A Mini-Review on Fibroblast-Derived Exosomes as Wound Healing Stimulators
-
Alireza Sadeghi Moghaddam Bijari
,
Mahdi Alijanianzadeh
,
Hoda Keshmiri Neghab
,
Mohammad Hasan Soheilifar
Abstract
The skin is a vital organ that plays a crucial role in healing disruptions and abnormalities. Cutaneous wound healing faces some obstacles in certain abnormalities, including in diabetic patients. Various therapeutic approaches have been explored to enhance healing and restore skin integrity.
In recent years, exosomes have been introduced as a new cell-free therapy for wound healing. They are defined as naturally secreted nanovesicles released from most cell types into the extracellular space that can impact many targeted cells. In contrast to previous methods, exosomes have a longer half-life in target tissue and exert a more lasting effect. They also have fewer side effects thanks to their natural biological source.
Exosomes derived from mesenchymal stem cells (MSCs) have been widely studied for their therapeutic potential, but those from other cell types, such as fibroblasts, remain less explored. This review aims to comprehensively evaluate existing research on the wound-healing effects of fibroblast-derived exosomes (FB-EXOs), highlighting their potential as a novel treatment strategy.
1. Liu Y, Wang H, Wang J. Exosomes as a novel pathway for regulating development and diseases of the skin. Biomed Rep. 2018;8(3):207–14.
2. Rani S, Ritter T. The exosome‐A naturally secreted nanoparticle and its application to wound healing. Adv Mater. 2016;28(27):5542–52.
3. Broughton II G, Janis JE, Attinger CE. Wound healing: an overview. Plast Reconstr Surg. 2006; 117(7Suppl):1e-S-32e-S.
4. Deshmukh CD, Jain A, Nahata B. Diabetes mellitus: a review. Int J Pure App Biosci. 2015;3(3):224–30.
5. Li X, Xie X, Lian W, 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.
6. Han X, Wu P, Li L, et al. Exosomes derived from autologous dermal fibroblasts promote diabetic cutaneous wound healing through the Akt/β-catenin pathway. Cell Cycle. 2021;20(5–6):616–29.
7. Snyder RJ, Hanft JR. Diabetic foot ulcers--effects on QOL, costs, and mortality and the role of standard wound care and advanced-care therapies. Ostomy Wound Manage. 2009;55(11):28–38.
8. Yazdanpanah L, Nasiri M, Adarvishi S. Literature review on the management of diabetic foot ulcer. World J Diabetes. 2015;6(1):37-53.
9. Chavda VP, Pandya A, Kumar L, et al. Exosome nanovesicles: A potential carrier for therapeutic delivery. Nano Today. 2023;49:101771.
10. Hajialiasgary Najafabadi A, Soheilifar MH, Masoudi-Khoram N. Exosomes in skin photoaging: biological functions and therapeutic opportunity. Cell Commun Signal. 2024;22(1):32.
11. Gonzalez AC de O, Costa TF, Andrade Z de A, et al. Wound healing-A literature review. An Bras Dermatol. 2016;91(5):614–20.
12. Enoch S, Leaper DJ. Basic science of wound healing. Surgery (Oxford). 2008;26(2):31–37.
13. Mester A, Opincariu D, Benedek I, et al. Stem cell therapy in wound healing. J Interdiscip Med. 2017;2(s4):20–4.
14. Oneto P, Etulain J. PRP in wound healing applications. Platelets. 2021;32(2):189–99.
15. Lv H, Liu H, Sun T, et al. Exosome derived from stem cell: A promising therapeutics for wound healing. Front Pharmacol. 2022;13:957771.
16. Shi A, Li J, Qiu X, et al. TGF-β loaded exosome enhances ischemic wound healing in vitro and in vivo. Theranostics. 2021;11(13):6616-6631.
17. Wong VW, Sorkin M, Gurtner GC. Enabling stem cell therapies for tissue repair: current and future challenges. Biotechnol Adv. 2013;31(5):744–51.
