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CELL BIOLOGY: ON THE DEVELOPMENT OF RED BLOOD CELLS

The following points are made by James Palis (Nature 2004 432:964):

1) As adults, we make more than 2 million red blood cells (erythrocytes) in our bone marrow every second to replace those lost through normal attrition. The mammalian erythrocyte is unique among the blood cells of the animal kingdom because it discards its nucleus (enucleates) and all its internal organelles before entering the circulation. This maturation of red cells is aided by white blood cells called macrophages, and somehow requires the retinoblastoma protein (Rb). New work[1] suggests that Rb regulates the maturation of macrophages, which bind to immature nucleated erythrocytes (erythroblasts) to form "islands" that nurture red-cell synthesis.

2) In the early 1940s, Giovanni Di Guglielmo observed that erythroblasts are associated with macrophages in the bone marrow. Subsequently, pioneering studies by Marcel Bessis[2] indicated that all red cells mature within "erythroblast islands" consisting of a central macrophage that extends cytoplasmic protrusions to a ring of surrounding erythroblasts. Such islands exist in adult bone marrow and also in fetal liver, where erythrocytes are produced before the bone marrow is fully developed. Bessis postulated that the central macrophage nurses erythroblasts by supplying nutrients and growth factors. The macrophages also gobble up the nuclei left behind by mature erythrocytes as they leave the island to enter the turbulent world of the circulation.

3) The Rb protein is a nuclear protein found in all cells and is key to the cell's decision to traverse the cell cycle and divide. Mice lacking Rb die at mid-gestation (embryonic day 14.5), having defects in the nervous system, placenta and eye lens, as well as deficiencies in the production of red blood cells. Specifically, erythroblasts in the livers of Rb-deficient fetuses mature abnormally and fail to enucleate[3,4].

4) The mechanism responsible for this Rb-dependent defect in red-cell maturation has remained controversial for more than a decade. Is the role of Rb intrinsic to maturing red cells, or is it extrinsic -- that is, does Rb act through other cell types that provide a supportive microenvironment for erythroblasts? Red cells derived from Rb-deficient erythroid progenitor cells fail to differentiate normally when grown in culture[5], suggesting that the erythroid defect is intrinsic to red cells. However, chimeric mice composed of both normal and Rb-deficient cells generate normal erythrocytes that are derived from Rb-deficient cells, suggesting instead that the defect is extrinsic to the red-cell lineage. The controversy over the site of action of Rb has been further fuelled by a study of Rb-deficient hematopoietic stem cells (that is, cells that can generate all the blood cells found in the body). When these mutant stem cells were transplanted into normal adult mice, the animals developed anemia and their red cells failed to enucleate, suggesting that Rb function is intrinsic to the red-cell lineage. However, these results could also be explained if the Rb protein has a key role in another blood-cell type that supports erythroid maturation.

References (abridged):

1. Iavarone, A. et al. Nature 432, 1040-1045 (2004)

2. Bessis, M. Rev. Hematol. 13, 8-12 (1958)

3. Lee, E. Y. -H. P. et al. Nature 359, 288-294 (1992)

4. Clarke, A. R. et al. Nature 359, 328-330 (1992)

5. Jacks, T. et al. Nature 359, 295-300 (1992)

Nature http://www.nature.com/nature

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Related Material:

DIFFERENTIATION OF HUMAN PERIPHERAL-BLOOD STEM CELLS INTO LIVER CELLS AND EPITHELIAL CELLS

The following points are made by M. Korbling et al (New Engl. J. Med. 2002 346:738):

1) Circulating blood is known to contain stem cells that can completely restore the production of blood cells (hematopoiesis) after ablation of the bone marrow. Recently, mesenchymal stem cells with a capacity for self-renewal and the potential to differentiate into bone, cartilage, fat, tendon, muscle, or marrow stroma have been identified in human bone marrow. Whether such stem cells circulate in the blood is unsettled. A stem cell in rat bone marrow has been found to differentiate into the epithelial lineage that generates hepatic oval cells, and in mice with a metabolic defect that impairs liver function, the infusion of purified hematopoietic stem cells can restore both hematopoiesis and liver function. Progenitor cells in mouse bone marrow have also been shown to differentiate into muscle cells and can induce muscle regeneration.

2) The existence of stem cells with multiple differentiating capabilities was conclusively demonstrated by Krause et al (2001), who showed that a single bone marrow stem cell not only can restore hematopoiesis in mice that have received otherwise lethal doses of radiation, but also can differentiate into mature epithelial cells of the skin, lungs, and gastrointestinal tract. Moreover, human progenitor cells transplanted into fetal sheep have been reported to differentiate into hematopoietic cells and hepatocytes. There is also evidence that human kidney, liver, and muscle cells can transform into blood-forming cells. Moreover, two groups have reported the presence of donor-derived hepatocytes and cholangiocytes in recipients of sex-mismatched bone marrow transplants.

3) The authors report their investigations indicate that human blood contains stem cells that can differentiate into cells of the liver, gastrointestinal tract, and skin. The origin of these stem cells and the ways in which they generate hepatocytes and epithelial cells are unknown.

New Engl. J. Med. http://www.nejm.org

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