What hormone stimulates the production of red blood cells by bone marrow?

Erythropoiesis

Erythropoiesis is the process whereby a fraction of primitive multipotent HSCs becomes committed to the red-cell lineage. Erythropoiesis involves highly specialized functional differentiation and gene expression. The main role of RBCs is to carry O2 in the blood by the hemoglobin molecule. Therefore, erythropoiesis needs to be tightly regulated to maintain homeostasis and to meet changes in O2 supply and demand.

The principal factor in the regulation of erythropoiesis is the hormone erythropoietin (Epo), essential for definitive erythropoiesis in all vertebrates studied to date. Epo binds the erythropoietin receptor (EpoR) on erythroid progenitors, stimulating a conserved intracellular signaling program that regulates vertebrate erythropoiesis. In fish, Epo and its receptor have low amino-acid sequence identity compared with mammalian species, and recombinant human Epo is inactive in fish. Even so, the critical functional residues and the physiological role in the regulation of erythropoiesis are well conserved.

Erythropoiesis and Erythroid Iron Intake

Erythropoiesis is one of the most important physiological processes, essential to all basic organ activities and for survival. Functional erythropoiesis requires a constant support of iron. For this reason, erythropoiesis profoundly influences iron metabolism in order to provide a constant supply of this metal to developing erythroid cells. Conversely, lack of iron negatively modulates erythropoiesis, as chronic insufficiency of iron can lead to severe anemia. Due to its fundamental role for survival, it is not surprising that erythropoiesis exhibits great plasticity under condition of stress. For instance, erythropoiesis can respond very rapidly to insufficient production or loss of red cells (i.e., at high altitude or following a trauma), by expanding the proliferation of erythroid precursors and synthesis of red cells. This process is indicated as stress erythropoiesis (SE). Escalation of red cells synthesis requires the concerted activity of erythropoietin (EPO), iron, and stress erythropoiesis macrophage activity (SEMA). SEMA supports the erythroid proliferation by iron-dependent and iron-independent mechanisms.

The Janus kinase-2 (Jak2) is a signaling molecule that regulates proliferation, differentiation, and survival of erythroid progenitor cells in response to EPO. When EPO binds to its receptor, JAK2 is phosphorylated and activated. This triggers the proliferation of erythroid progenitors, mostly by the activity of the transcriptional factor STAT5. SEMA is an EPO-complementary function supporting erythroid development, particularly under stress conditions. This function likely requires direct contact between macrophages and erythroid progenitors, suggesting that macrophage–erythroblast adhesion interactions are essential to support SEMA.

Of the iron transported by transferrin, 80% is utilized for the production of erythrocytes, resulting in the formation of approximately 2 × 1011 new cells at steady state each day. Consequently, iron metabolism in erythroid cells is tightly regulated and depends highly on cellular iron availability.

After the binding of either mono- or biferric Tf to TfR1 on the membrane of erythroid precursors, and subsequent endosomal translocation of the resulting Tf-TfR complex, the Tf-bound iron is liberated and exported to the cytoplasm. Within erythroid cells, the transmembrane protein mitoferrin ensures transferal of the imported iron to the mitochondria, where it is employed for the synthesis of heme from protoporphyrin IX, as well as the production of iron–sulfur proteins. Although the synthetic pathway of heme takes place partly within and partly outside of the mitochondrial structure, the mechanism by which the heme(-precursor) is transported to the cytoplasm is currently unknown. In the cytoplasm, the heme is primarily used for the formation of α- and β-globins, and two of each subunits eventually associate to form Hb.

When the intracellular iron level is low, IRP1/2 bind an IRE element present in the mRNA, regulating the synthesis of heme, reducing its translation, and thereby limiting the utilization of iron. Heme deficiency, either caused by a shortage of iron or by a downregulation of the heme production, limits, in turn, the production of α- and β-globins through the heme-regulated eIF2α kinase. In addition, while the association of IRP1 with the IRE in the mRNA regulating ferroportin expression suppresses ferroportin expression and limits cellular iron egress, this mechanism may be circumvented in early erythroid progenitors, which express an additional, IRP1/2-IRE-insensitive type of ferroportin (FPN1B), allowing the export of iron from these cells in low-iron circumstances. On a systemic level, a reduced iron concentration weakens the responsiveness of EPO/EPO receptor-mediated signaling, slowing down erythropoiesis to ensure availability of iron for other essential purposes. Additionally, HFE, which is involved in hepcidin regulation in the liver, is shown to be involved in erythroid iron metabolism as well, possibly by limiting the erythroid iron uptake when systemic availability of iron is restricted.

Erythropoiesis

Erythropoiesis is a highly regulated, multistep process by which the body generates mature RBCs or erythrocytes. During mammalian development, erythropoiesis consists of two major waves: (1) primitive erythropoiesis, which is initiated in the yolk sac with the generation of large nucleated erythroblasts, and (2) definitive erythropoiesis, which arises from the fetal liver with the development of smaller enucleated erythrocytes [14]. Definitive erythropoiesis in fetal liver features the production of enucleated RBCs that quickly become dominant in embryonic circulation. The switch of hemoglobin to fetal types (α2γ2) also occurs at the initiation of definitive erythropoiesis [15–17]. However, reports show that yolk sac–derived primitive erythroblasts can also enucleate in the circulation of a mouse embryo and persist throughout gestation [18,19].

