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Angaben zur Quelle [Bearbeiten]

Autor     Clayton Smith
Titel    Hematopoietic Stem Cells and Hematopoiesis
Zeitschrift    Cancer Control. Journal of the Moffitt Cancer Center
Jahr    2003
Jahrgang    10(1)
URL    http://www.medscape.com/viewarticle/449118

Literaturverz.   

no
Fußnoten    no
Fragmente    6


Fragmente der Quelle:
[1.] Analyse:Rsi/Fragment 008 07 - Diskussion
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All of the mature blood cells in the body are generated from a relatively small number of hematopoietic stem cells (HSC) and progenitors [3, 4]. Murine models, particularly short- and long-term transplant studies, have provided a number of insights into the biology of HSC and progenitors [5, 6]. The results of these studies have demonstrated that HSC are able to generate every lineage found in the hematopoietic system including red blood cells, platelets, and a variety of lymphoid and myeloid cells [3-6]. All of the mature blood cells in the body are generated from a relatively small number of hematopoietic stem cells (HSCs) and progenitors.[1,2] Murine models, particularly short-and long-term transplant studies, have provided a number of insights into the biology of HSCs and progenitors.[3,4] The results of these studies have demonstrated that HSCs are able to generate every lineage found in the hematopoietic system including red blood cells, platelets, and a variety of lymphoid and myeloid cells.[1-4]
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[2.] Analyse:Rsi/Fragment 009 01 - Diskussion
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[Some of the most important] lymphoid cells include natural killer (NK) cells,T cells, and B cells, while important myeloid cells include granulocytes, monocytes, macrophages, microglial cells, and dendritic cells [7]. Each of these cell types can be generated from a single HSC, and each HSC has an enormous capacity to generate large numbers of these cells over many years and perhaps even decades. In the mouse, a single HSC can reconstitute the entire hematopoietic system for the natural lifespan of the animal [8]. HSC are detected in the bone marrow at a frequency between 1: 107 - 108 [9]. While HSC are primarily found in the bone marrow, they are present in a variety of other tissues including peripheral blood and umbilical cord blood, and are found at low numbers in the liver, spleen, and perhaps many organs [10]. These HSC may have somewhat different properties, but they all have the ability to generate all the different blood lineages in large numbers for a prolonged period of time.

Downstream of the common lymphoid progenitors (CLPs) and common myeloid progenitors (CMPs) are more mature progenitors that are further restricted in the number and type of lineages that they can generate [11, 12]. When a bone marrow or blood stem cell transplant is performed, it appears that progenitors contribute to engraftment for only a short period of time, while long-term blood production is derived primarily from HSC [13].

Some of the most important lymphoid cells include natural killer (NK) cells,T cells, and B cells, while important myeloid cells include granulocytes, monocytes, macrophages, microglial cells, and dendritic cells.[5] Each of these cell types can be generated from a single HSC, and each HSC has an enormous capacity to generate large numbers of these cells over many years and perhaps even decades. In the mouse, a single HSC can reconstitute the entire hematopoietic system for the natural lifespan of the animal.[6] Murine HSCs are rare and are present at a frequency of 1/10,000 to 1/1,000,000 cells in the bone marrow depending on the species, age, and technical aspects of the model. While HSCs are primarily found in the bone marrow, they are present in a variety of other tissues including peripheral blood and umbilical cord blood, and are found at low numbers in the liver, spleen, and perhaps many organs.[7] These HSCs may have somewhat different properties, but they all have the ability to generate all the different blood lineages in large numbers for a prolonged period of time.

[...]

Downstream of the CLPs and CMPs are more mature progenitors that are further restricted in the number and type of lineages that they can generate.[10] [...] When a bone marrow or blood stem cell transplant is performed, it appears that progenitors contribute to engraftment for only a short period of time, while long-term blood production is derived primarily from HSCs.[12]

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[3.] Analyse:Rsi/Fragment 010 01 - Diskussion
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1.2.2 Hematopoiesis

