Thursday, 28 March 2019

Bone marrow function

Bone marrow function 

The formation of blood cells (hemopoiesis) is determined by the interaction of multiple genes and involves cytokines and other protein factors. The relative ease with which hematopoietic cells can be studied and the development of new techniques in cell biology have enabled us to understand many of the factors determining cell renewal and differentiation. Based on this knowledge, major progress has been made in the last 15 yr in the treatment and diagnosis of many hematological disorders. In this article, we describe the cell types involved in normal hematopoiesis and their interactions with one another. Furthermore, the basic techniques necessary for the study of hematopoietic cells in the normal and pathological state are outlined.


Sites of Hematopoiesis
During the first few weeks of embryonic life, the formation of blood cells takes place in the yolk sac. Later, until the sixth or seventh month of fetal development, the liver and spleen are the major hematopoietic organs. By the time of birth, more than 90% of all new blood cells are formed in the bone marrow. Here, the progenitor cells are found, in various stages of development, situated in anatomical niches in the bone marrow from where they are then released into the marrow sinuses, the marrow circulation, and further on into the systemic circulation. During infancy and childhood, the marrow of all bones contributes to hematopoiesis. During adult life, hematopoietic marrow is restricted to certain bones (e.g., pelvic bones, vertebral column, proximal ends of the femur, skull, ribs, and sternum). Even in these areas, a proportion of the marrow cavity consists of fat. During periods of hematopoietic stress (e.g., in severe hemolytic anemias and in some myeloproliferative disorders), the fatty marrow as well as the spleen and liver can resume the production of blood cells. This situation is called extramedullary hematopoiesis.

Stromal Cells
Growth and differentiation of hematopoietic cells in the bone marrow is regulated by the extracellular matrix and microenvironment provided by stromal cells. These cells, including macrophages, fibroblasts in various stages of differentiation, endothelial cells, fat cells, and reticulum cells, nurture hematopoietic stem cells and progenitor cells by producing growth factors like granulocyte/ macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), interleukin (IL)-6, or stem cell factor. Other cytokines secreted by stromal cells regulate the adhesion molecules present on hematopoietic cells, allowing them to remain in the bone marrow or migrate to an area where the respective cell type is needed.

Hematopoietic Stem Cells
All hematopoietic cells of the organism derive from pluripotent stem cells that are capable of both self-renewal and differentiation into all hematopoietic lineages. One stem cell provides progenitor cells for myelo- and monopoiesis, erythropoiesis, megakaryopoiesis, and lymphopoiesis. Other cell types such as stromal cells or dendritic cells also derive from the pluripotent hematopoietic stem cell. It has been estimated that one stem cell gives rise to at least 106 mature hematopoietic cells. Under normal conditions, the stem cells provide hematopoietic cells for the entire life span. Each day, a healthy adult organism produces more than 1012 hematopoietic cells. Many blood disorders (e.g., leukemias, aplastic anemias, or myelodysplastic syndromes) are disorders of stem cells.

Stem cells are very rare, representing less than 0.01% of all nucleated cells in the normal bone marrow. Based on animal experiments, the morphology of stem cells is thought to be similar to that of small lymphoid cells. In recent years, the marker expression of human stem cells has been studied. Human stem cells express the surface proteins CD34 and c-kit and are negative for CD38 and lineage-specific markers. In animal systems, stem cells can be assayed as spleen colony-forming units (CFU) in irradiated hosts. Only the more differentiated progenitors of human hematopoietic cells can be tested for their ability to form colonies in soft agar or methylcellulose. One of the earliest progenitor cells in such systems is CFUGEMM, which contains granulocytes, monocytes, erythroid
cells, and platelet progenitors. From this pluripotent progenitor, more specialized progenitors are formed. Under normal conditions, the majority of stem cells is dormant (G0 phase of the cell cycle). A stem cell divides only to maintain the steady state of hematopoiesis or to meet the body’s demand for progenitor cells (stochastic model of hematopoiesis). The daughter cells then either differentiate into determined progenitor cells (e.g., lymphohematopoietic cells) or return to dormancy by reentering the stem cell pool. Stem cells can be enriched and transplanted (stem cell or bone marrow transplantation). The stem cell donor does not experience a detectable loss of stem cells.

There are several hierarchical levels of stem and progenitor cells. In general, the hematopoietic growth factors do not act on true stem cells, but support the survival and the differentiation of committed cells. Although “early-acting” cytokines such as stem cell factor, FLT3-ligand, G-CSF, or IL-6 regulate the earliest progenitor cells, “late-acting” cytokines such as erythropoietin for erythropoiesis or thrombopoietin for megakaryopoiesis support the growth and differentiation of progenitor cells that are already committed to their respective lineage. Many other cytokines play a positive or negative role in the differentiation of hematopoietic cells. 

The gene expression in early stem cells is complex and involves the co-expression of multiple transcription factors. For example, the combination of C/EBP α and Pu 1 directs the expression of the receptor for G-CSF, which is critical for early myelopoiesis. Pu 1 binds to and regulates the promotors of several myeloid growth-factor receptor genes. The Notch family of transmembrane receptors was described in Drosophila as a ligand-dependent suppressor of cell differentiation. Similar receptors have recently been found on human stem cells, suggesting that they may also be involved in maintaining an undifferentiated state.

The significance of telomeres present in human stem cells and the activity of telomerase in these cells is currently of interest. Telomeres are specialized structures at the end of chromosomes that change with cell division. Shortening of telomeres is associated with cellular aging. Telomerase is an enzyme capable of extending the length of telomeres. It has now been found that adult stem cells have shorter telomeres than fetal stem cells and that the length of telomeres shortens further after transplantation. The activity of telomerase is generally low in stem cells (which corresponds to their quiescent state), but can be upregulated on entry into the cell cycle. The implications of these findings are not yet clear, but they may indicate that not all stem cells are immortal.

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