18. Duscher D, Barrera J, Wong VW, et al. Stem cells in wound healing: The future of regenerative medicine? A mini-review. Gerontology. 2016;62(2):216–25.
19. desJardins-Park HE, Foster DS, Longaker MT. Fibroblasts and wound healing: an update. Regen Med. 2018;13(5):491-495.
20. Patil AA, Rhee WJ. Exosomes: biogenesis, composition, functions, and their role in pre-metastatic niche formation. Biotechnology and Bioprocess Engineering. 2019;24:689–701.
21. Li X, Corbett AL, Taatizadeh E, et al. Challenges and opportunities in exosome research—Perspectives from biology, engineering, and cancer therapy. APL Bioeng. 2019;3(1):011503.
22. Yue B, Yang H, Wang J, et al. Exosome biogenesis, secretion and function of exosomal miRNAs in skeletal muscle myogenesis. Cell Prolif. 2020;53(7):e12857.
23. Nilforoushzadeh MA, Ashtiani HRA, Jaffary F, et al. Dermal fibroblast cells: biology and function in skin regeneration. J Skin Stem Cell. 2017; 4(2):e69080.
24. Haniffa MA, Collin MP, Buckley CD, et al. Mesenchymal stem cells: the fibroblasts’ new clothes? Haematologica. 2009;94(2):258-63.
25. Hu S, Li Z, Cores J, et al. Needle-free injection of exosomes derived from human dermal fibroblast spheroids ameliorates skin photoaging. ACS Nano. 2019;13(10):11273–82.
26. D’Urso M, Kurniawan NA. Mechanical and Physical Regulation of Fibroblast–Myofibroblast Transition: From Cellular Mechanoresponse to Tissue Pathology. Front Bioeng Biotechnol. 2020:8:609653.
27. Ahmadpour F, Rasouli HR, Talebi S, et al. Effects of exosomes derived from fibroblast cells on skin wound healing in Wistar rats. Burns. 2023; 49(6):1372-1381.
28. Oh EJ, Gangadaran P, Rajendran RL, et al. Extracellular vesicles derived from fibroblasts promote wound healing by optimizing fibroblast and endothelial cellular functions. Stem Cells. 2021;39(3):266–79.
29. Yoo K, Thapa N, Lee J, et al. Dermal fibroblast cell‐derived exosomes for atopic dermatitis: in‐vitro test. Skin Res Technol. 2023;29(7):e13382.
30. Zhang J, Guan J, Niu X, et al. Exosomes released from human induced pluripotent stem cells-derived MSCs facilitate cutaneous wound healing by promoting collagen synthesis and angiogenesis. J Transl Med. 2015:13:49.
31. Xia W, Li M, Jiang X, et al. Young fibroblast-derived exosomal microRNA-125b transfers beneficial effects on aged cutaneous wound healing. J Nanobiotechnology. 2022;20(1):144.
32. Clément V, Roy V, Paré B, et al. Tridimensional cell culture of dermal fibroblasts promotes exosome-mediated secretion of extracellular matrix proteins. Sci Rep. 2022;12(1):19786.
33. Zou Q, Zhang M, Yuan R, et al. Small extracellular vesicles derived from dermal fibroblasts promote fibroblast activity and skin development through carrying miR-218 and ITGBL1. J Nanobiotechnology. 2022;20(1):296.
34. Fafián-Labora JA, Rodríguez-Navarro JA, O’Loghlen A. Small extracellular vesicles have GST activity and ameliorate senescence-related tissue damage. Cell Metab. 2020;32(1):71–86.e5.
35. Roy V, Paquet A, Touzel‐Deschênes L, et al. Heterozygous NF1 dermal fibroblasts modulate exosomal content to promote angiogenesis in a tissue‐engineered skin model of neurofibromatosis type‐1. J Neurochem. 2023;167(4):556–570.
36. Bhandari R, Yang H, Kosarek NN, et al. Human dermal fibroblast-derived exosomes induce macrophage activation in systemic sclerosis. Rheumatology (Oxford). 2023;62(SI):SI114-SI124.