The process of hematopoiesis involves a complex interplay between the intrinsic genetic processes of blood cells and their environment. This interplay determines whether HSC, progenitors, and mature blood cells remain quiescent, proliferate, differentiate, self-renew, or undergo apoptosis.[14-16] All of the genetic and environmental mechanisms that govern blood production operate by affecting the relative balance of these fundamental cellular processes. Under normal conditions, the majority of HSC and many progenitors are quiescent in the G0 phase of the cell cycle; however, many of the more mature progenitors are proliferating and producing mature offspring [17]. In the absence of any stresses, this is balanced by the rate of apoptosis in progenitors and mature cells [15]. In the event of a stress such as bleeding or infection, several processes occur. Stored pools of cells in the marrow or adherent to the endothelium are quickly released into the circulation in order to localize to the site of injury [18]. Fewer progenitors and mature cells undergo apoptosis [19, 20]. In addition, quiescent progenitors and HSC are stimulated by a variety of growth factors to proliferate and differentiate into mature white cells, red blood cells, and platelets. When the bleeding, infection, or other underlying stress ceases and the demand for blood cells returns to normal, the antiapoptotic and proliferative processes wind down, blood cells are redistributed back to their storage sites, and the kinetics of hematopoiesis return to baseline levels. This process repeats itself innumerable times during the lifespan of an individual and is seen in an exaggerated form following chemotherapy or bone marrow transplantation.

Probably the best characterized environmental regulators of hematopoiesis are cellular microenvironment, known as niche. It functions as an extrinsic regulatory system, which maintains and governs the location, adhesiveness, retention, homing, mobilization, quiescence/activation, symmetric/asymmetric division and differentiation. [21]

Cytokines are a broad family of proteins that mediate positive and negative affects on cellular quiescence, apoptosis, proliferation, and differentiation. In general, cytokines function by engaging a specific receptor and activating a [variety of signaling pathways.]

The process of hematopoiesis involves a complex interplay between the intrinsic genetic processes of blood cells and their environment. This interplay determines whether HSCs, progenitors, and mature blood cells remain quiescent, proliferate, differentiate, self-renew, or undergo apoptosis.[30-32] All of the genetic and environmental mechanisms that govern blood production operate by affecting the relative balance of these fundamental cellular processes. Under normal conditions, the majority of HSCs and many progenitors are quiescent in the G0 phase of the cell cycle; however, many of the more mature progenitors are proliferating and producing mature offspring.[33] In the absence of any stresses, this is balanced by the rate of apoptosis in progenitors and mature cells.[31] In the event of a stress such as bleeding or infection, several processes occur. Stored pools of cells in the marrow or adherent to the endothelium are quickly released into the circulation in order to localize to the site of injury.[34] Fewer progenitors and mature cells undergo apoptosis.[35,36] In addition, quiescent progenitors and HSCs are stimulated by a variety of growth factors to proliferate and differentiate into mature white cells, red blood cells, and platelets. When the bleeding, infection, or other underlying stress ceases and the demand for blood cells returns to normal, the anti-apoptotic and proliferative processes wind down, blood cells are redistributed back to their storage sites, and the kinetics of hematopoiesis return to baseline levels. This process repeats itself innumerable times during the lifespan of an individual and is seen in an exaggerated form following chemotherapy or bone marrow transplantation.

Probably the best characterized environmental regulators of hematopoiesis are cytokines.[37] Cytokines are a broad family of proteins that mediate positive and negative affects on cellular quiescence, apoptosis, proliferation, and differentiation. In general, cytokines function by engaging a specific receptor and activating a variety of signaling pathways

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[4.] Analyse:Rsi/Fragment 011 01 - Diskussion
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This includes activation of tyrosine kinases such

as focal adhesion kinase, pp60src, and c-Abl, MAP kinases, jun Kinase (JNK), and protein kinase C (PKC) [22]. Mediators of cell growth and differentiation such as c-src, phosphoinositides, protein kinase C, and growth factor-mediated signaling pathways are also modulated by cytokines. Cytokines including interleukin-3 and GM-CSF induce cell proliferation, while other cytokines including flt-3 ligand and kit ligand protect cells from apoptosis and sensitize them to the effects of growth promoting cytokines [23-25]. Cytokines may also facilitate the interactions between stem cells and elements in the microenvironment including extracellular matrix (ECM) components [26]. Regulators of HSC including transforming growth factor-beta (TGF-􀈕) and tumor necrosis factor-alpha (TNF-􀄮) modulate cell cycle activity and engraftment [27]. Some cytokines including Wnt and the notch ligand family may also have important effects on stem cell biology [28, 29]. Some cytokines, including TNF-􀄮, may be either inhibitory or activating depending on their concentration and other ongoing physiologic processes [30]. Several known cytokines, such as kit ligand, exist in either a soluble or membrane-bound form and have different activities depending on whether they are bound or soluble and on the environmental context in which they are acting [25]. Hematopoietic regulatory cytokines are produced through both autocrine and paracrine mechanisms and in many cases are produced by non-hematopoietic cells including bone marrow stroma and endothelium.

