://doi.org/10.1161/01.CIR.0000121425.42966.F1.

    Article  PubMed  Google Scholar 

  92. Schratzberger P, et al. Reversal of experimental diabetic neuropathy by VEGF gene transfer. J Clin Investig. 2001;107(9):1083–92. https://doi.org/10.1172/JCI12188.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Wang C, et al. A pilot study on ex vivo expanded autologous adipose-derived stem cells of improving fat retention in localized scleroderma patients. Stem Cells Translational Medicine. 2021;10(8):1148–56. https://doi.org/10.1002/sctm.20-0419.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Chen L, et al. Autologous nanofat transplantation accelerates foot wound healing in diabetic rats. Regen Med. 2019;14(3):231–41. https://doi.org/10.2217/rme-2018-0169.

    Article  CAS  PubMed  Google Scholar 

  95. Seo E, et al. Exendin-4 in combination with adipose-derived stem cells promotes angiogenesis and improves diabetic wound healing. J translational Med. 2017;15(1):1–9. https://doi.org/10.1186/s12967-017-1145-4.

    Article  CAS  Google Scholar 

  96. Liu R, et al. Adipose-derived stem cells for the treatment of diabetic wound: from basic study to clinical application. Front Endocrinol. 2022;13. https://doi.org/10.3389/fendo.2022.882469.

  97. Kuo Y-R, et al. Adipose-derived stem cells accelerate diabetic wound healing through the induction of autocrine and paracrine effects. Cell Transplant. 2016;25(1):71–81. https://doi.org/10.3727/096368915X687921.

    Article  PubMed  Google Scholar 

  98. Shi R, et al. Localization of human adipose-derived stem cells and their effect in repair of diabetic foot ulcers in rats. Stem Cell Res Ther. 2016;7(1):1–13. https://doi.org/10.1186/s13287-016-0412-2.

    Article  CAS  Google Scholar 

  99. Kaisang L, et al. Adipose-derived stem cells seeded in pluronic F-127 hydrogel promotes diabetic wound healing. J Surg Res. 2017;217:63–74. https://doi.org/10.1016/j.jss.2017.04.032.

    Article  CAS  PubMed  Google Scholar 

  100. Chen L, et al. Adipose-derived stem cells promote diabetic wound healing via the recruitment and differentiation of endothelial progenitor cells into endothelial cells mediated by the VEGF-PLCγ-ERK pathway. Arch Biochem Biophys. 2020;692:108531DOI. https://doi.org/10.1016/j.abb.2020.108531.

    Article  CAS  Google Scholar 

  101. Diao Y, et al. A vascular endothelial growth factor activating transcription factor increases the endothelial progenitor cells population and induces therapeutic angiogenesis in a type 1 diabetic mouse with hindlimb ischemia. Chin Med J. 2014;127(20):3623–9. https://doi.org/10.3760/cma.j.issn.0366-6999.20140883.

    Article  PubMed  Google Scholar 

  102. Li Q, et al. Stromal cell-derived factor-1 promotes human adipose tissue-derived stem cell survival and chronic wound healing. Experimental and therapeutic medicine. 2016;12(1):45–50. https://doi.org/10.3892/etm.2016.3309.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Rennert RC, et al. Stem cell recruitment after injury: lessons for regenerative medicine. Regen Med. 2012;7(6):833–50. https://doi.org/10.2217/rme.12.82.

    Article  CAS  PubMed  Google Scholar 

  104. Wu Q, et al. Stromal cell-derived factor 1 promoted migration of adipose-derived stem cells to the wounded area in traumatic rats. Biochem Biophys Res Commun. 2015;467(1):140–5. https://doi.org/10.1016/j.bbrc.2015.09.097.

    Article  CAS  PubMed  Google Scholar 

  105. Di Rocco G et al. Enhanced healing of diabetic wounds by topical administration of adipose tissue-derived stromal cells overexpressing stromal-derived factor-1: biodistribution and engraftment analysis by bioluminescent imaging Stem cells international, 2010. 2011. DOI: https://doi.org/10.4061/2011/304562.

  106. Li X, et al. Exosomes from adipose-derived stem cells overexpressing Nrf2 accelerate cutaneous wound healing by promoting vascularization in a diabetic foot ulcer rat model. Exp Mol Med. 2018;50(4):1–14. https://doi.org/10.1038/s12276-018-0058-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Mazini L, et al. Hopes and limits of adipose-derived stem cells (ADSCs) and mesenchymal stem cells (MSCs) in wound healing. Int J Mol Sci. 2020;21(4):1306. https://doi.org/10.3390/ijms21041306.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Kim EK, et al. The effect of human adipose-derived stem cells on healing of ischemic wounds in a diabetic nude mouse model. Plast Reconstr Surg. 2011;128(2):387–94. https://doi.org/10.1097/PRS.0b013e31821e6de2.

