Key points

Introduction

“The blood has always fascinated humanity. Blood has been regarded as a living substance, the very essence of life. Poets have written of thick blood and thin, pale blood, red blood and blue blood, royal blood, and pure and eloquent blood.”

Hematopoiesis refers to the continuous process of blood cell formation. Because mature blood cells are predominantly short lived, the establishment and maintenance of the blood system requires self-renewing hematopoietic stem cells (HSC) throughout life to replenish multilineage progenitors and precursors committed to individual hematopoietic lineages. The ceaseless hematopoietic process replenishes the senescent cells that leave the circulation and produces nearly 200 billion red blood cells, 10 billion white blood cells, and 400 billion platelets every day. Blood cell production is closely regulated and responds to challenges to the host, like infection, hemorrhage, allergy, or inflammation.

Current understanding of hematopoiesis is based on the hypothesis that there is an HSC capable of self-renewal and differentiation into all hematopoietic cell lines. HSC transplantation has confirmed the remarkable regenerative properties of the HSCs for a variety of human disorders.

Introduction

“The blood has always fascinated humanity. Blood has been regarded as a living substance, the very essence of life. Poets have written of thick blood and thin, pale blood, red blood and blue blood, royal blood, and pure and eloquent blood.”

Hematopoiesis refers to the continuous process of blood cell formation. Because mature blood cells are predominantly short lived, the establishment and maintenance of the blood system requires self-renewing hematopoietic stem cells (HSC) throughout life to replenish multilineage progenitors and precursors committed to individual hematopoietic lineages. The ceaseless hematopoietic process replenishes the senescent cells that leave the circulation and produces nearly 200 billion red blood cells, 10 billion white blood cells, and 400 billion platelets every day. Blood cell production is closely regulated and responds to challenges to the host, like infection, hemorrhage, allergy, or inflammation.

Current understanding of hematopoiesis is based on the hypothesis that there is an HSC capable of self-renewal and differentiation into all hematopoietic cell lines. HSC transplantation has confirmed the remarkable regenerative properties of the HSCs for a variety of human disorders.

Development of the hematopoietic system

Hematopoiesis comprises a continuum of functionally distinct hematopoietic cell compartments during the embryonic period that starts with the presence of the HSC. In mammals, hematopoiesis occurs as a sequential process that moves to different anatomic sites during embryonic and fetal development. The sites of hematopoiesis include the yolk sac; the aorta-gonad-mesonephros region (AGM) (a sheet of lateral mesoderm that migrates medially, touches the endoderm, and then forms a single aorta tube where clusters of HSC appear); the fetal liver; and, finally, the bone marrow.

HSCs can divide to give rise to a daughter cell that retains all of the pluripotentiality of the parent (self-renewal) or it can proliferate into daughter cells that have lost some multipotentiality and have become committed to produce multipotential progenitor (MPP) cells. Pluripotent HSCs generate cells with the capacity for long-term engraftment and are, therefore, also called LT-HSCs. As illustrated in Fig. 1 , once committed, the MPP cell gives rise to progressively more lineage-committed hematopoietic progenitor cells and eventually to mature cells. HSCs require a combination of transcription factors (intrinsic determinants of cellular phenotype) for their survival and proliferation. In addition, adjacent cells and local cytokines (microenvironment) are necessary for optimal HSC growth and differentiation. Lineage-committed progenitor cells are dependent on lineage-specific factors to undergo final differentiation. Fig. 1 provides a general overview of the interactions between cytokines, transcription factors, and growth factors in the proliferation and differentiation of hematopoietic cells. Table 1 summarizes the function of the interleukins in hematopoiesis.