In adults, all blood cell types, including lymphocytes, myeloid cells, and RBCs, are derived from HSCs residing in the bone marrow. The initial differentiation of a multipotential HSC into a common myeloid progenitor (CMP) determines its capacity to differentiate further into granulocytes, erythrocytes, megakaryocytes, and macrophages, but not lymphoid cells. As the CMP continues to differentiate, it undergoes significant expansion and will eventually commit to one particular lineage. Erythroid unilineage commitment leads to the appearance of the pronormoblast (also called the proerythroblast or rubriblast). The pronormoblast will then pass through early, intermediate, and late normoblast (erythroblast) stages before expelling its nucleus and becoming a reticulocyte. Upon exiting the bone marrow, reticulocytes enter the blood circulation and become fully mature RBCs, expressing adult forms of hemoglobin (α2β2) and delivering oxygen to tissues of the body. They circulate for about 120 days before they are engulfed by macrophages and recycled [20]. The various stages of erythropoiesis can also be distinguished by characteristic morphological features in the cell cytoplasm and nucleus, which become evident after Wright–Giemsa staining. In addition, using an in vitro colony-forming assay, CMP progenitors can be identified by their ability to form a characteristic colony-forming unit (CFU), called the CFU–granulocyte, erythroid, macrophage, megakaryocyte (GEMM) whereas early erythroid progenitors develop into burst-forming units–erythroid (BFU-E), and late erythroid progenitors become CFU-erythroid (CFU-E) in this assay [14].

Erythropoiesis

Erythropoiesis is a complex multi-step process that involves the differentiation of hematopoietic stem cells (HSCs) into mature erythrocytes (red blood cells, RBCs). Erythropoiesis begins when a multi-potential HSC undergoes erythroid uni-lineage commitment and continues through the proliferation and terminal maturation of the erythroid committed progenitor cell. This process is highly regulated and involves multiple steps, including the differentiation of early erythroid progenitors (burst-forming units-erythroid, BFU-E) to late erythroid progenitors (colony-forming units-erythroid, CFU-E), and finally leads to the terminal enucleation and maturation of RBCs. Because of its functional importance in early development, erythroid lineage appears first during ontogeny in the blood island of the yolk sac. Later, different anatomic sites, such as the fetal liver and finally the bone marrow (BM), are recruited for erythropoiesis.

During mammalian embryonic development, erythropoiesis progresses through distinct stages. The hematopoietic progenitors appear in four waves. The first wave is the formation of blood islands in the extraembryonic mesoderm (yolk sac). These primitive erythroblasts are large, nucleated and express embryonic hemoglobin type ε2ζ2. The second wave occurs in the intraembryonic mesoderm, specifically in the region of the para-aorta splanchpleural (P-Sp), which later becomes the aorta-gonad mesonephros (AGM). The third wave occurs in the fetal liver, and finally the long-lasting hematopoietic activity homes to the BM. The erythrocytes from the yolk sac enter the circulation mostly as nucleated cells, whereas the cells entering the circulation from fetal liver and BM are enucleated.

Definitive erythropoiesis in the fetal liver features the production of enucleated RBCs that quickly become dominant in embryonic circulation. The switch of hemoglobin to fetal types (α2γ2) also occurs at the initiation of definitive erythropoiesis. However, recent reports show that yolk sac-derived primitive erythroblasts can also enucleate in the circulation of a mouse embryo and persist throughout gestation. In adults, all blood cell types, including lymphocytes, myeloid cells, and RBCs are derived from HSCs residing in bone marrow. Within the bone marrow, erythroid progenitors undergo a series of maturation stages prior to becoming reticulocytes. Each stage is associated with the defining morphological characteristics in the cytoplasm and the nucleus of the precursor cells distinguishable after Wright's stain. In the final stage of the maturation process, along with a dramatic reduction in cell size, basophilic pro- normoblasts lose their nuclei to become reticulocytes, which then enter the blood circulation as fully mature RBCs.

The in vivo development of the mammalian blood system has been well-studied, including numerous research advances involving mouse embryonic stem cells (mES) and subsequent gene knockout mice models. Inactivation/deletion of genes required for the formation of the circulation system has contributed to a better understanding of the biology of blood formation from the early embryonic stage to adulthood. The complex process of erythropoiesis proceeds with dramatic changes in gene expression and cell morphology. Erythropoietin (EPO) has been identified as a key factor in a feedback loop mechanism. EPO is a hormone produced in the kidney and liver that stimulates the production of RBCs in the bone marrow in response to hypoxia stress. One mechanism of EPO's action is to promote the survival and expansion of erythroid progenitors. Other factors, such as retinoic acid and dexamethasone, are also shown to be important during erythropoiesis. In the murine system, the transcription factor GATA1 has been shown to be an essential regulator of erythroid lineage commitment, as well as terminal differentiation.

Bilirubin Metabolism in the Gut

The gut flora hydrolyze bilirubin diglucuronide and reduce free bilirubin to the colorless urobilinogen. Urobilinogen is further processed to produce stercobilin, which gives feces their characteristic brown color. Some urobilinogen is reabsorbed from the gut and removed from the circulation in urine as urobilin; this is responsible for the amber color of urine.