| Autor: |
Von Levetzow, Gregor, Spanholtz, Jan, Beckmann, Julia, Fischer, Johannes, Punzel, Michael, Giebel, Bernd |
| Předmět: |
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| Zdroj: |
Regenerative Medicine; Nov2007 Supplement, Vol. 2, pS9-S9, 2/3p |
| Abstrakt: |
Hematopoietic stem cells are the most investigated mammalian stem cells. Like other stem cells they are undifferentiated cells that can self-renew over a long period of time and give rise to progenitor cells that will reconstitute the whole immune and blood system. Although the mechanisms regulating the decision process self-renewal versus differentiation remain largely unknown, there is good evidence that a combination of both extrinsic and intrinsic factors as well as the Notch signaling pathway are involved in controlling the cell fates of primitive hematopoietic cells and their arising daughter cells. Similarly, the Notch signaling pathway, its extrinsic ligands and its intrinsic modulators specify the cell fates of the four cells of developing external sensory organs of Drosophila melanogaster. In this system, the so-called sensory organ precursor cells divide asymmetrically to give rise to IIa and IIb daughter cells. Mechanistically, the cell fate determinant Numb, an antagonistic protein of Notch, segregates mainly into IIa daughter cells and inhibits the signal transduction of Notch, being activated by its ligands Delta and Serrate (the homolog of mammalian Jagged). Depending on the transduction of the Notch signal, daughter cells are either specified as IIa (no transduced signal) or as IIb (transduced signal). Since Numb is conserved during evolution and Notch activity seems to be required to maintain primitive hematopoietic cell fates, we wondered whether Numb is involved in cell fate specification during early hematopoiesis as well. GeneChip analyzes performed in collaboration with N Ivanova and I Lemischka (Princeton University) or with L Klein-Hitpass, T Moritz and J Thomale (Universitätklinikum Essen) together with numb specific RT-PCR analyzes revealed that numb is expressed in primitive hematopoietic cells of the lin-CD34+CD38low/- and lin-CD34+CD38+ cell fractions. By immunohistochemical and flow cytometric analyzes we could further show that even on the protein level Numb is expressed in all CD34+ cells. To functionally analyze the impact of Numb on the biology of primitive hematopoietic cells, in other words on CD34+ cells, we performed over-expression experiments and realized that enforced Numb expression inhibits the maintenance of primitive hematopoietic cell fates. In contrast to this and in agreement with published data, CD34+ cells expressing a constitutive active variant of Notch-1 contained a higher rate of more primitive cells than CD34+ cells of corresponding controls. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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