37. Wang P, Theocharidis G, Vlachos IS, et al. Exosomes derived from epidermal stem cells improve diabetic wound healing. J Invest Dermatol. 2022;142(9):2508-2517.e13.
38. Cui HS, Joo SY, Lee SY, et al. Effect of Hypertrophic Scar Fibroblast-Derived Exosomes on Keratinocytes of Normal Human Skin. Int J Mol Sci. 2023;24(7):6132.
39. Yoo K, Thapa N, Lee J, et al. Dermal fibroblast cell‐derived exosomes for atopic dermatitis: In‐vitro test. Skin Res Technol. 2023;29(7):e13382.
40. Zhang X, Huang J, Zhao J, et al. Exosome-mimetic vesicles derived from fibroblasts carrying matrine for wound healing. Burns Trauma. 2024:12:tkae015.
41. Eelen G, de Zeeuw P, Treps L, et al. Endothelial cell metabolism. Physiol Rev. 2018;98(1):3–58.
42. Jin W, Li Y, Yu M, et al. Advances of exosomes in diabetic wound healing. Burns Trauma. 2025;13:tkae078.
43. Jiang D, de Vries JC, Muschhammer J, et al. Local and transient inhibition of p21 expression ameliorates age‐related delayed wound healing. Wound Repair Regen. 2020;28(1):49–60.
44. Su CW, Lin CW, Yang WE, et al. TIMP-3 as a therapeutic target for cancer. Ther Adv Med Oncol. 2019:11:1758835919864247.
45. Kasolang S, Adlina WA, Rahman NA, et al. Common skin disorders: a review. J Tribol. 2020;25:59–82.
46. Radner FPW, Fischer J. The important role of epidermal triacylglycerol metabolism for maintenance of the skin permeability barrier function. Biochim Biophys Acta. 2014;1841(3):409-15.
47. Burgy O, Königshoff M. The WNT signaling pathways in wound healing and fibrosis. Matrix Biol. 2018:68-69:67-80.
48. Soheilifar MH, Masoudi-Khoram N. Wound dressings incorporating microRNAs: Innovative therapy for diabetic wound treatment. Iran J Basic Med Sci. 2022;25(9):1042-1044.
49. Zhou S, Zhang P, Liang P, et al. The expression of miR-125b regulates angiogenesis during the recovery of heat-denatured HUVECs. Burns. 2015;41(4):803–11.
50. Blank MF, Grummt I. The seven faces of SIRT7. Transcription. 2017;8(2):67-74.
51. Guo F, Carter DE, Leask A. miR-218 regulates focal adhesion kinase–dependent TGFβ signaling in fibroblasts. Mol Biol Cell. 2014;25(7):1151–8.
52. Miller R, Wormald JCR, Wade RG, et al. Systematic review of fibrin glue in burn wound reconstruction. Br J Surg. 2019;106(3):165-173.
53. Hopfner U, Aitzetmueller MM, Neßbach P, et al. Fibrin Glue Enhances Adipose-Derived Stromal Cell Cytokine Secretion and Survival Conferring Accelerated Diabetic Wound Healing. Stem Cells Int. 2018:2018:1353085.
54. Badekila AK, Kini S, Jaiswal AK. Fabrication techniques of biomimetic scaffolds in three‐dimensional cell culture: A review. J Cell Physiol. 2021;236(2):741–62.
55. Zhou H, Xiao J, Wu N, et al. MicroRNA-223 regulates the differentiation and function of intestinal dendritic cells and macrophages by targeting C/EBPβ. Cell Rep. 2015;13(6):1149–60.
56. Tahamtan A, Teymoori-Rad M, Nakstad B, et al. Anti-inflammatory microRNAs and their potential for inflammatory diseases treatment. Front Immunol. 2018;9:1377.
57. Colletti M, Galardi A, De Santis M, et al. Exosomes in systemic sclerosis: messengers between immune, vascular and fibrotic components? Int J Mol Sci. 2019;20(18):4337.
