Human hair follicles are an extrarenal source and a nonhematopoietic target of erythropoietin

Abstract

Erythropoietin primarily serves as an essential growth factor for erythrocyte precursor cells. However, there is increasing evidence that erythropoietin (EPO)/EPO receptor (EPO-R) signaling operates as a potential tissue-protective system outside the bone marrow. Arguing that growing hair follicles (HF) are among the most rapidly proliferating tissues, we have here explored whether human HFs are sources of EPO and targets of EPO-R-mediated signaling. Human scalp skin and microdissected HFs were assessed for EPO and EPO-R expression, and the effects of EPO on organ-cultured HFs were assessed in the presence/absence of a classical apoptosis-inducing chemotherapeutic agent. Here, we show that human scalp HFs express EPO on the mRNA and protein level in situ, up-regulate EPO transcription under hypoxic conditions, and express transcripts for EPO-R and the EPO-stimulatory transcriptional cofactor hypoxia-inducible factor-1alpha. Although EPO does not significantly alter human hair growth in vitro, it significantly down-regulates chemotherapy-induced intrafollicular apoptosis and changes the gene expression program of the HFs. The current study points to intriguing targets of EPO beyond the erythropoietic system: human HFs are an extrarenal site of EPO production and an extrahematopoietic site of EPO-R expression. They may recruit EPO/EPO-R signaling e.g., for modulating HF apoptosis under conditions of hypoxia and chemotherapy-induced stress.

Erythropoietin improves skin wound healing and activates the TGF-β signaling pathway

“…Both EPO and EPOR transcripts were detected in hair bulbs of hair follicles. 19 In addition, EPO-like immunoreactivity was observed in hair follicle epithelium and in large blood vessels of human scalp. 19 Moreover, in vitro studies demonstrated the expression of EPOR by melanocytes.…”

“…19 In addition, EPO-like immunoreactivity was observed in hair follicle epithelium and in large blood vessels of human scalp. 19 Moreover, in vitro studies demonstrated the expression of EPOR by melanocytes. 20 In this study, we demonstrate that non-wounded and wounded skin of the mouse as well as murine primary fibroblasts and keratinocytes express EPOR.…”

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

“…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. In contrast with the homodimer hematopoietic EPO receptor (EPOR), 12 the tissue protective receptor is postulated to be a heterodimer formed by the EPO receptor in assembly with the βCR subunit, otherwise known as CD131, which is also used by other type I cytokines.…”

Erythropoietin-induced upregulation of endothelial nitric oxide synthase but not vascular endothelial growth factor prevents musculocutaneous tissue from ischemic damage

“…13 NO is an enzymatic product from L-arginine that mediates numerous biological actions through the activation of cyclic guanosine monophosphate, which inhibits intracellular calcium release and induces smooth muscle relaxation. 14 As EPO and its receptor are also present in human skin, 15 ischemic wound complications and tissue necrosis might be prevented by administration of EPO. Despite advances in surgical techniques, patients may still suffer from wound breakdown and ischemic necrosis.…”