Erythropoietin in brain development and beyond

Abstract

Erythropoietin is known as the requisite cytokine for red blood cell production. Its receptor, expressed at a high level on erythroid progenitor/precursor cells, is also found on endothelial, neural, and other cell types. Erythropoietin and erythropoietin receptor expression in the developing and adult brain suggest their possible involvement in neurodevelopment and neuroprotection. During ischemic stress, erythropoietin, which is hypoxia inducible, can contribute to brain homeostasis by increasing red blood cell production to increase the blood oxygen carrying capacity, stimulate nitric oxide production to modulate blood flow and contribute to the neurovascular response, or act directly on neural cells to provide neuroprotection as demonstrated in culture and animal models. Clinical studies of erythropoietin treatment in stroke and other diseases provide insight on safety and potential adverse effects and underscore the potential pleiotropic activity of erythropoietin. Herein, we summarize the roles of EPO and its receptor in the developing and adult brain during health and disease, providing first a brief overview of the well-established EPO biology and signaling, its hypoxic regulation, and role in erythropoiesis.

Figure 1

Erythropoietin signaling. EPO binding to the homodimeric EpoR on the cell surface changes the conformation of EpoR and brings the respective cytoplasmic domains in closer proximity resulting in transphosphorylation and activation of the associated Janus kinase JAK2 proteins. JAK2 activation results in phosphorylation, dimerization, and translocation of signal transducer and activator of transcription (STAT) proteins, and activation of other downstream signaling pathways such as mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K/AKT), and, in neuronal cells, nuclear factor-(NF-) κB (p50 and p65) with dissociation and degradation of the inhibitory IκB protein.

Figure 2

Erythropoietin receptor expression in mice during brain development. (a) Quantification of EpoR mRNA in mouse brain (circles) compared with liver (triangles) beginning at embryonic day E10 from Liu et al., [68]. (b) Hypoplasia of neuroepithelium of the fourth ventricle at embryonic day E12.5 in EpoR^−/− embryo (right) compared with EpoR^+/+ embryo (left) (bars, 0.4 mm) from Yu et al., [69].

Figure 3

Ischemic brain injury and erythropoietin neuroprotection. EpoR expression by neurons mediates a direct neuroprotective EPO response. EPO production in astrocytes and neurons and EPO crossing the blood-brain barrier that is compromised during injury contribute to increased EPO in the local microenvironment. Endothelial cell EPO response can contribute indirectly to neuroprotection via improved oxygen delivery and secretion of neurotrophic factors.