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Autor     David Bryder, Derrick J. Rossi, Irving L. Weissman
Titel    Hematopoietic Stem Cells. The Paradigmatic Tissue-Specific Stem Cell
Zeitschrift    The American Journal of Pathology
Herausgeber    American Society for Investigative Pathology
Ausgabe    169
Datum    2. August 2006
Nummer    2
DOI    10.2353/ajpath.2006.060312
URL    http://classes.biology.ucsd.edu/bggn231.FA07/8.R1.pdf

Literaturverz.   

yes
Fußnoten    yes
Fragmente    4


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Because of the very short life span of most effecter-cells [sic], mature blood cell production is an ongoing process, with the production of 1.5x106 blood cells every second in an adult human. This high turnover rate necessitates some homeostatic controlmechanisms; the primary level of which resides with the HSCs. Because of the very short life span of most effector cells, mature blood cell production is an ongoing process with estimates suggesting the production of 1.5x106 blood cells every second in an adult human. This high turnover rate necessitates profound homeostatic control mechanisms, the primary level of which resides with the HSCs.
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There is an enormous proliferative and developmental capacity of the more committed multipotent, oligo-potent and lineage-restricted progenitor cells within the haematopoietic hierarchy. A significant degree of homeostatic control of mature blood cells is also mediated at the level of these progenitors.25

25.Dzierzak E, Speck NA. Of lineage and legacy: the development of mammalian hematopoietic stem cells. Nat Immunol. 2008;9:129-136.

However, because of the enormous proliferative and developmental capacity of the more committed multipotent, oligo-potent, and lineage-restricted progenitor cells within the hematopoietic hierarchy, a significant degree of homeostatic control of mature blood cells is also mediated at the level of these progenitors.
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Figure 1.2.2: A model of the haematopoietic developmental hierarchy. Self-renewing HSCs reside at the top of the hierarchy, thereby giving rise to a number of multipotent progenitors. Multipotent progenitors give rise to oligo-potent progenitors including the CLP, which gives rise to mature B lymphocytes, T lymphocytes, and natural killer (NK) cells. The common myeloid progenitor (CMP) gives rise to granulocyte-macrophage progenitors, which differentiate into monocytes/macrophages and granulocytes, and megakaryocyte/erythrocyte progenitors, which differentiate into megakaryocytes/platelets and erythrocytes. The cell surface phenotype of many of these cell types is shown for the murine and human systems 50(Figure adapted from Bryder D et al., 2006).


50. Bryder D, Rossi DJ, Weissman IL. Hematopoietic stem cells: the paradigmatic tissue-specific stem cell. Am J Pathol. 2006;169:338-346.

15a source Pak.png

Figure 1. Model of the hematopoietic developmental hierarchy. Self-renewing HSCs reside at the top of the hierarchy, giving rise to a number of multipotent progenitors. Multipotent progenitors give rise to oligo-potent progenitors including the CLP, which gives rise to mature B lymphocytes, T lymphocytes, and natural killer (NK) cells. The common myeloid progenitor (CMP) gives rise to granulocyte-macrophage progenitors, which differentiate into monocytes/macrophages and granulocytes, and megakaryocyte/erythrocyte progenitors, which differentiate into megakaryocytes/platelets and erythrocytes. Both CMPs and CLPs have been proposed to give rise to dendritic cells. The cell surface phenotype of many of these cell types is shown for the murine and human systems.

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HSCs express a great diversity of transcripts, including a wide range of genes originally believed to be restricted to more mature and lineage-committed cell types. The single-cell polymerase chain reaction strategies had suggested that such loose transcription of lineage-associated transcripts was necessary to prime primitive progenitor cells for differentiation toward downstream fates.63

An alternative interpretation is that stem cells possess global transcriptional accessibility and that it is the step-wise restriction of locus accessibility that underlies lineage specification.64,65 Cell fate can also be switched from one committed cell type to another on over expression of IL2R or GM-CSF receptors 17,18 GATA-166 or C/EBP /ß [sic] .67 An additional mechanism of lineage specification has been revealed which attributes to the ablation of the transcription factors Pax5 or GATA-1 in lineage-restricted progenitors. This was sufficient to despecify their B-cell and erythroid fate, respectively, and allow a multilineage developmental potential.


