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(from Greek haima for blood and poiein, to make) Hematopoiesis is the dynamic and complex developmental process of the formation of new blood cells, which includes red blood cells (erythrocytes), white blood cells (leukocytes), and platelets (Orkin et al, 1995, 1996). Per day, hematopoiesis yields approximately 175 billion red cells, 70 billion granulocytes (neutrophils, eosinophils, basophils), and 175 billion platelets. If needed, production can be increased 5-10 fold.
Studies in mice and birds have shown that an early intra-embryonic site of hematopoiesis is found in the Paraaortic splanchnopleura and in a structure termed aorta-gonad-mesonephros region (AGM) (Nishikawa et al, 2001). The establishment of blood islands in the extraembyronic yolk sac marks the onset of hematopoiesis and vasculogenesis in the developing embryo. There is a close developmental association of hematopoietic and endothelial lineages within the blood islands. The central cells within blood islands are thought to give rise to embryonic hematopoietic cells while the peripheral population differentiates to endothelial cells (Wagner, 1980). Both cell types are thought to arise from common precursors termed hemangioblasts. Hematopoiesis taking place prior to the development of the fetal liver is referred to as primitive hematopoiesis, which is transient and restricted to the production of erythrocytes and megakaryocytes. The fetal liver is the site of definitive hematopoiesis early during embryonal development (Hann et al, 1983). The term definitive hematopoiesis is used to describe blood formation after the formation of the fetal liver. It takes place in spleen and lymph nodes and, from fetal week 20 up, in bone marrow. The bone marrow with its intersinusoidal spaces is also the site responsible for the generation of blood cells in the post-natal phase. Red marrow (hematopoietically active marrow) usually becomes restricted to proximal ends of long bones, and flat bones (ileum, sternum, vertebrae, ribs). During growth, the red marrow is gradually replaced by yellow marrow, which is mostly fat. This marrow may may re-expand peripherally to liver and spleen under certain conditions, e. g., thalassemia.
The sinusoids (venous channels) feed into the marrow venous drainage system. The sinusoids are lined with specialized fenestrated endothelial cells. They produce growth factors and cytokines, which influence proliferation and differentiation of hematopoietic cells and thus play an important regulatory role. Mature blood cells enter the blood stream by passing through the sinusoidal wall to get into the sinuses. In order to do this, maturing cells become more deformable and no longer express adherence receptor.
Immature hematopoietic cells bind to the stromal matrix and to receptors on the stromal cells by expressing special receptors that recognize proteoglycans on the target cells. This is also the mechanism underlying the homing of bone marrow cells that have been injected intravenously.
The nature of hematopoietically active structures is determined predominantly by a network of stromal cells (see also: long-term BMC (bone marrow culture) and an amorphous substance in which the blood-forming cells are embedded. The morphologically discernible areas of active hematopoiesis are referred to frequently as Cobblestone area. The corresponding cells are known as CAFC (cobblestone area-forming cells).
The microenvironment of a cell plays an important role in the differentiation of individual bone marrow cells. Further differentiation of cells into one of several lineages critically depends on the nature of factors acting on these cells at a particular time, at a particular concentration, and/or in a particular sequence.
The bone marrow stroma contains many different cell types, including macrophages, fibroblasts, endothelial cells, smooth muscle cells, T-lymphocytes, monocytes etc. These cells, in combination with components of the extracellular matrix and basement membranes as well as a plethora of soluble and membrane-bound cytokines and growth factor, form the so-called Hematopoietic inductive microenvironment (abbr. HIM), which maintains the functional integrity of this complex system of resident and circulating cells. Cells of the hematopoietic microenvironment show low or no detectable cell growth and are believed to be in the G0 phase of the cell cycle. Without bone marrow stromal cells, hematopoietic stem cells cannot be maintained in vitro, even when they are cultured with a cocktail of growth factors and cytokines. Some proteins such as KIRRE, have been shown to accumulate in the areas of contact between stroma and hematopoietic stem cells and maintain these stem cells in an undifferentiated, proliferative state. Sacchetti et al (2007) have studied the identity of cells that establish the hematopoietic microenvironment in human bone marrow, and of clonogenic skeletal progenitors found in bone marrow stroma. They have reported that subendothelial cells in human bone marrow stroma expressing CD146 and Angiopoietin-1 are capable of transferring, upon transplantation, the hematopoietic environment to heterotopic sites.
All different types of blood cells are derived from a small common pool of totipotent cells, called hematopoietic stem cells, laid down in hematopoietic organs early during embryogenesis. These totipotent stem cells are referred to also as HSC (hematopoietic stem cells), PHSC (primitive (or pluripotent) hematopoietic stem cells), PLSC (pluripotent lymphoid stem cells), PPSC (pluripotent stem cells, or PSC), and THSC (totipotent hematopoietic stem cells).