58. Sgonc R, Gruber J. Age-related aspects of cutaneous wound healing: a mini-review. Gerontology. 2013;59(2):159–64.
59. Erlendsson AM, Haedersdal M, Rossi AM. Needle‐free injection assisted drug delivery—histological characterization of cutaneous deposition. Lasers Surg Med. 2020;52(1):33–37.
2. Rani S, Ritter T. The exosome‐A naturally secreted nanoparticle and its application to wound healing. Adv Mater. 2016;28(27):5542–52.
3. Broughton II G, Janis JE, Attinger CE. Wound healing: an overview. Plast Reconstr Surg. 2006; 117(7Suppl):1e-S-32e-S.
4. Deshmukh CD, Jain A, Nahata B. Diabetes mellitus: a review. Int J Pure App Biosci. 2015;3(3):224–30.
5. Li X, Xie X, Lian W, 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.
6. Han X, Wu P, Li L, et al. Exosomes derived from autologous dermal fibroblasts promote diabetic cutaneous wound healing through the Akt/β-catenin pathway. Cell Cycle. 2021;20(5–6):616–29.
7. Snyder RJ, Hanft JR. Diabetic foot ulcers--effects on QOL, costs, and mortality and the role of standard wound care and advanced-care therapies. Ostomy Wound Manage. 2009;55(11):28–38.
8. Yazdanpanah L, Nasiri M, Adarvishi S. Literature review on the management of diabetic foot ulcer. World J Diabetes. 2015;6(1):37-53.
9. Chavda VP, Pandya A, Kumar L, et al. Exosome nanovesicles: A potential carrier for therapeutic delivery. Nano Today. 2023;49:101771.
10. Hajialiasgary Najafabadi A, Soheilifar MH, Masoudi-Khoram N. Exosomes in skin photoaging: biological functions and therapeutic opportunity. Cell Commun Signal. 2024;22(1):32.
11. Gonzalez AC de O, Costa TF, Andrade Z de A, et al. Wound healing-A literature review. An Bras Dermatol. 2016;91(5):614–20.
12. Enoch S, Leaper DJ. Basic science of wound healing. Surgery (Oxford). 2008;26(2):31–37.
13. Mester A, Opincariu D, Benedek I, et al. Stem cell therapy in wound healing. J Interdiscip Med. 2017;2(s4):20–4.
14. Oneto P, Etulain J. PRP in wound healing applications. Platelets. 2021;32(2):189–99.
15. Lv H, Liu H, Sun T, et al. Exosome derived from stem cell: A promising therapeutics for wound healing. Front Pharmacol. 2022;13:957771.
16. Shi A, Li J, Qiu X, et al. TGF-β loaded exosome enhances ischemic wound healing in vitro and in vivo. Theranostics. 2021;11(13):6616-6631.
17. Wong VW, Sorkin M, Gurtner GC. Enabling stem cell therapies for tissue repair: current and future challenges. Biotechnol Adv. 2013;31(5):744–51.
18. Duscher D, Barrera J, Wong VW, et al. Stem cells in wound healing: The future of regenerative medicine? A mini-review. Gerontology. 2016;62(2):216–25.
19. desJardins-Park HE, Foster DS, Longaker MT. Fibroblasts and wound healing: an update. Regen Med. 2018;13(5):491-495.
20. Patil AA, Rhee WJ. Exosomes: biogenesis, composition, functions, and their role in pre-metastatic niche formation. Biotechnology and Bioprocess Engineering. 2019;24:689–701.
21. Li X, Corbett AL, Taatizadeh E, et al. Challenges and opportunities in exosome research—Perspectives from biology, engineering, and cancer therapy. APL Bioeng. 2019;3(1):011503.
22. Yue B, Yang H, Wang J, et al. Exosome biogenesis, secretion and function of exosomal miRNAs in skeletal muscle myogenesis. Cell Prolif. 2020;53(7):e12857.