Schematic Representation of Hematopoiesis. Early–acting hematopoietic growth factors are represented in red. Transcriptions factors are in green box. Growth factors are represented in colored circles. BFU-E, burst-forming unit-Erythrocyte; BFU-Eo, burst-forming unit-Eosinophil; BFU-G, burst-forming unit-Granulocyte; BFU-M, burst-forming unit-Monocyte/Macrophage; BFU-MK, burst-forming unit-Mekagaryocyte; CFU-E, colony-forming unit-Erythrocyte; CFU-Eo, colony-forming unit-Eosinophil; CFU-G, colony-forming unit-Granulocyte; CFU-M, colony-forming unit-Monocyte/Macrophage; CFU-MK, colony-forming unit-Megakaryocytes; CLP, common lymphoid progenitors; CMP, common myeloid progenitors; EPO, erythropoietin; G-CSF, granulocyte colony stimulating factor; GM-CSF, granulocyte/(Monocyte/Macrophage) colony stimulating factor; GMP, granulocyte/macrophage progenitors; HSC, hematopoietic stem cells; M-CSF, Monocyte/Macrophage colony stimulating factor; MEP, megakaryocyte/erythroid progenitors; MPP, multipotent progenitors; TPO, thrombopoietin.

The initial phase of hematopoiesis occurs in the yolk sac ( Fig. 2 A). The first wave of blood production, termed primitive , is red blood cell production to facilitate tissue oxygenation and allow for the rapid growth of the embryo. Although this initial phase of blood production is largely erythropoietic, megakaryocytes and macrophages are also included. Primitive progenitors can be found from embryonic day (E) 7.25 in the mouse and within 3 to 4 weeks of human gestation.

( A ) Sequential sites of hematopoiesis, showing the primitive and definitive waves of erythropoiesis as well as the hematopoietic stem cells arising from the AGM in ( B ). The first wave of blood production is termed primitive and occurs in the yolk sac. Large erythroid progenitors are produced to facilitate tissue oxygenation and allow the rapid growth of the embryo. The second hematopoietic wave called definitive also originates in the yolk sac. During this phase, definitive progenitors migrate to the fetal liver where they expand, mature and give origin to erythroid and meyloid cells. The third wave of hematopoiesis arises from HSCs produced in AGM region . These HSC seed the liver and the bone marrow. From the fetal liver, hematopoietic progenitors migrate and colonize the thymus, spleen, and ultimately the bone marrow. Crecendo/decrecendo figures illustrate the predominant sites of hematopoiesis during fetal life.

The second hematopoietic wave also begins in the yolk sac and demonstrates definitive progenitors around embryonic day (E) 8.25 in the mouse and by week 4 in humans. The second wave contains erythroid and myeloid lineages. During this phase, definitive progenitors migrate from the yolk sac to the fetal liver where they expand and mature.

The third wave of hematopoiesis is more complex and arises from HSCs produced in the AGM, major blood vessels, and the placenta. Whether these stem cells are endogenous to the AGM or arise from the yolk sac is controversial.

From the fetal liver, hematopoietic progenitors migrate and colonize the thymus, spleen, and ultimately the bone marrow. None of these sites are characterized by de novo generation of HSCs, but rather these niches support the expansion of HSCs that migrated to these new sites (see Fig. 2 B) from earlier sites. The production of all blood lineages is not achieved by intraembryonic HSC until colonization and development of the bone marrow. Colonization of the bone marrow results in the production of a small pool of HSCs that are responsible for the maintenance of hematopoiesis throughout life.

In humans, by week 10 to 12 of gestation, extraembryonic hematopoiesis has essentially ceased. The liver remains the predominant erythropoietic organ through 20 to 24 weeks of gestation. Hepatic hematopoietic production diminishes during the second trimester, whereas bone marrow hematopoiesis increases (see Fig. 2 ).

Fetal erythropoiesis

After their initial development in yolk-sac blood islands (see Fig. 2 ), primitive erythroid progenitors (EryP) enter the newly formed vasculature of the embryo where they continue to divide for several days. EryP differentiate within the bloodstream, gradually accumulating increasing amounts of hemoglobin (Hb) and becoming progressively less basophilic. Hb synthesis, directed by stable globin transcripts, continues until cell replication ceases.