Chemokines are another class of compounds that are important regulators of hematopoiesis [31-33]. These molecules regulate blood cell trafficking and homing to sites of need and may also be negative and positive growth regulators [34]. Chemokines are composed of a large family of proteins that mediate a variety of processes including inflammation, leukocyte migration and development, angiogenesis, and tumor cell growth and metastasis. Chemokines bind to one or more of a large family of structurally related guanine protein-coupled transmembrane receptors. In hematopoiesis, chemokines inhibit progenitor growth, regulate migration of hematopoietic progenitors. For example, the chemokine SDF-1 (which binds the receptor CCXR4) is essential for trafficking of hematopoietic cells in the developing embryo, mediating [homing of HSC and progenitors to the bone marrow following transplantation and, in stem cell mobilization, for collecting peripheral blood stem cells for transplant purposes [31].]

This includes activation of a tyrosine kinases such as focal adhesion kinase, pp60src, and c-Abl, MAP kinases, jun Kinase (JNK), and protein kinase C (PKC).[38] Mediators of cell growth and differentiation such as c-src, phosphoinositides, protein kinase C, and growth factor-mediated signaling pathways are also modulated by cytokines. Cytokines including interleukin-3 and GM-CSF induce cell proliferation, while other cytokines including flt-3 ligand and kit ligand protect cells from apoptosis and sensitize them to the effects of growth promoting cytokines.[39-41] Cytokines may also facilitate the interactions between stem cells and elements in the microenvironment including extracellular matrix (ECM) components.[42] Regulators of HSCs including transforming growth factor-beta (TGF- ) and tumor necrosis factor-alpha (TNF- ) modulate cell cycle activity and engraftment.[43] Newly discovered cytokines including Wnt and the notch ligand family may also have important effects on stem cell biology.[44,45] Some cytokines, including TNF- , may be either inhibitory or activating depending on their concentration and other ongoing physiologic processes.[46] Several known cytokines, such as kit ligand, exist in either a soluble or membrane-bound form and have different activities depending on whether they are bound or soluble and on the environmental context in which they are acting.[41] Hematopoietic regulatory cytokines are produced through both autocrine and paracrine mechanisms and in many cases are produced by nonhematopoietic cells including bone marrow stroma and endothelium.

Chemokines are another class of compounds that are important regulators of hematopoiesis.[47-49] These molecules regulate blood cell trafficking and homing to sites of need and may also be negative and positive growth regulators.[50] Chemokines are composed of a large family of proteins that mediate a variety of processes including inflammation, leukocyte migration and development, angiogenesis, and tumor cell growth and metastasis. Chemokines bind to one or more of a large family of structurally related guanine protein-coupled transmembrane receptors. In hematopoiesis, chemokines can inhibit progenitor growth, regulate migration of hematopoietic progenitors, and mediate T-cell development in the thymus. For example, the chemokine SDF-1 (which binds the receptor CCXR4) is essential for trafficking of hematopoietic cells in the developing embryo, mediating homing of HSCs and progenitors to the bone marrow following transplantation and, in stem cell mobilization, for collecting peripheral blood stem cells for transplant purposes.[47]

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[5.] Analyse:Rsi/Fragment 012 01 - Diskussion
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[For example, the chemokine SDF-1 (which binds the receptor CCXR4) is essential

for trafficking of hematopoietic cells in the developing embryo, mediating] homing of HSC and progenitors to the bone marrow following transplantation and, in stem cell mobilization, for collecting peripheral blood stem cells for transplant purposes [31]. A number of other chemokines likely play important roles in hematopoiesis and are under active investigation.

