Regenerative Properties of Recombinant Human Erythropoietin in the Wound Healing




EPO, wound healing, VEGF, reepithelization, skin, erythropietin


BACKGROUND: Erythropoietin (EPO) is the main stimulator of erythropoiesis, but EPO also has non-hematopoietic effects. The recent data show the positive effects of EPO on tissue regeneration.

AIM: This review aims to know highlights the pathophysiological mechanisms of EPO at different stages of tissue regeneration, and possible clinical applications in wound healing.

METHODS: A review of the literature considering reviews, clinical studies, original papers, and articles from electronic data has been used.

RESULTS: Analysis of animal studies and several clinical trials using EPO in context of wound healing revealed that EPO has a positive effect on all stages of regeneration process and may be a promising therapeutic strategy for the treatment of chronic wounds.

CONCLUSION: An improved understanding of the functions and regulatory mechanisms of EPO in the context of wound healing may lead to new considerations of this growth hormone for its regular clinical application in patients.


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Peng B, Kong G, Yang C, Ming Y. Erythropoietin and its derivatives: From tissue protection to immune regulation. Cell Death Dis. 2020;11:79. DOI:

Suyono H, Sanjaya K, Susanti D. The role of antiapoptotic erythropoietin on ultraviolet B-induced photodamaged skin through inhibition of sunburn cells. Fol Med Indones. 2020;56(2):2114-7. DOI:

French C. Erythropoietin in critical illness and trauma. Crit Care Clin. 2019;35(2):277-87. PMid:30784609 DOI:

Chamorro ME. Role of protein tyrosine phosphatase 1B (PTP1B) in the increased sensitivity of endothelial cells to a promigratory effect of erythropoietin in an inflammatory environment. Biol Chem. 2020;401(10):1167-80. PMid:32386183 DOI:

Lee YM, Choi JH, Min WK, Han JK, Oh JW. Induction of functional erythropoietin and erythropoietin receptor gene expression by gamma-aminobutyric acid and piperine in kidney epithelial cells. Life Sci. 2018;215(15):207-15. PMid:30439377 DOI:

Kimáková P, Solár P, Solárová Z, Komel R, Debeljak N. Erythropoietin and its angiogenic activity. Int J Mol Sci. 2017;18(7):1519. PMid:28703764 DOI:

Teramo KA, Klemetti MM, Widness JA. Robust increases in erythropoietin production by the hypoxic fetus is a response to protect the brain and other vital organs. Pediatr Res. 2018;84(6):807-12. PMid:29895839 DOI:

Collino M, Thiemermann C, Cerami A, Brines M. Flipping the molecular switch for innate protection and repair of tissues: Long-lasting effects of a non-erythropoietic small peptide engineered from erythropoietin. Pharmacol Ther. 2015;151:32- 40. PMid:25728128 DOI:

Hamed S, Ullmann Y, Egozi D, Keren A, Daod E, Anis O, et al. Topical erythropoietin treatment accelerates the healing of cutaneous burn wounds in diabetic pigs through an aquaporin- 3-dependent mechanism. Diabetes. 2017;66(8):2254-65. PMid:28546424 DOI:

Siebert N, Xu W, Grambow E, Zechner D, Vollmar B. Erythropoietin improves skin wound healing and activates the TGF-β signaling pathway. Lab Invest. 2011;91(12):1753-65. PMid:21894148 DOI:

Javadmoosavi S Y, Parsamanesh N, Afshar M, Zardast M, Ghaderi R. Comparison of the effects of systemic and subcutaneous injection of recombinant human erythropoietin on the tissue-healing process in BALB/c Mice. J Surg Trauma. 2020;8(1):16-22. DOI:

Sayan H, Ozacmak VH, Guven A, Aktas RG, Ozacmak ID. Erythropoietin stimulates wound healing and angiogenesis in mice. J Invest Surg. 2006;19(3):163-73. / 08941930600674694 PMid:16809226 DOI:

Bader A, Ebert S, Giri S, Kremer M, Liu S, Nerlich A, et al. Skin regeneration with conical and hair follicle structure of deep second-degree scalding injuries via combined expression of the EPO receptor and beta common receptor by local subcutaneous injection of nanosized rhEPO. Int J Nanomed. 2012;7:1227-37. PMid:22419870 DOI:

Erbayraktar Z, Erbayraktar S, Yilmaz O, Cerami A, Coleman T, Brines M. Nonerythropoietic tissue protective compounds are highly effective facilitators of wound healing. Mol Med. 2009;15(7- 8):235-41. PMid:19593407 DOI:

Bodó E, Kromminga A, Funk W, Laugsch M, Duske U, Jelkmann W, et al. Human hair follicles are an extrarenal source and a nonhematopoietic target of erythropoietin. FASEB J. 2007;21(12):3346-54. PMid:17540710 DOI:

Paus R, Bodó E, Kromminga A, Jelkmann W. Erythropoietin and the skin: A role for epidermal oxygen sensing? Bioessays. 2009;31(3):344-8. PMid:19260015 DOI:

Buemi M, Galeano M, Sturiale A, Ientile R, Crisafulli C, Parisi A, et al. Recombinant human erythropoietin stimulates angiogenesis and healing of ischemic skin wounds. Shock. 2004;22(2):169- 73. PMid:15257091 DOI:

Galeano M, Altavilla D, Cucinotta D, Russo GT, Calò M, Bitto A, et al. Recombinant human erythropoietin stimulates angiogenesis and wound healing in the genetically diabetic mouse. Diabetes. 2004;53(9):2509-17. PMid:15331568 DOI:

Hamed S, Ullmann Y, Egozi D, Daod E, Hellou E, Ashkar M, et al. Fibronectin potentiates topical erythropoietin-induced wound repair in diabetic mice. J Invest Dermatol. 2011;131(6):1365-75. PMid:21326299 DOI:

Imam RA, Rizk AA. Efficacy of erythropoietin-pretreated mesenchymal stem cells in murine burn wound healing: Possible in vivo transdifferentiation into keratinocytes. Folia Morphol (Warsz). 2019;78(4):798-808. PMid:30949996 DOI:

Holderfield MT, Hughes CC. Crosstalk between vascular endothelial growth factor, notch, and transforming growth factor-beta in vascular morphogenesis. Circ Res. 2008;102(6):637-52. PMid:18369162 DOI:

Corwin HL, Gettinger A, Fabian TC, May A, Pearl RG, Heard S, et al. Efficacy and safety of epoetin alfa in critically ill patients. N Engl J Med. 2007;357(10):965-76. PMid:17804841 DOI:

Brines M, Patel NS, Villa P, Brines C, Mennini T, De Paola M, et al. Nonerythropoietic, tissue-protective peptides derived from the tertiary structure of erythropoietin. Proc Natl Acad Sci U S A. 2008;105(31):10925-30. PMid:18676614 DOI:

Bor-Kucukatay M, Yalcin O, Meiselman HJ, Baskurt OK. Erythropoietin-induced rheological changes of rat erythrocytes. Br J Haematol. 2000;110(1):82-8. PMid:10930982 DOI:

Kwaan HC, Wang J. Hyperviscosity in polycythemia vera and other red cell abnormalities. Semin Thromb Hemost. 2003;29(5):451-8. PMid:14631544 DOI:

Chatzikyrkou C, Bahlmann FH, Sushakova N, Scurt FG, Menne J, Nawroth P, et al. Low-dose erythropoietin promotes wound-healing of ulcers in diabetics: Evidence from a phase-IIa clinical study. Diabetes Metab. 2016;42(6):466-70. PMid:27324461 DOI:

Günter CI, Machens HG, Ilg FP, Hapfelmeier A, Jelkmann W, Egert-Schwender S, et al. A randomized controlled trial: Regenerative effects, efficacy and safety of erythropoietin in burn and scalding injuries. Front Pharmacol. 2018;9:951. PMid:30429786 DOI:

Hamed S, Belokopytov M, Ullmann Y, Safadi M, Stark Y, Shoufani A, et al. Interim results of the remede d’Or study: A multicenter, single-blind, randomized, controlled trial to assess the safety and efficacy of an innovative topical formulation of erythropoietin for treating diabetic foot ulcers. Adv Wound Care (New Rochelle). 2019;8(10):514-21. PMid:31832270 DOI:

Ferri C, Giuggioli D, Sebastiani M, Colaci M. Treatment of severe scleroderma skin ulcers with recombinant human erythropoietin. Clin Exp Dermatol. 2007;32(3):287-90. PMid:17397351 DOI:

Günter CI, Kern L, Giri S, Machens HG, Bader A. First results on three patients treated with topical recombinant human erythropoietin (rhEPO) to improve wound healing in diabetic foot ulcers. J Transplant Stem Cell Biol. 2015;2(1):2-5. / 2374-9326.1000007 DOI:

Keast DH, Fraser C. Treatment of chronic skin ulcers in individuals with anemia of chronic disease using recombinant human erythropoietin (EPO): A review of four cases. Ostomy Wound Manage. 2004;50(10):64-70. PMid:15509883




How to Cite

Toleubayev M, Dmitriyeva M, Kozhakhmetov S, Igissinov N, Turebayev M, Omarbekov A, Adaibayev K, Shakenov A, Izimbergenov M. Regenerative Properties of Recombinant Human Erythropoietin in the Wound Healing. Open Access Maced J Med Sci [Internet]. 2021 Apr. 4 [cited 2023 Mar. 21];9(F):113-7. Available from:



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