In the mouse, EryP are large nucleated primitive erythroid cells that express both embryonic and adult globins while confined to the yolk sac. In contrast, burst-forming unit erythroid (BFU-E), which later differentiate into colony-forming unit erythroid (CFU-E), are definitive erythroid progenitors (EryD) that give rise to colonies in 7 to 10 days and 2 to 3 days, respectively. EryD are found in the yolk sac; they enter the newly formed bloodstream of the embryo and seed the liver primordium as soon as it begins to form. Once there, EryD rapidly generate mature erythrocytes to support the growing fetus. Yolk sac–derived EryD (BFU-E and CFU-E) cannot fully differentiate within the yolk-sac environment; they experience definitive differentiation as they exit to the fetal liver (see Fig. 2 B). There are several features that distinguish primitive and definitive erythropoiesis: (1) EryP are 6-fold larger than EryD. (2) EryP express embryonic and adult globins. (3) EryD depend on erythropoietin (EPO) signaling for definitive EryD differentiation.

In humans, the yolk sac serves as the initial site of erythropoiesis from weeks 3 to 6 of gestation. The liver functions as the primary site for hematopoiesis from weeks 6 to 22 of gestation, after which the bone marrow becomes the predominant and lifelong site of blood-cell production.

Fetal erythropoiesis is regulated by growth factors produced by the fetus not by the mother. The role of EPO during primitive erythropoiesis is controversial, but it facilitates differentiation of EryD. EPO is produced in the fetal liver during the first and second trimesters, principally by cells of monocytic and macrophage origin ( Table 2 ). After birth, the anatomic site of EPO production shifts to the kidney. The specific stimulus for the shift is unknown but might involve the increase in arterial oxygen tension that occurs at birth. EPO mRNA and EPO protein can be found in fetal kidneys, but their relevance to fetal erythropoiesis is unclear because anephric fetuses have normal serum EPO concentrations and normal hematocrits.

Table 2

Hematopoietic growth factors

Growth Factor	Action	Developmental Facts
EPO	Stimulates the production of red blood cells	• It is produced in fetal liver during the first and second trimesters, principally by cells of monocytes and macrophage origin. • After birth, the anatomic site of its production shifts to the kidney. • Its role in the fetus may not have biologic relevance for normal fetal erythropoiesis. • Fetal production is independent of maternal production.
TPO	Physiologic regulator of platelet production Acts as a stimulator of all stages of megakaryocyte growth and development Stimulates the proliferation and survival of other cell line progenitors	• As pluripotent cells become more committed to megakaryocyte differentiation, they become more dependent on its stimulation to lose their proliferative capacity and be able to differentiate and mature.
G-CSF	Promotes the differentiation of neutrophils	• It is present in the developing fetal bone as early as 6 wk after conception and in the fetal liver at least as early as 8 wk after conception. • It causes monocytes in the fetal liver to produce less G-CSF in response to IL-1 than monocytes in the marrow.
GM-CSF	Stimulates phagocytosis, chemotaxis, adhesion, and tumor lysis	• It is produced by endothelial cells, T lymphocytes, macrophages, endothelial cells, trophoblasts and decidua, and the epithelial lining of the bronchi, trachea, amnion; a large amount is produced in the fetal lungs.
M-CSF	Promotes the growth of monocytes and macrophages	• M-CSF is present in the human fetal liver and developing fetal bone as early as 6 wk after conception. • Mice that are deficient in M-CSF lack osteoclastic activity and consequently develop osteopetrosis.
SCF	Promotes the growth and differentiation of mast cells Plays a role in the early stages of lymphocyte development Plays a role in fetal development of gut-associated lymphoid tissue	• During embryogenesis, SCF and c-kit are expressed along the migratory pathways and destinations of primordial germ cells, melanocytes, hematopoietic cells, the gut, and the central nervous system. • Absence of either SCF in mice leads to intrauterine death or death shortly after birth from severe macrocytic anemia.

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