Interactive Role of Trauma Cytokines and Erythropoietin and Their Therapeutic Potential for Acute and Chronic Wounds

Abstract

If controllable, stem cell activation following injury has the therapeutic potential for supporting regeneration in acute or chronic wounds. Human dermally-derived stem cells (FmSCs) were exposed to the cytokines interleukin-6 (IL-6), IL-1β, and tumor necrosis factor-α (TNF-α) in the presence of erythropoietin (EPO). Cells were cultured under ischemic conditions and phenotypically characterized using flow cytometry. Topical EPO application was performed in three independent clinical wound healing attempts. The FmSCs expressed the receptor for EPO. EPO had a strong inhibitory effect on FmSC growth in the absence of IL-6 and TNF-α. With IL-6, the EPO effects were reversed to that of growth stimulation. TNF-α had the strongest stimulatory effect. In contrast, IL-1β had an inhibitory effect. Topically applied EPO considerably enhanced wound healing and improved wound conditions of acute and chronic wounds. Site specificity of stem cell activation is mediated by IL-6 and TNF-α. In trauma, EPO ceases its inhibitory role and reverts to a clinically relevant boosting function. EPO may be an important therapeutic tool for the topical treatment of acute and chronic wounds.

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

“…19 We have previously demonstrated that EPO has an inhibitory effect on skin cells and stem cells in the normal ("healthy") environment, but the presence of inflammatory cytokines in the case of hypoxic skin conditions changes the function of EPO to one of stimulating stem cell proliferation and differentiation. 6,17 We were able to confirm this inhibitory effect of EPO by the above-described gene and protein expression results. Herndon et al 18 investigated growth hormone enhancement for re-epithelialization in burns patients and concluded that growth hormone affects wound healing and tissue repair.…”

“…Bodó et al 8 have previously reported on immunohistological and RNA expression of EPO and EPOR transcripts in the outer root sheath stem cells of the hair follicle and further on EPOR expression in human dermally derived fetal mesenchymal stem cells. 6 Therefore, it might be a promising approach to restore the deficiency of EPO using an exogenous supply to enhance healing of dermal thermal injuries.…”

“…5,6 So far, no publications could be found concerning the coexpression of βCR in addition to EPOR in dermal thermal injuries. Here we describe for the first time RNA expression of βCR during scald healing and report our results for the detection of EPOR and βCR expression in deep second-degree scalds ( Figure 4A).…”

“…In recent years, several studies have been conducted in which rhEPO was used successfully to stimulate angiogenesis and enhance wound healing, for example, by systemic application in both normal and genetically diabetic mice, 3,4 via topical treatment in a diabetic rat model, 5 and in our previous study of acute and chronic wounds in humans. 6 Moreover, a number of studies have reported that rhEPO affects the proliferation and differentiation of erythroid progenitor cells in hematopoietic organs, as well as nonhematopoietic cell types and organs, and plays a central role in tissue protection. [7][8][9][10][11] Although these reports have had encouraging outcomes, the lack of proof of common β subunit receptor (βCR) expression as the relevant tissue-based target for rhEPO in wound repair has been an important but missing link to explain the success of rhEPO in skin wound regeneration.…”

New Strategies in Clinical Care of Skin Wound Healing

“…Mesenchymal stem cells, when grown under hypoxic conditions and with the addition of IL-6 to the culture medium, showed decreased proliferation rates, but when EPO was also added this changed to increased proliferation rates [39]. …”