    Article  CAS  PubMed  Google Scholar 

  109. Ding S, et al. Effect of collagen scaffold with bcl-2-modified adipose-derived stem cells on diabetic mice wound healing. Int J Low Extrem Wounds. 2020;19(2):139–47. https://doi.org/10.1177/1534734619880055.

    Article  CAS  PubMed  Google Scholar 

  110. Kato Y, et al. 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. https://doi.org/10.2337/db14-1133. Epub 2015 Mar 20.

    Article  CAS  PubMed  Google Scholar 

  111. Ebrahim N, et al. Adipose mesenchymal stem cells combined with platelet-rich plasma accelerate diabetic wound healing by modulating the notch pathway. Stem Cell Res Ther. 2021;12(1):1–24. https://doi.org/10.1186/s13287-021-02454-y.

    Article  CAS  Google Scholar 

  112. Wang X, et al. Adipose-derived stem cell-secreted exosomes enhance angiogenesis by promoting macrophage M2 polarization in type 2 diabetic mice with limb ischemia via the JAK/STAT6 pathway. Heliyon. 2022;8(11):e11495. https://doi.org/10.1016/j.heliyon.2022.e11495.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Wang J, et al. Hypoxia adipose stem cell-derived exosomes promote high-quality healing of diabetic wound involves activation of PI3K/Akt pathways. J Nanobiotechnol. 2021;19(1):1–13. https://doi.org/10.1186/s12951-021-00942-0.

    Article  CAS  Google Scholar 

  114. Huang C, et al. Human mesenchymal stem cells promote ischemic repairment and angiogenesis of diabetic foot through exosome miRNA-21-5p. Stem Cell Research. 2021;52:102235. https://doi.org/10.1016/j.scr.2021.102235.

    Article  CAS  PubMed  Google Scholar 

  115. Gangadaran P, et al. Extracellular vesicles from mesenchymal stem cells activates VEGF receptors and accelerates recovery of hindlimb ischemia. J Controlled Release. 2017;264:112–26. https://doi.org/10.1016/j.jconrel.2017.08.022.

    Article  CAS  Google Scholar 

  116. Yu M, et al. Exosomes derived from atorvastatin-pretreated MSC accelerate diabetic wound repair by enhancing angiogenesis via AKT/eNOS pathway. Stem Cell Res Ther. 2020;11:1–17. https://doi.org/10.1186/s13287-020-01824-2.

    Article  CAS  Google Scholar 

  117. An Y, et al. Exosomes from adipose-derived stem cells (ADSCs) overexpressing miR-21 promote vascularization of endothelial cells. Sci Rep. 2019;9(1):12861. https://doi.org/10.1038/s41598-019-49339-y.

    Article  PubMed  PubMed Central  Google Scholar 

  118. Fadini GP, et al. Angiogenic abnormalities in diabetes mellitus: mechanistic and clinical aspects. J Clin Endocrinol Metabolism. 2019;104(11):5431–44. https://doi.org/10.1210/jc.2019-00980.

    Article  Google Scholar 

  119. Seo Y, Shin T-H, Kim H-S. Current strategies to enhance adipose stem cell function: an update. Int J Mol Sci. 2019;20(15):3827. https://doi.org/10.3390/ijms20153827.

    Article  PubMed  PubMed Central  Google Scholar 

  120. Huang W, et al. Fibroblast growth factor 21 enhances angiogenesis and wound healing of human brain microvascular endothelial cells by activating PPARγ. J Pharmacol Sci. 2019;140(2):120–7. https://doi.org/10.1016/j.jphs.2019.03.010.

    Article  CAS  PubMed  Google Scholar 

  121. Oh EJ, et al. In vivo migration of mesenchymal stem cells to burn injury sites and their therapeutic effects in a living mouse model. J Controlled Release. 2018;279:79–88. https://doi.org/10.1016/j.jconrel.2018.04.020.

    Article  CAS  Google Scholar 

  122. Li J, Xiao L, Rao C. Comparison of isolation and biological characteristics of adipose-derived stem cells from human and rat. J Jinan Univ (Natural Sci Med Edition). 2015;36:324–9. https://doi.org/10.1155/2019/1609876.

