Haematopoiesis and Erythropoiesis — Sites by Age, Maturation Stages and Erythropoietin

Haematopoiesis is the production of erythrocytes, platelets, granulocytes, lymphocytes, monocytes and other blood cells. It starts from multipotent haematopoietic stem cells (HSCs), which can either self-renew or differentiate into multipotent progenitors. Progenitors lose the ability to self-renew and divide into increasingly specialised lineages. The classical model splits them into a common myeloid progenitor and a common lymphoid progenitor.

Fate is decided mainly by signalling factors such as erythropoietin, IL-2, IL-3, IL-6, IL-7 and colony-stimulating factors, and by the niche the cell occupies. Newer lineage-tracing studies suggest fewer branch points and a more heterogeneous HSC pool than the textbook tree, but the classical model is still the one asked in examinations. HSCs are lineage-negative and carry markers such as CD34; fluorescent staining for CD34 is a key method for separating progenitors.

Blood-cell development begins by the 7th day of embryonic life. The site then shifts in a fixed order: the yolk sac (blood islands) and the aorta-gonad-mesonephros (AGM) region first, then the fetal liver, then the spleen, and finally the bone marrow. HSCs arise from haemogenic endothelium in the ventral wall of the developing aorta (paraaortic splanchnopleure) and colonise the liver by the 7th week, when it becomes the dominant site.

Extramedullary haematopoiesis is blood-cell production outside the marrow. It is normal in the fetus but abnormal later in life, when haematopoiesis may return to former sites in pathological conditions. Within the marrow, haematopoietic tissue forms islands surrounded by vascular sinuses, and cells enter the circulation through the venous sinuses; megakaryocytes lie next to the sinuses so that they can shed platelets directly into them.

Haematopoietic ontogeny has two phases. Primitive erythroid cells (EryP) appear first in the yolk sac. They are larger than their progenitors, retain nuclei initially, express embryonic globins and form blood islands. Primitive erythropoiesis is transient, and complete failure of it is embryonically lethal. Definitive erythroid cells (EryD) then arise, first from erythro-myeloid progenitors that colonise the liver and later from HSCs, and rapidly become the predominant population.

Definitive cells make fetal haemoglobin (HbF, α2γ2), which dominates for most of gestation. At about 32 weeks a globin switch begins: γ-globin is down-regulated and β-globin is up-regulated, giving adult haemoglobin (HbA); the switch continues after birth. The key repressor of γ-globin is BCL11A (acting with SOX6); other loci influencing HbF include the HBS1L–MYB intergenic region and the β-globin locus. These are the genes targeted by therapies aiming to raise HbF in haemoglobinopathies such as thalassaemia.

Erythroid cells come from the common myeloid lineage via the megakaryocyte–erythroid progenitor. The earliest erythroid-restricted progenitor is the burst-forming unit–erythroid (BFU-E), which forms large colonies of thousands of haemoglobinised cells in culture. It responds to EPO, stem cell factor, IL-3, IL-6, corticosteroids and IGF-1. BFU-E gives the colony-forming unit–erythroid (CFU-E), which is committed to the erythroid lineage and depends on EPO for survival. CFU-E then becomes a proerythroblast.

At each division the maturing cell gets smaller, its nucleus condenses and haemoglobin accumulates. One proerythroblast ultimately yields 16 reticulocytes (2 basophilic, 4 polychromatic and 8 orthochromatic cells on the way). By the orthochromatic stage the cell has left the cell cycle; the nucleus is extruded and engulfed by macrophages. Reticulocytes carry high CD71 and acquire glycophorin A (CD235a) as they mature into erythrocytes. The whole sequence can take up to about 5 days.

Terminal differentiation takes place in erythroblastic islands in the marrow: a central macrophage ('nurse cell') surrounded by differentiating erythroid cells. In anaemia the process may speed up, and the red cells then carry visible debris such as Heinz bodies, Pappenheimer bodies and Howell-Jolly bodies. Compare the resulting morphology in anaemia classification and megaloblastic anaemia.

Erythropoietin (EPO) is a 30.4 kDa glycoprotein hormone of 165 amino acids. The peritubular fibroblasts of the renal cortex are the main site of synthesis, while the liver is the main site in the fetus. EPO production is controlled by tissue oxygen tension through hypoxia-inducible factors (HIFs); the main activator of the EPO gene is HIF-2. Falling oxygen delivery therefore raises EPO, and EPO raises red-cell production.

• Action: EPO stimulates division and survival of erythroid progenitors, promotes erythroid-specific gene expression and prevents apoptosis; CFU-E depend on it.
• Normal count and turnover: about 5 million red cells per microlitre (4.7–6.1 million in men, 4.2–5.4 million in women); they live about 120 days; the marrow makes about 2.5 million reticulocytes per second to balance loss.
• Feedback: circulating EPO rises exponentially as haemoglobin falls in uncomplicated anaemia, restoring red-cell mass.
• Deficiency: lack of EPO is the primary cause of anaemia in chronic kidney disease, where injured renal fibroblasts lose EPO-producing capacity.
• Therapy: erythropoiesis-stimulating agents (ESAs). Epoetin has a terminal half-life of 6–9 hours, darbepoetin alfa about 25 hours (three- to fourfold longer).
• ESA resistance: often due to reduced iron availability from hepcidin, shown by low ferritin, low transferrin saturation and hypochromic red cells.

• Ineffective erythropoiesis — erythroid precursors die in the marrow before release (for example when GATA-1 is disrupted); see thalassaemia and megaloblastic anaemia.
• Haemolytic states — marrow compensates with increased reticulocyte output; see haemolytic anaemias.
• Marrow failure and neoplasia — assessed on aspiration or biopsy, usually from the iliac crest; H&E identifies mature cells, whereas immature progenitors look like lymphoblasts and need CD34 staining or flow cytometry. See leukaemias and myeloproliferative neoplasms.
• Chronic kidney disease — reduced EPO produces normocytic anaemia treated with ESAs and iron as needed.