These cells have the unique property of self-renewal (abbr. SRP for Self-renewal potential), i.e., they give rise to progeny identical in appearance and differentiation potential. These cells persist throughout adult life and are therefore responsible for the maintenance of hematopoiesis. This process is called also Steady-state hematopoiesis or Constitutive hematopoiesis.
The remarkable biological activities of the stem cells are illustrated by their ability to colonize the bone marrow of lethally irradiated animals (see: MRA, marrow repopulating ability) and, by their lymphopoietic and myelopoietic potential, to reconstitute the entire hematopoietic system. Since no other cell types are capable of achieving this task long-term repopulating activity is used as a functional assay for pluripotent stem cells (see also: BMC; CFC; CFU, CFU-S).
Pluripotent stem cells are quiescent cells (see also: SCI, stem cell inhibitor, CFU-S). This is shown by their resistance to treatment with Fluorouracil or 4-HC (4-hydroperoxycyclophosphamide), which spare them and eliminates dividing cells without adversely affecting the long-term repopulating ability of bone marrow.
These cells are of interest not only because of their developmental capacity but also because of their potential usefulness as a source of autologous bone marrow cells for the treatment of hematological disorders (see: 4-HC) and as vectors for gene therapy (see also: Cytokine gene transfer). This type of cell is found not only in bone marrow but also in peripheral blood (PBPC, peripheral blood progenitor cells). Treatment of patients with colony stimulating factors (see: CSF) such as G-CSF and GM-CSF induce an impressive rise of up to 100-fold in levels of progenitor cells of all lineages in the peripheral blood. Stem cells are elevated in this response, with the blood populations being capable of initiating long-term repopulation of irradiated recipients. The mechanisms responsible for the release of progenitor and stem cells from the marrow probably involve changes in adhesion to marrow stromal elements and also CSF induced changes induced in the cells destined to leave the marrow.
The totipotent hematopoietic stem cells give rise to transit populations with restricted differentiation capacity. Differentiation of stem cells in vivo has long thought to be a stochastic process but it appears that hematopoiesis progresses through an ordered restriction process rather than random processes with a hierarchy in the lineage restriction process (Orkin et al, 1995; Singh, 1996; Brown et al, 1985; Lu et al, 2002). Cell fate decisions also involve a process of asymmetric cell division (Congdon and Reya, 2008). The Progenitor cells arising as the result of stem cell differentiation are called Committed cells, or, for historical reasons, colony-forming units because experimentally they were detected by their ability to form colonies in soft agar in a colony formation assay (see also: CFU; see also individual types: BFU-E, CFU-E, CFU-Eo, CFU-G, CFU-GEMM, CFU-GM, CFU-M, CFU-MEG).
Committed cells, which can be identified by expression of specific lineage markers, comprise multipotent (MPSC), bipotent (BPSC), and unipotent (UPSC) cell types. These cells are determined to differentiate into any of the hematopoietic lineages, i.e., lymphoid cells that ultimately give rise to B-cells and T-cells, and myeloid cells that eventually give rise to monocytes, platelets, granulocytes/monocytes (neutrophils, eosinophils, basophils), and erythrocytes (see also: lineage markers; for a common progenitor see also: B-cell/myeloid common progenitor).
These lineages are defined by the nature of the fully differentiated cells eventually evolving from these precursor cells. The developmental potential of these cells is generally limited to only one or two of the hematopoietic lineages, and these cells progressively display the antigenic, biochemical, and morphological features characteristic of the mature cells of the appropriate lineages and lose their capacity for self-renewal. Their proliferation is normally tightly controlled and coupled to development. Cells leaving the bone marrow usually possess little or no proliferative potential; erythrocytes and platelets do not contain genetic material, and neutrophils have condensed DNA and cannot undergo replication. Some hematopoietic cells, including pre-T-cells, mast cells, and monocytes can undergo further replication and development in various tissues.
Pluripotent stem cells are still difficult to characterize morphologically. The pool of determined stem cells can usually be differentiated in functional assays. Most of the distinct intermediate forms can be distinguished from each other by the stage-specific expression of cell surface markers and by their dependence on the presence of one or several growth factors or cytokines that are absolutely required for their survival and proliferation. All members of a particular lineage that are still capable of proliferation can give rise to malignant variants at all stages of differentiation.