HSC and progenitors bind tightly to a number of ECM components including heparin sulfates, chemokines, collagens, laminin, thrombospondin-1, fibronectin, and others. These molecules provide a scaffold for colocalizing progenitors and HSC with a wide array of positive and negative cytokines and other growth regulators. In addition, ECM and stromal components may directly mediate signaling to HSC to activate growth, protect cells from apoptosis, or modulate responses to positive and negative regulatory factors. The adhesion molecules on HSC and progenitors that mediate binding to these ECM components include CD44, integrins, selectins, and mucins. Adherence of cells to microenvironmental elements can trigger a variety of signaling pathways and can lead to changes in intracellular ions such as proton (pH), calcium, and the small GTPase Rho as well as lipid mediators such as phosphoinositides, diacylglycerol, and arachidonic acid metabolites [35]. Adhesion may also regulate expression of immediate-early genes such as c-fos and key cell cycle events such as kinase activity of cyclin-cdk complexes and phosphorylation of the retinoblastoma (Rb) protein [36]. Cell adhesion may potentiate the responses to growth factors and by modulating the downstream components of growth factor signaling cascades including PI-3 kinase, AKT, and p70rsk [37]. Hematopoietic and non-hematopoietic cells that may regulate hematopoiesis include NK cells, T cells, macrophages, fibroblasts, osteoblasts, adipocytes, and perhaps even neurons [38, 39]. These cells may produce important growth factors, facilitate engraftment, or induce apoptosis. A number of nutrients, trace elements, and vitamins (zinc, selenium, copper, vitamins A, D, and E) are also critical to hematopoiesis. Retinoids and particularly retinoid antagonists play important roles in differentiation at even low concentrations.

For example, the chemokine SDF-1 (which binds the receptor CCXR4) is essential for trafficking of hematopoietic cells in the developing embryo, mediating homing of HSCs and progenitors to the bone marrow following transplantation and, in stem cell mobilization, for collecting peripheral blood stem cells for transplant purposes.[47] A number of other chemokines likely play important roles in hematopoiesis and are under active investigation.

Other important environmental regulators of hematopoiesis include the ECM components, other hematopoietic and nonhematopoietic cells, nutrients and vitamins, and a variety of physiologic processes. HSCs and progenitors bind tightly to a number of ECM components including heparin sulfates, chemokines, collagens, laminin, thrombospondin-1, fibronectin, and others. These molecules provide a scaffold for colocalizing progenitors and HSCs with a wide array of positive and negative cytokines and other growth regulators. In addition, ECM and stromal components may directly mediate signaling to HSCs to activate growth, protect cells from apoptosis, or modulate responses to positive and negative regulatory factors. The adhesion molecules on HSCs and progenitors that mediate binding to these ECM components include integrins, selectins, and mucins. Adherence of cells to microenvironmental elements can trigger a variety of signaling pathways and can lead to changes in intra-cellular ions such as proton (pH), calcium, and the small GTPase Rho as well as lipid mediators such as phosphoinositides, diacylglycerol, and arachidonic acid metabolites.[51] Adhesion may also regulate expression of immediate-early genes such as c-fos and key cell cycle events such as kinase activity of cyclincdk complexes and phosphorylation of the retinoblastoma (Rb) protein.[52] Cell adhesion may potentiate the responses to growth factors and by modulating the downstream components of growth factor signaling cascades including PI 3 kinase, AKT, and p70rsk.[53] Hematopoietic and nonhematopoietic cells that may regulate hematopoiesis include NK cells, T cells, macrophages, fibroblasts, osteoblasts, adipocytes, and perhaps even neurons.[54,55] These cells may produce important growth factors, facilitate engraftment, or induce apoptosis. A number of nutrients, trace elements, and vitamins (eg, zinc, selenium, copper, vitamins A, D, and E) are also critical to hematopoiesis. Retinoids and particularly retinoid antagonists play important roles in differentiation at even low concentrations.

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[6.] Analyse:Rsi/Fragment 013 07 - Diskussion
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Phenotypically, murine HSCs are small cells with minimal cytoplasm, and they express high levels of the multidrug resistant (MDR) proteins and high levels of aldehyde dehydrogenase (ALDH) [42, 43].

42 Jones RJ, Collector MI, Barber JP, et al., Characterization of mouse lymphohematopoietic stem cells lacking spleen colony-forming activity. Blood. 1996; 88:487-491.

43 Sharkis SJ, Collector MI, Barber JP, et al., Phenotypic and functional characterization of the hematopoietic stem cell. Stem Cells. 1997;15(suppl 1):41-45.

Phenotypically, murine HSCs are small cells with minimal cytoplasm, and they express high levels of the multidrug resistant (MDR) proteins and high levels of aldehyde dehydrogenase (ALDH).[4,8]

4. Jones RJ, Collector MI, Barber JP, et al. Characterization of mouse lymphohematopoietic stem cells lacking spleen colony-forming activity. Blood. 1996;88:487-491.

8. Sharkis SJ, Collector MI, Barber JP, et al. Phenotypic and functional characterization of the hematopoietic stem cell. Stem Cells. 1997;15(suppl 1):41-45.

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