23. Nilforoushzadeh MA, Ashtiani HRA, Jaffary F, et al. Dermal fibroblast cells: biology and function in skin regeneration. J Skin Stem Cell. 2017; 4(2):e69080.
24. Haniffa MA, Collin MP, Buckley CD, et al. Mesenchymal stem cells: the fibroblasts’ new clothes? Haematologica. 2009;94(2):258-63.
25. Hu S, Li Z, Cores J, et al. Needle-free injection of exosomes derived from human dermal fibroblast spheroids ameliorates skin photoaging. ACS Nano. 2019;13(10):11273–82.
26. D’Urso M, Kurniawan NA. Mechanical and Physical Regulation of Fibroblast–Myofibroblast Transition: From Cellular Mechanoresponse to Tissue Pathology. Front Bioeng Biotechnol. 2020:8:609653.
27. Ahmadpour F, Rasouli HR, Talebi S, et al. Effects of exosomes derived from fibroblast cells on skin wound healing in Wistar rats. Burns. 2023; 49(6):1372-1381.
28. Oh EJ, Gangadaran P, Rajendran RL, et al. Extracellular vesicles derived from fibroblasts promote wound healing by optimizing fibroblast and endothelial cellular functions. Stem Cells. 2021;39(3):266–79.
29. Yoo K, Thapa N, Lee J, et al. Dermal fibroblast cell‐derived exosomes for atopic dermatitis: in‐vitro test. Skin Res Technol. 2023;29(7):e13382.
30. Zhang J, Guan J, Niu X, et al. Exosomes released from human induced pluripotent stem cells-derived MSCs facilitate cutaneous wound healing by promoting collagen synthesis and angiogenesis. J Transl Med. 2015:13:49.
31. Xia W, Li M, Jiang X, et al. Young fibroblast-derived exosomal microRNA-125b transfers beneficial effects on aged cutaneous wound healing. J Nanobiotechnology. 2022;20(1):144.
32. Clément V, Roy V, Paré B, et al. Tridimensional cell culture of dermal fibroblasts promotes exosome-mediated secretion of extracellular matrix proteins. Sci Rep. 2022;12(1):19786.
33. Zou Q, Zhang M, Yuan R, et al. Small extracellular vesicles derived from dermal fibroblasts promote fibroblast activity and skin development through carrying miR-218 and ITGBL1. J Nanobiotechnology. 2022;20(1):296.
34. Fafián-Labora JA, Rodríguez-Navarro JA, O’Loghlen A. Small extracellular vesicles have GST activity and ameliorate senescence-related tissue damage. Cell Metab. 2020;32(1):71–86.e5.
35. Roy V, Paquet A, Touzel‐Deschênes L, et al. Heterozygous NF1 dermal fibroblasts modulate exosomal content to promote angiogenesis in a tissue‐engineered skin model of neurofibromatosis type‐1. J Neurochem. 2023;167(4):556–570.
36. Bhandari R, Yang H, Kosarek NN, et al. Human dermal fibroblast-derived exosomes induce macrophage activation in systemic sclerosis. Rheumatology (Oxford). 2023;62(SI):SI114-SI124.
37. Wang P, Theocharidis G, Vlachos IS, et al. Exosomes derived from epidermal stem cells improve diabetic wound healing. J Invest Dermatol. 2022;142(9):2508-2517.e13.
38. Cui HS, Joo SY, Lee SY, et al. Effect of Hypertrophic Scar Fibroblast-Derived Exosomes on Keratinocytes of Normal Human Skin. Int J Mol Sci. 2023;24(7):6132.
39. Yoo K, Thapa N, Lee J, et al. Dermal fibroblast cell‐derived exosomes for atopic dermatitis: In‐vitro test. Skin Res Technol. 2023;29(7):e13382.
40. Zhang X, Huang J, Zhao J, et al. Exosome-mimetic vesicles derived from fibroblasts carrying matrine for wound healing. Burns Trauma. 2024:12:tkae015.