    Article  CAS  Google Scholar 

  123. Cha H, et al. Stem cell-derived exosomes and nanovesicles: promotion of cell proliferation, migration, and anti-senescence for treatment of wound damage and skin ageing. Pharmaceutics. 2020;12(12):1135. https://doi.org/10.3390/pharmaceutics12121135.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Niu J, et al. MCP-1-induced protein promotes endothelial-like and angiogenic properties in human bone marrow monocytic cells. J Pharmacol Exp Ther. 2013;347(2):288–97. https://doi.org/10.1124/jpet.113.207316.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Chen H, et al. Pleiotropic roles of CXCR4 in wound repair and regeneration. Front Immunol. 2021;12:668758. https://doi.org/10.3389/fimmu.2021.668758.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Jin W, et al. Modelling of the SDF-1/CXCR4 regulated in vivo homing of therapeutic mesenchymal stem/stromal cells in mice. PeerJ. 2018;6:e6072. https://doi.org/10.7717/peerj.6072.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Planat-Benard V, et al. Plasticity of human adipose lineage cells toward endothelial cells: physiological and therapeutic perspectives. Circulation. 2004;109(5):656–63. https://doi.org/10.1161/01.CIR.0000114522.38265.61.

    Article  PubMed  Google Scholar 

  128. Kim H, Hyun MR, Kim SW. The effect of adipose-derived stem cells on wound healing: comparison of methods of application. Stem cells international, 2019. 2019. DOI: https://doi.org/10.1155/2019/2745640.

  129. Yuan X, et al. Strategies for improving adipose-derived stem cells for tissue regeneration. Burns & Trauma. 2022;10. https://doi.org/10.1093/burnst/tkac028.

  130. Dung T, et al. Autologous adipose-derived stem cell (adsc) transplantation in the management of chronic wounds. Annals of Burns and Fire Disasters. 2021;34(4):343.

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Sen S, et al. Genetic modification of human mesenchymal stem cells helps to reduce adiposity and improve glucose tolerance in an obese diabetic mouse model. Stem Cell Res Ther. 2015;6(1):1–14. https://doi.org/10.1186/s13287-015-0224-9.

    Article  CAS  Google Scholar 

  132. Takiishi T, et al. Vitamin D and diabetes. Rheumatic Disease Clinics. 2012;38(1):179–206. https://doi.org/10.1016/j.ecl.2013.09.010.

    Article  PubMed  Google Scholar 

  133. Zatterale F, et al. Chronic adipose tissue inflammation linking obesity to insulin resistance and type 2 diabetes. Front Physiol. 2020;1607. https://doi.org/10.3389/fphys.2019.01607.

  134. Zhou C, et al. Autologous adipose-derived stem cells for the treatment of Crohn’s fistula-in-ano: an open-label, controlled trial. Stem Cell Res Ther. 2020;11(1):1–13. https://doi.org/10.1186/s13287-020-01636-4.

    Article  CAS  Google Scholar 

  135. Weisberg SP, et al. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Investig. 2003;112(12):1796–808. https://doi.org/10.1172/JCI19246.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Yu J, et al. Cell sheet composed of adipose-derived stem cells demonstrates enhanced skin wound healing with reduced scar formation. Acta Biomater. 2018;77:191–200. https://doi.org/10.1016/j.actbio.2018.07.022.

    Article  CAS  PubMed  Google Scholar 

  137. Vanderstichele S, Vranckx JJ. Anti-fibrotic effect of adipose-derived stem cells on fibrotic scars. World J Stem Cells. 2022;14(2):200. https://doi.org/10.4252/wjsc.v14.i2.200.

    Article  PubMed  PubMed Central  Google Scholar 

  138. Zhang J, et al. Spleen-derived anti-inflammatory cytokine IL-10 stimulated by adipose tissue-derived stem cells protects against type 2 diabetes. Stem Cells Dev. 2017;26(24):1749–58. https://doi.org/10.1089/scd.2017.0119.

    Article  CAS  PubMed  Google Scholar 

  139. Shapiro AJ, et al. Insulin expression and C-peptide in type 1 diabetes subjects implanted with stem cell-derived pancreatic endoderm cells in an encapsulation device. Cell Rep Med. 2021;2(12):100466. https://doi.org/10.1016/j.xcrm.2021.100466.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Araujo DB, et al. Allogenic adipose tissue-derived stromal/stem cells and vitamin D supplementation in patients with recent-onset type 1 diabetes mellitus: a 3-month follow-up pilot study. Front Immunol. 2020;11:993. https://doi.org/10.3389/fimmu.2020.00993.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Lu J, et al. One repeated transplantation of allogeneic umbilical cord mesenchymal stromal cells in type 1 diabetes: an open parallel controlled clinical study. Stem Cell Res Ther. 2021;12(1):1–10. https://doi.org/10.1186/s13287-021-02417-3.

    Article  CAS  Google Scholar 

  142. Estrada EJ, et al. Combination treatment of autologous bone marrow stem cell transplantation and hyperbaric oxygen therapy for type 2 diabetes mellitus: a randomized controlled trial. Cell Transplant. 2019;28(12):1632–40. https://doi.org/10.1177/0963689719883813.

