Hematopoiesis is the process of blood cell formation. In adult mammals it takes place in the bone marrow (BM). In normal humans hematopoietic BM is located in flat bones (skull, sternum, ribs, pelvis) and vertebrae. It may extend in case of increased hematopoietic demand (e.g., in anemias) or in some blood neoplastic diseases (e.g., chronic or acute leukemias) to long bones (humerus, femur, tibia). In rodents long bones are hematopoietic under normal conditions.
During development hematopoiesis occurs at different sites. In the embryo, hematopoiesis is first detected in the yolk sac and on the ventral floor of the dorsal aorta. In the fetus, hematopoiesis develops in the liver. By the second half of gestation, hematopoiesis finds its final location, that is, the BM. Spleen also constitutes a late fetal site of hematopoiesis, transient in humans, but persisting into adulthood in the mouse.
All blood cells derive from a small compartment of hematopoietic stem cells (HSCs). HSCs are characterized by two cardinal properties: They are multipotent and they self-renew. HSCs give rise to hematopoietic progenitors, in turn the progeny of precursors. The mature cells having completed their differentiative cycle must enter the circulat ing blood to be delivered to the different peripheral tissues. The finely tuned process of release into blood of mature cells is taking place in a vascular structure specific for the BM, the BM sinus.
In the adult mammal, HSCs are located in the BM. During development HSCs migrate from one site to the other. For example, in the fetus HSCs migrate from the liver to the BM via the circulating blood where HSC concentration is high. In the adult such HSC migration is restricted and the HSC blood concentration is small. When patients lacking BM hematopoiesis because of a blood disease (aplastic anemia) or following myelotoxic treatment (heavy radio- or chemotherapy) are given allogeneic HSCs by intravenous injection, the stem cells circulate until they settle within the marrow tissue. This process called engraftment is experimentally duplicated by injecting allogeneic or syngeneic BM HSCs to animals that have been lethally irradiated and can be rescued by the marrow graft. Instead of being recovered from the BM, HSCs can be mobilized from BM to peripheral blood using myelotoxic chemotherapeutic agents and/or hematopoietic growth factors (HGFs), in particular granulocyte colony-stimulating factor (G-CSF). This procedure is in wide use since it allows the collection of HSCs from the peripheral blood, avoiding the surgical act of marrow collection under general anesthesia.
The BM tissue is made essentially of hematopoietic cells packed in the hematopoietic parenchyma (the marrow cords or "logettes"). The nonhematopoietic cells found in the BM constitute the hematopoietic microenvironment, consisting of endosteal cells lining bone trabeculae, of scattered fat-laden adipocytes, and of vascular cells forming the various vascular structures. The description of long-term marrow cultures where HSCs are maintained for months in mice and weeks in humans has shown that "stromal" cells generated in the adherent layer are required for survival, proliferation, and differentiation of HSCs. A subset of stromal cells forms the hematopoietic niche where HSCs in physical contact with stromal cells maintain the adequate balance between self-renewal and differentiation. In vivo, the BM counterpart for stromal cells appears to be a subpopulation of microenvironmental cells with vascular smooth muscle cell characteristics. Such a cell population belongs to the BM vasculature. Cells from the BM vasculature are therefore essential for blood cell formation since they regulate both HSC self-renewal/differentiation and hematopoietic cell trafficking.
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