41. Eelen G, de Zeeuw P, Treps L, et al. Endothelial cell metabolism. Physiol Rev. 2018;98(1):3–58.
42. Jin W, Li Y, Yu M, et al. Advances of exosomes in diabetic wound healing. Burns Trauma. 2025;13:tkae078.
43. Jiang D, de Vries JC, Muschhammer J, et al. Local and transient inhibition of p21 expression ameliorates age‐related delayed wound healing. Wound Repair Regen. 2020;28(1):49–60.
44. Su CW, Lin CW, Yang WE, et al. TIMP-3 as a therapeutic target for cancer. Ther Adv Med Oncol. 2019:11:1758835919864247.
45. Kasolang S, Adlina WA, Rahman NA, et al. Common skin disorders: a review. J Tribol. 2020;25:59–82.
46. Radner FPW, Fischer J. The important role of epidermal triacylglycerol metabolism for maintenance of the skin permeability barrier function. Biochim Biophys Acta. 2014;1841(3):409-15.
47. Burgy O, Königshoff M. The WNT signaling pathways in wound healing and fibrosis. Matrix Biol. 2018:68-69:67-80.
48. Soheilifar MH, Masoudi-Khoram N. Wound dressings incorporating microRNAs: Innovative therapy for diabetic wound treatment. Iran J Basic Med Sci. 2022;25(9):1042-1044.
49. Zhou S, Zhang P, Liang P, et al. The expression of miR-125b regulates angiogenesis during the recovery of heat-denatured HUVECs. Burns. 2015;41(4):803–11.
50. Blank MF, Grummt I. The seven faces of SIRT7. Transcription. 2017;8(2):67-74.
51. Guo F, Carter DE, Leask A. miR-218 regulates focal adhesion kinase–dependent TGFβ signaling in fibroblasts. Mol Biol Cell. 2014;25(7):1151–8.
52. Miller R, Wormald JCR, Wade RG, et al. Systematic review of fibrin glue in burn wound reconstruction. Br J Surg. 2019;106(3):165-173.
53. Hopfner U, Aitzetmueller MM, Neßbach P, et al. Fibrin Glue Enhances Adipose-Derived Stromal Cell Cytokine Secretion and Survival Conferring Accelerated Diabetic Wound Healing. Stem Cells Int. 2018:2018:1353085.
54. Badekila AK, Kini S, Jaiswal AK. Fabrication techniques of biomimetic scaffolds in three‐dimensional cell culture: A review. J Cell Physiol. 2021;236(2):741–62.
55. Zhou H, Xiao J, Wu N, et al. MicroRNA-223 regulates the differentiation and function of intestinal dendritic cells and macrophages by targeting C/EBPβ. Cell Rep. 2015;13(6):1149–60.
56. Tahamtan A, Teymoori-Rad M, Nakstad B, et al. Anti-inflammatory microRNAs and their potential for inflammatory diseases treatment. Front Immunol. 2018;9:1377.
57. Colletti M, Galardi A, De Santis M, et al. Exosomes in systemic sclerosis: messengers between immune, vascular and fibrotic components? Int J Mol Sci. 2019;20(18):4337.
58. Sgonc R, Gruber J. Age-related aspects of cutaneous wound healing: a mini-review. Gerontology. 2013;59(2):159–64.
59. Erlendsson AM, Haedersdal M, Rossi AM. Needle‐free injection assisted drug delivery—histological characterization of cutaneous deposition. Lasers Surg Med. 2020;52(1):33–37.
| Files | ||
| Issue | Vol 19 No 3 (2025) | |
| Section | Review Article(s) | |
| Keywords | ||
| Exosomes; Fibroblasts; Wound healing; Stem cell research | ||
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How to Cite
1.
Sadeghi Moghaddam Bijari A, Alijanianzadeh M, Keshmiri Neghab H, Soheilifar MH. A Mini-Review on Fibroblast-Derived Exosomes as Wound Healing Stimulators. Int J Hematol Oncol Stem Cell Res. 2025;19(3):237-247.
