The Glucocorticoid Receptor Cooperates With the Erythropoietin Receptor and c-Kit to Enhance and Sustain Proliferation of Erythroid Progenitors In Vitro

Abstract

Although erythropoietin (Epo) is essential for the production of mature red blood cells, the cooperation with other factors is required for a proper balance between progenitor proliferation and differentiation. In avian erythroid progenitors, steroid hormones cooperate with tyrosine kinase receptors to induce renewal of erythroid progenitors. We examined the role of corticosteroids in the in vitro expansion of primary human erythroid cells in liquid cultures and colony assays. Dexamethasone (Dex), a synthetic glucocorticoid hormone, cooperated with Epo and stem cell factor to induce erythroid progenitors to undergo 15 to 22 cell divisions, corresponding to a 105- to 106-fold amplification of erythroid cells. Dex acted directly on erythroid progenitors and maintained the colony-forming capacity of the progenitor cells expanded in liquid cultures. The hormone delayed terminal differentiation into erythrocytes, which was assayed by morphology, hemoglobin accumulation, and the expression of genes characteristic for immature cells. Sustained proliferation of erythroid progenitors could be induced equally well from purified erythroid burst-forming units (BFU-E), from CD34+ blast cells, and from bone marrow depleted from CD34+ cells.

Mononuclear cells from a rare blood donor, after freezing under good manufacturing practice conditions, generate red blood cells that recapitulate the rare blood phenotype

“…The development of culture techniques, defined by us as human erythroid massive amplification (HEMA) cultures, which produce large numbers of cultured RBCs (cRBCs),10‐14 allowed studies that demonstrate that CD34 pos cells from various sources generate ex vivo great numbers of erythroblasts (ERYs) that mature into functional RBCs . A subsequent study demonstrated that autologous cRBCs generated by mobilized CD34 pos cells survive in vivo as long as their natural counterpart, providing the proof of concept that cRBCs may be used for transfusion .…”

The influence of extracellular matrix proteins and mesenchymal stem cells on erythropoietic cell maturation

“…This development is controlled by multiple growth factors, the two most important being the glycoproteins EPO and SCF [33,34]. A variety of other factors, such as insulin‐like growth factor 1, transforming growth factor‐ß and glucocorticoids, have been proposed to have a supportive effect on human RBC development [35–37]. However, despite this increasing knowledge about soluble factors influencing erythropoiesis, little is known about the impact of stromal cells and various ECM proteins on erythropoiesis and whether these factors may arrest or induce the lineage‐committed maturation of HSCs into RBCs.…”

Concise Review: Stem Cell-Based Approaches to Red Blood Cell Production for Transfusion

“…Under conditions of stress such as erythrolysis or hypoxia, rapid expansion of erythroid precursors is achieved in vivo by what is defined as “stress erythropoiesis.” Mimicking stress erythropoiesis, erythroid precursors can be expanded in vitro by activation of the glucocorticoid receptor [65, 66]. Along with SCF, EPO, and insulin‐like growth factor I, a glucocorticoid receptor agonist such as dexamethasone has been shown to induce proliferation of erythroid precursors on the order of 10 5 to 10 6 [66, 67]. Even with better protocols, the amplification fold of CB‐derived erythroid precursors is restricted to <10 10 ‐fold [66].…”