    Article  PubMed  PubMed Central  Google Scholar 

  143. Al Demour S, et al. Safety and efficacy of 2 intracavernous injections of allogeneic Wharton’s jelly-derived mesenchymal stem cells in diabetic patients with erectile dysfunction: phase 1/2 clinical trial. Urol Int. 2021;105(11–12):935–43. https://doi.org/10.1159/000517364.

    Article  CAS  PubMed  Google Scholar 

  144. Lee W-S, et al. Intra-articular injection of autologous adipose tissue-derived mesenchymal stem cells for the treatment of knee osteoarthritis: a phase IIb, randomized, placebo-controlled clinical trial. Stem cells translational medicine. 2019;8(6):504–11. https://doi.org/10.1002/sctm.18-0122.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Zhang Y et al. The Effect of Autologous Adipose-Derived Stromal Vascular Fractions on Cartilage Regeneration Was Quantitatively Evaluated Based on the 3D-FS-SPGR Sequence: A Clinical Trial Study BioMed Research International, 2022. 2022. DOI: https://doi.org/10.1155/2022/2777568.

  146. Freitag J, et al. Adipose-derived mesenchymal stem cell therapy in the treatment of knee osteoarthritis: a randomized controlled trial. Regen Med. 2019;14(3):213–30. https://doi.org/10.2217/rme-2018-0161.

    Article  CAS  PubMed  Google Scholar 

  147. Carstens MH, et al. Treatment of chronic diabetic foot ulcers with adipose-derived stromal vascular fraction cell injections: Safety and evidence of efficacy at 1 year. Stem cells translational medicine. 2021;10(8):1138–47. https://doi.org/10.1002/sctm.20-0497.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Kumar H, et al. Safety and tolerability of intradiscal implantation of combined autologous adipose-derived mesenchymal stem cells and hyaluronic acid in patients with chronic discogenic low back pain: 1-year follow-up of a phase I study. Stem Cell Res Ther. 2017;8(1):1–14. https://doi.org/10.1186/s13287-017-0710-3.

    Article  CAS  Google Scholar 

  149. Kastrup J, et al. Cryopreserved off-the-shelf allogeneic adipose-derived stromal cells for therapy in patients with ischemic heart disease and heart failure—a safety study. Stem Cells Translational Medicine. 2017;6(11):1963–71. https://doi.org/10.1002/sctm.17-0040.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Huang K-C et al. Transplantation with GXHPC1 for liver cirrhosis: phase 1 trial Cell Transplantation, 2019. 28(1_suppl): p. 100S-111S. DOI: https://doi.org/10.1177/0963689719884885.

  151. Carstens M, et al. Sustained clinical improvement of Parkinson’s disease in two patients with facially-transplanted adipose-derived stromal vascular fraction cells. J Clin Neurosci. 2020;81:47–51. https://doi.org/10.1016/j.jocn.2020.09.001.

    Article  CAS  PubMed  Google Scholar 

  152. Qayyum AA, et al. Autologous adipose-derived stromal cell treatment for patients with refractory angina (MyStromalCell Trial): 3-years follow-up results. J Translational Med. 2019;17(1):1–9. https://doi.org/10.1186/s12967-019-2110-1.

    Article  CAS  Google Scholar 

  153. Abumoawad A, et al. A phase 1a escalating clinical trial, autologous mesenchymal stem cell infusion for renovascular disease increases blood flow and the glomerular filtration rate while reducing inflammatory biomarkers and blood pressure. Kidney Int. 2020;97(4):793–804. https://doi.org/10.1016/j.kint.2019.11.022.

    Article  CAS  PubMed  Google Scholar 

  154. Paitazoglou C, et al. Rationale and design of the european multicentre study on Stem Cell therapy in IschEmic non-treatable cardiac diseasE (SCIENCE). Eur J Heart Fail. 2019;21(8):1032–41. https://doi.org/10.1002/ejhf.1412.

    Article  PubMed  Google Scholar 

  155. Squassoni SD, et al. Autologous infusion of bone marrow and mesenchymal stromal cells in patients with chronic obstructive Pulmonary Disease: phase I randomized clinical trial. Int J Chronic Obstr Pulm Dis. 2021;16:3561. https://doi.org/10.2147/COPD.S332613.

    Article  Google Scholar 

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Tajali, R., Eidi, A., Tafti, H.A. et al. Transplantation of adipose derived stem cells in diabetes mellitus; limitations and achievements. J Diabetes Metab Disord 22, 1039–1052 (2023). https://doi.org/10.1007/s40200-023-01280-8

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