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| Simplified diagram of hematopoiesis and cytokines involved in its regulation Apologies for presenting this old diagram taken from my Dictionary of Cytokines published in 1995. I thought this is better than none and I am working on an update (see also: Some personal remarks). Individual cell types are boxed. Early totipotent or pluripotent hematopoietic stem cells with self-renewing ability (green box) are not identifiable morphologically and their exact position within the hierarchy is not known. These cell types may themselves consist of a hierarchy of cells of increasing maturity. Hematopoietic stem cells and early progenitor cells give rise to a series of myeloid (red) or lymphoid (blue) cell types differing from each other by their degree of differentiation. The hematopoietic microenvironment (yellow box) plays an important role in the physiological regulation of these processes. Later stages derived from these stem cells are multipotent, bipotent, or unipotent progenitors that can be identified by means of sets of cell surface markers. Most likely these stages also consist of subpopulations of cell types differing in their responsiveness to various cytokines. The earliest morphologically identifiable cell types are marked by boxes with rounded corners; functionally mature end cells are marked by darker red or blue shading. Factors shown in green are generally regarded as being more important than factors shown in black which, at least in vitro, appear to affect these cell types in a positive way. The latter can, for example, prime these cells and render them more responsive to other factors, enhance their survival, or promote act as maintenance or commitment factors, or augment their proliferation. Factors in red have been shown to affect growth, survival or differentiation in a negative way. In addition, all factors can influence each other, showing synergistic, antagonistic and/or additive effects. For abbreviations see individual entries in COPE. The actual situation in vivo is more complicated than that depicted in this diagram. It has been shown that great importance must be attached to combinations of factors acting in synergy rather than individual factors acting on their own. The fact that some factors seem to disappear from the boxed cell types at some point of the hierarchy does not necessarily mean that these factors do not influence the particular cell type. It only means that data pertaining to their action on these particular cell types have not been reported. In addition, some factors appear to act on subsets of cell types. This is demonstrated by the activities of Activin A and some chemokines. * Activin A suppresses the proliferation of IL3 responsive CFU-GM progenitors and stimulates the proliferation and differentiation of IL3 responsive BFU-E progenitors. CFU-GM colony formation is inhibited by activin A only when the cells are stimulated with IL3, but not when stimulated with G-CSF, GM-CSF, or SCF plus G-CSF. BFU-E colony formation is enhanced by activin A only when the cells are exposed to IL3 plus Epo, but not when exposed to Epo or Epo plus SCF. ‡ MIP-1-alpha, MIP-2-alpha, PF4, IL8, and MCAF suppress in dose-response fashion colony formation of immature subsets of myeloid progenitor cells (CFU-GEMM, BFU-E, and CFU-GM) stimulated by GM-CSF plus SCF. MIP-1-beta blocks the suppressive effects of MIP-1-alpha. MIP-2-beta or gro-alpha block the suppressive effects of IL8 and PF4. |
Approximately 10**9 nucleated cells are produced per kilogram of body weight within the hematopoietic system per day. The continuity of vital functions is strictly dependent on the constant production of new cells and under normal conditions there is a quantitative and qualitative equilibrium for all blood cells, maintaining mature cell numbers within quite narrow limits.
The life span of the fully differentiated mature forms of blood cells may vary considerably, being on the order of several hours for some cells (granulocytes), several weeks (erythrocytes) and several years (memory cells). Blood loss and cell losses, caused, for example, by a variety of pathological processes, infections, or treatment with cytotoxic drugs, can be compensated by an almost exponential increase in the generation of new cells. This process is called Induced hematopoiesis. Increased production of cells is largely restricted to the specific cell type that is required in the particular stress situation: hemolysis, for example, induces hyperplasia of erythroid cells, while hyperplasia of granulocytes is observed in respose to bacterial infections. Alterations in the balance between self-renewal and differentiation can lead to the emergence of cells that survive and grow in situations unfavorable for the growth of normal cells and hence to the establishment of leukemias.
The self-renewal of the stem cell population in the bone marrow, the proliferation and differentiation of hematopoietic progenitor cells, their survival, and also all functional activities of the circulating mature forms are subject to regulation by a cascade of proteins that are generally known as Hematopoietic growth factors or Hematopoietins. These factors are products of stromal cells (see also: long-term BMC (bone marrow culture) and other cells. In addition also many other low molecular weight factors (see also: AcSDKP; pEEDCK, Thymic hormones) function as promoters or inhibitors (see also: Restrictins) of differentiation and positively or negatively influence hematopoietic processes. Gene-regulatory microRNAs are thought to modulate hematopoietic cell differentiation and proliferation and also the activity of hematopoietic cells, in particular those related to immune function, and have been shown to be critical for B-cell development, granulopoiesis, immune functions, and B-lymphoproliferative disorders (Garzon and Croce, 2008).
The molecular basis of cell commitment and differentiation of hematopoietic cells is still under intense investigation. Homeotic genes appear to be of fundamental importance in these and other cellular processes. Transcription factors play a central role in the genesis of mature lineage committed cells from multipotent progenitors.
For other entries pertaining to hematopoiesis see also the Hematology Dictionary section of this encyclopedia.
LAST MODIFIED: March 2008
See REFERENCES for entry Hematopoiesis
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