Erythropoietin modulation of podocalyxin and a proposed erythroblast niche

Abstract

Epo's erythropoietic capacity is ascribed largely to its antiapoptotic actions. In part via gene profiling of bone marrow erythroblasts, Epo is now shown to selectively down-modulate the adhesion/migration factors chemokine receptor-4 (Cxcr4) and integrin alpha-4 (Itga4) and to up-modulate growth differentiation factor-3 (Gdf3), oncostatin-M (OncoM), and podocalyxin like-1 (PODXL). For PODXL, Epo dose-dependent expression of this CD34-related sialomucin was discovered in Kit(+)CD71(high) proerythroblasts and was sustained at subsequent Kit(-)CD71(high) and Ter119(+) stages. In vivo, Epo markedly induced PODXL expression in these progenitors and in marrow-resident reticulocytes. This was further associated with a rapid release of PODXL(+) reticulocytes to blood. As studied in erythroblasts expressing minimal Epo receptor (EpoR) alleles, efficient PODXL induction proved dependence on an EpoR-PY343 Stat5 binding site. Moreover, in mice expressing an EpoR-HM F343 allele, compromised Epo-induced PODXL expression correlated with abnormal anucleated red cell representation in marrow. By modulating this select set of cell-surface adhesion molecules and chemokines, Epo is proposed to mobilize erythroblasts from a hypothesized stromal niche and possibly promote reticulocyte egress to blood.

Raves and risks for erythropoietin

“…Closely linked to these transcription pathways are the mitogen-activated protein kinases that include the extracellular signal-related kinases (ERKs), the c-Jun-amino terminal kinases, and p38 MAP kinase that can oversee erythroid proliferation and differentiation [3,47]. Yet, in regards to cytoprotection, EPO has been shown to not only activate STAT 3 [17,44], STAT 5 [13,17], and ERK 1/2 [17], but also to employ these pathways for cell development and cell protection. For example, EPO significantly activates STAT3, STAT5, and ERK 1/2 in primary cerebral vascular cells, suggesting that EPO may require these cellular pathways to confer EC cytoprotection during oxidative stress [17].…”

“…This results in an elevation in the number of mature erythrocytes and the improvement of oxygen supply. EPO also functions to stimulate colony-forming erythroid cells to induce these cells to proliferate, mature into erythrocytes, and possibly assist with reticulocyte release to the blood [13].…”

“…At the cellular level, EPO plays a critical role in the vascular and renal systems. EPO can maintain erythrocyte [13] and podocyte [43] integrity, regulate the survival of ECs [21,26], and function as a powerful endogenous protectant during cardiac injury [44].…”

“…This results in an elevation in the number of mature erythrocytes and the improvement of oxygen supply. EPO also functions to stimulate colony-forming erythroid cells to induce these cells to proliferate, mature into erythrocytes, and possibly assist with reticulocyte release to the blood [13].In most tissues including the brain, hypoxia-dependent expression of EPO and EPOR are controlled by hypoxia-inducible factor 1 (HIF-1). HIF-1 is essential for the production and secretion of EPO in response to hypoxia.…”

Hematopoiesis and bone remodeling

“…1 Instead, they suggested the involvement of Oncostatin M (OsM), which is produced by erythroblasts. 5 OsM is one of the cytokines that bind to and signal through the gp130 co-receptor subunit including IL-6, IL-11, leukemia inhibitory factor (LIF), cardiotrophin-1 (CT-1), and ciliary neutrophic factor (CNTF). Apart from contributing to inflammation, gp130 signaling cytokines also function in the maintenance of bone homeostasis.…”