The non-hematopoietic biological effects of erythropoietin

Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
British Journal of Haematology (Impact Factor: 4.71). 05/2008; 141(1):14-31. DOI: 10.1111/j.1365-2141.2008.07014.x
Source: PubMed


In the haematopoietic system, the principal function of erythropoietin (Epo) is the regulation of red blood cell production, mediated by its specific cell surface receptor (EpoR). Following the cloning of the Epo gene (EPO) and characterization of the selective haematopoietic action of Epo in erythroid lineage cells, recombinant Epo forms (epoetin-alfa, epoetin-beta and the long-acting analogue darbepoetin-alfa) have been widely used for treatment of anaemia in chronic kidney disease and chemotherapy-induced anaemia in cancer patients. Ubiquitous EpoR expression in non-erythroid cells has been associated with the discovery of diverse biological functions for Epo in non-haematopoietic tissues. During development, Epo-EpoR signalling is required not only for fetal liver erythropoiesis, but also for embryonic angiogenesis and brain development. A series of recent studies suggest that endogenous Epo-EpoR signalling contributes to wound healing responses, physiological and pathological angiogenesis, and the body's innate response to injury in the brain and heart. Epo and its novel derivatives have emerged as major tissue-protective cytokines that are being investigated in the first human studies involving neurological and cardiovascular diseases. This review focuses on the scientific evidence documenting the biological effects of Epo in non-haematopoietic tissues and discusses potential future applications of Epo and its derivatives in the clinic.

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    • "Rather, EPO exerts its dynamic control over red cell formation by supporting the growth, survival, and differentiation of the progeny of erythroid committed progenitor cells, with the highest amounts of EPOR being found on late progenitor cells such as CFU-E. Once EPO has bound and activated EPOR, a cascade of events is set in motion, including activation of the dimerized receptor [35] and signal transduction through JAK2, Stat5, MAP kinase protein kinase, PI3 kinase, and protein kinase C [36]. The actions of EPO include promotion of the survival of sensitive progenitors through prevention of apoptotic processes, stimulation of proliferation [37], and differentiation into large numbers of hemoglobinized cells. "
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    ABSTRACT: Erythropoiesis is a vital process governed through various factors. There is extreme unavailability of suitable donor due to rare phenotypic blood groups and other related complications like hemoglobinopathies, polytransfusion patients, and polyimmunization. Looking at the worldwide scarcity of blood, especially in low income countries and the battlefield, mimicking erythropoiesis using ex vivo methods can provide an efficient answer to various problems associated with present donor derived blood supply system. Fortunately, there are many ex vivo erythropoiesis methodologies being developed by various research groups using stem cells as the major source material for large scale blood production. Most of these ex vivo protocols use a cocktail of similar growth factors under overlapping growth conditions. Erythropoietin (EPO) is a key regulator in most ex vivo protocols along with other growth factors such as SCF, IL-3, IGF-1, and Flt-3. Now transfusable units of blood can be produced by using these protocols with their set of own limitations. The present paper focuses on the molecular mechanism and significance of various growth factors in these protocols that shall remain helpful for large scale production.
    09/2014; 8. DOI:10.1155/2014/426520
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    • "Moderate expression of goldfish epor was also observed in non-hematopoietic tissues such as the heart, gill, and brain, which is similar to the expression profile of epor in zebrafish (Paffett-Lugassy et al., 2007). The epor expression in other goldfish tissues is consitant with reports that mammalian EPO/EPOR signaling plays roles not only erythropoiesis but also several non-hematopoietic functions including neurogenesis, neuroprotection, wound healing, and cardiovascular protection (Arcasoy, 2008; Marzo et al., 2008). It would be hard to deny a possibility that there would be residual erythrocytes in these tissues and these cells would contribute to the epor mRNA transcript levels observed. "
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    ABSTRACT: Erythropoietin receptor (EPOR) is a member of the class I cytokine receptor superfamily and signaling through this receptor is important for the proliferation, differentiation and survival of erythrocyte progenitor cells. This study reports on the molecular and functional characterization of goldfish EPOR. The identified goldfish EPOR sequence possesses the conserved EPOR ligand binding domain, the fibronectin domain, the class I cytokine receptor superfamily motif (WSXWS) as well as several intracellular signaling motifs characteristic of other vertebrate EPORs. The expression of epor mRNA in goldfish tissues, cell populations and cells treated with recombinant goldfish EPO (rgEPO) were evaluated by quantitative PCR revealing that goldfish epor mRNA is transcribed in both erythropoietic tissues (blood, kidney and spleen) and non-hematopoietic tissues (brain, heart and gill), as well as in immature erythrocytes. Recombinant goldfish EPOR (rgEPOR), consisting of its extracellular domain, dose-dependently inhibited proliferation of progenitor cells induced by rgEPO. In vitro binding studies indicated that rgEPO exists as monomer, dimer and/or trimmer and that rgEPOR exists as monomer and/or homodimer, and when incubated together, formed a ligand–receptor complex. Our results demonstrate that goldfish EPO/EPOR signaling has been highly conserved throughout vertebrate evolution as a required mechanism for erythrocyte development.
    Developmental & Comparative Immunology 08/2014; 45(2):191-198. DOI:10.1016/j.dci.2014.02.017 · 2.82 Impact Factor
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    • "The tissue protective effects of EPO require higher concentrations but systemic administration of EPO would also fully activate its haematopoietic and vascular activities, like pro-coagulopathy and haemodynamic effects. To avoid these adverse effects, we chose to put EPO into the scaffold instead of using a systemic application [15]. In 2010, de Spiegelaere et al. localized EPO in and around growing cartilage, suggesting a role in cartilage formation and early endochondral ossification [46]. "
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    ABSTRACT: All available treatment options for osteochondral and chondral defects do not restore hyaline cartilage and are limited to decreasing associated pain, and maintaining or improving joint function. The purpose of this study was to evaluate the potential of erythropoietin (EPO) in combination with bone marrow aspiration concentrate (BMAC) in the treatment of osteochondral defects of mini-pigs. 14 Goettinger mini-pigs, in which a 6×10 mm osteochondral defect in the medial femoral condyle of both knee joints was created, were randomized into four groups: biphasic scaffold alone, scaffold with EPO, scaffold with BMAC and scaffold in combination with EPO and BMAC. After 26 weeks all animals were euthanized and histological slides were evaluated using a modified ÓDriscoll Score. In the therapy groups, areas of chondrogenic tissue that contained collagen II were present. Adding EPO (p = 0.245) or BMAC (p = 0.099) alone to the scaffold led to a non-significant increase in the score compared to the control group. However, the combination of EPO and BMAC in the implanted scaffold showed a significant improvement (p = 0.02) in the histological score. The results of our study show that in mini-pigs, the combination of EPO and BMAC leads to an enhanced osteochondral healing. However, additional research is necessary to further improve the repair tissue and to define the role of MSCs and EPO in cartilage repair.
    PLoS ONE 03/2014; 9(3):e92766. DOI:10.1371/journal.pone.0092766 · 3.23 Impact Factor
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