In addition to the miRNAs listed in the previous 3 paragraphs, many other miRNAs are also abundant and developmentally regulated during erythroid differentiation. RBC levels are normally tightly regulated by Epo, which stimulates erythropoiesis by promoting survival, proliferation, and terminal differentiation of CFU-E cells and more mature erythroblasts. However, because each Epo-responsive CFU-E cell in the bone marrow can undergo only 3 to 5 terminal cell divisions under maximum Epo stimulation, the number of CFU-E cells limits the maximum Epo-dependent erythrocyte output.
Steady-state erythropoiesis alone is therefore not able to correct the RBC deficiency during extreme conditions, such as recovery from bone marrow irradiation or chronic anemia. During such conditions of stress erythropoiesis, new CFU-E are produced from the most immature committed definitive erythroid progenitor cells, the BFU-E cells.
The ability of BFU-E progenitors to undergo limited self-renewal during stress erythropoiesis allows rescue of lethally irradiated mice from anemia, and retransplantation also protects secondary and tertiary recipients.
Early observations showed that erythropoiesis moves from the bone marrow to the spleen during stress erythropoiesis Figure 3. BFU-E self-renewal: The probability of erythroid progenitor self-renewal versus differentiation depends on extrinsic and intrinsic factors.
Although BFU-E self-renewal is very limited during steady-state erythropoiesis in the bone marrow, it is virtually limitless in the spleen during conditions of stress erythropoiesis. The cytokines Scf, Bmp4, and Shh promote self-renewal in addition, as does stimulation by GCs and hypoxia. Release of cortisol from the adrenal glands is increased during conditions of stress erythropoiesis, such as sepsis or severe trauma.
The therapeutic effect of the GC analog prednisone in patients with the RBC progenitor disorder Diamond-Blackfan anemia is well documented, although severe side effects limit its use. Mice that lack the GC receptor or express only a GC receptor defective in DNA binding and transactivation have normal steady-state erythropoiesis, whereas stress erythropoiesis is severely impaired.
Identification of BFU-E as the target cell of GCs in stress erythropoiesis, together with our novel method to isolate BFU-E, will allow studies toward development of novel erythropoiesis-stimulating agents that act by promoting SE by the same mechanisms used by GCs. SCF Kit ligand exists both in a soluble and a membrane-bound form. Kit signaling is important not only for erythroid progenitor proliferation but also for HSC growth, mast cell function, melanogenesis, and spermatogenesis.
Bone morphogenetic protein 4 BMP4 is also essential for stress erythropoiesis. The flexed-tail mouse strain, which expresses a dominant-negative Smad5 mutant that inhibits BMP4 signaling, exhibits a neonatal anemia that resolves 2 weeks after birth. These studies have provided profound insights into the multiple complex mechanisms by which the body regulates the number of RBCs within a narrow normal range. Equally importantly, they provide novel insights into possible treatments for anemias and other RBC disorders.
Furthermore, deeper understanding of mechanisms regulating BFU-E self-renewal and thus the output of CFU-E progenitors and mature erythroid cells could result in the development of drugs that stimulate the physiologic mechanisms of stress erythropoiesis.
Correspondence: Harvey F. Sign In or Create an Account. Sign In. Skip Nav Destination Content Menu. Close Abstract. Extracellular signals regulating proliferation and differentiation of CFU-E progenitors. Transcriptional regulators of erythroid proliferation and function. Epigenetic changes in chromatin during erythroid differentiation. Interplay of cell cycle and terminal erythroid differentiation.
Histone deacetylation and erythroblast enucleation. Regulation of erythropoiesis by miRNAs. Article Navigation. Red Cells, Iron, and Erythropoiesis December 8, From stem cell to red cell: regulation of erythropoiesis at multiple levels by multiple proteins, RNAs, and chromatin modifications Shilpa M.
Hattangadi , Shilpa M. This Site. Google Scholar. Lingbo Zhang , Lingbo Zhang. Johan Flygare , Johan Flygare. Harvey F. Lodish Harvey F. Blood 24 : — Article history Submitted:. Cite Icon Cite. Figure 1. View large Download PPT. Figure 2. Table 1 microRNAs are important regulators for erythropoiesis. Organism and experimental system. View Large. Figure 3. National Institutes of Health. Contribution: S. Conflict-of-interest disclosure: The authors declare no competing financial interests.
With aging, hemoglobin and hematocrit Hct decrease slightly, but not below normal values. In menstruating women, the most common cause of lower RBC levels is iron deficiency due to chronic blood loss resulting from menstruation.
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Common Health Topics. Videos Figures Images Quizzes Symptoms. Endogenously produced erythropoietin circulates in the plasma to act on specific target cells in the marrow through cell surface receptors.
The primary target of erythropoietin action is the erythroid colony-forming cell. Male sex hormone works in the kidneys to increase the production of renal erythropoietic factor, therefore increasing the amount of active erythropoietin to act in the bone marrow.
This is the indirect effect. The direct effect involves sex hormones acting directly on base cells in the bone marrow. Female sexual hormones act directly on bone marrow cells and cause a decrease in the production of DNA, RNA and proteins in the cells therefore reducing the rate of erythropoiesis.
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