17. Kondo M, Scherer DC, Miyamoto T, et al. Cell-fate conversion of lymphoid-committed progenitors by instructive actions of cytokines. Nature. 2000;407:383-386.

18. Kondo M, Wagers AJ, Manz MG, et al. Biology of hematopoietic stem cells and progenitors: implications for clinical application. Annu Rev Immunol. 2003;21:759-806.

63. Mikkola HK, Fujiwara Y, Schlaeger TM, Traver D, Orkin SH. Expression of CD41 marks the initiation of definitive hematopoiesis in the mouse embryo. Blood. 2003;101:508-516.

64. Akashi K, Reya T, Dalma-Weiszhausz D, Weissman IL. Lymphoid precursors. Curr Opin Immunol. 2000;12:144-150.

65. Akashi K, He X, Chen J, et al. Transcriptional accessibility for genes of multiple tissues and hematopoietic lineages is hierarchically controlled during early hematopoiesis. Blood. 2003;101:383- 389.

66. Iwasaki H, Mizuno S, Wells RA, Cantor AB, Watanabe S, Akashi K. GATA-1 converts lymphoid and myelomonocytic progenitors into the megakaryocyte/erythrocyte lineages. Immunity. 2003;19:451-462.

67. Xie H, Ye M, Feng R, Graf T. Stepwise reprogramming of B cells into macrophages. Cell. 2004;117:663-676.

One surprising finding of these studies is the discovery that HSCs express a great diversity of transcripts, including a wide range of genes originally believed to be restricted to more mature and lineage-committed cell types. The findings of these genome-wide expression studies had in fact been foreshadowed by earlier studies using single-cell polymerase chain reaction strategies that had suggested that such promiscuous transcription of lineage-associated transcripts was necessary to prime primitive progenitor cells for differentiation toward downstream fates.39,40 An alternative interpretation posits that stem cells possess global transcriptional accessibility and that it is the step-wise restriction of locus accessibility that underlies lineage specification.37 [...] This has been exemplified in experiments in which cell fate was switched from one committed cell type to another on overexpression of IL2R or GM-CSF receptors,41 GATA-1,42 or C/EBPα/β.43 An additional mechanism of lineage specification was revealed in experiments in which ablation of the transcription factors Pax5 or GATA-1 in lineage-restricted progenitors was found to be sufficient to despecify their B-cell and erythroid fate, respectively, and allow a multilineage developmental potential.44,45

37. Akashi K, He X, Chen J, Iwasaki H, Niu C, Steenhard B, Zhang J, Haug J, Li L: Transcriptional accessibility for genes of multiple tissues and hematopoietic lineages is hierarchically controlled during early hematopoiesis. Blood 2003, 101:383–389

39. Miyamoto T, Iwasaki H, Reizis B, Ye M, Graf T, Weissman IL, Akashi K: Myeloid or lymphoid promiscuity as a critical step in hematopoietic lineage commitment. Dev Cell 2002, 3:137–147

40. Hu M, Krause D, Greaves M, Sharkis S, Dexter M, Heyworth C, Enver T: Multilineage gene expression precedes commitment in the hemopoietic system. Genes Dev 1997, 11:774–785

41. Kondo M, Scherer DC, Miyamoto T, King AG, Akashi K, Sugamura K, Weissman IL: Cell-fate conversion of lymphoid-committed progenitors by instructive actions of cytokines. Nature 2000, 407:383–386

42. Iwasaki H, Mizuno S, Wells RA, Cantor AB, Watanabe S, Akashi K: GATA-1 converts lymphoid and myelomonocytic progenitors into the megakaryocyte/erythrocyte lineages. Immunity 2003, 19:451–462

43. Xie H, Ye M, Feng R, Graf T: Stepwise reprogramming of B cells into macrophages. Cell 2004, 117:663–676

44. Mikkola I, Heavey B, Horcher M, Busslinger M: Reversion of B cell commitment upon loss of Pax5 expression. Science 2002, 297:110–113

45. Kitajima K, Zheng J, Yen H, Sugiyama D, Nakano T: Multipotential differentiation ability of GATA-1-null erythroid-committed cells. Genes Dev 2006, 20:654–659

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