Interaction between Differentiating Cell- and Niche-Derived Signals in Hematopoietic Progenitor Maintenance

Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, CA 90095, USA.
Cell (Impact Factor: 32.24). 12/2011; 147(7):1589-600. DOI: 10.1016/j.cell.2011.11.041
Source: PubMed


Maintenance of a hematopoietic progenitor population requires extensive interaction with cells within a microenvironment or niche. In the Drosophila hematopoietic organ, niche-derived Hedgehog signaling maintains the progenitor population. Here, we show that the hematopoietic progenitors also require a signal mediated by Adenosine deaminase growth factor A (Adgf-A) arising from differentiating cells that regulates extracellular levels of adenosine. The adenosine signal opposes the effects of Hedgehog signaling within the hematopoietic progenitor cells and the magnitude of the adenosine signal is kept in check by the level of Adgf-A secreted from differentiating cells. Our findings reveal signals arising from differentiating cells that are required for maintaining progenitor cell quiescence and that function with the niche-derived signal in maintaining the progenitor state. Similar homeostatic mechanisms are likely to be utilized in other systems that maintain relatively large numbers of progenitors that are not all in direct contact with the cells of the niche.

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    • "Accumulating evidence also suggests that adenosine signaling has a role in hematopoietic cells. Adenosine signaling induces the proliferation and differentiation of hematopoietic progenitor cells in the lymph gland of Drosophila melanogaster embryos (Mondal et al., 2011). In the adult mice, administration of drugs that elevate extracellular adenosine levels increases hematopoietic spleen colony formation in sublethally gamma-irradiated animals (Hofer et al., 1997) and enhances cell cycling of hematopoietic progenitor cells (Pospísil et al., 2001). "
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    Journal of Experimental Medicine 04/2015; 209(2). DOI:10.1084/jem.20141528 · 12.52 Impact Factor
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    • "Prohemocyte, plasmatocyte, and crystal cell counts were divided by the total primary lobe area to normalize for differences in lymph gland size. Blood cell counts were analyzed using Zeiss Axioplan software as previously described [32], [69]. The statistical significance was evaluated using the Student's t-test. "
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    PLoS ONE 09/2014; 9(9):e107768. DOI:10.1371/journal.pone.0107768 · 3.23 Impact Factor
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    • "The progenitor maintenance function of Pvr signaling in differentiated cells requires the downstream function of the STAT transcriptional activator and the secreted enzyme ADGF-A (Mondal et al., 2011), "
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    ABSTRACT: Blood progenitors within the lymph gland, a larval organ that supports hematopoiesis in Drosophila melanogaster, are maintained by integrating signals emanating from niche-like cells and those from differentiating blood cells. We term the signal from differentiating cells the ‘equilibrium signal’ in order to distinguish it from the ‘niche signal’. Earlier we showed that equilibrium signaling utilizes Pvr (the Drosophila PDGF/VEGF receptor), STAT92E, and adenosine deaminase-related growth factor A (ADGF-A) (Mondal et al., 2011). Little is known about how this signal initiates during hematopoietic development. To identify new genes involved in lymph gland blood progenitor maintenance, particularly those involved in equilibrium signaling, we performed a genetic screen that identified bip1 (bric à brac interacting protein 1) and Nucleoporin 98 (Nup98) as additional regulators of the equilibrium signal. We show that the products of these genes along with the Bip1-interacting protein RpS8 (Ribosomal protein S8) are required for the proper expression of Pvr. DOI:
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