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      1. Author :
        Abdel-Azim, H.; Zhu, Y.; Hollis, R.; Wang, X.; Ge, S.; Hao, Q. L.; Smbatyan, G.; Kohn, D. B.; Rosol, M.; Crooks, G. M.
      2. Title :
        Expansion of multipotent and lymphoid-committed human progenitors through intracellular dimerization of Mpl
      3. Type :
        Journal Article
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      11. Keywords :
        IVIS, Xenogen
      12. Abstract :
        Self-renewal capacity is rapidly lost during differentiation of hematopoietic stem cells to lineage-committed progenitors. We demonstrate here that regulated intracellular signaling through the cytokine receptor Mpl induces profound expansion of not only multipotent (ie, lymphomyeloid) but also lymphoid-committed human hematopoietic progenitors. A fusion protein containing the intracellular signaling domain of Mpl and a dimerization domain was constitutively expressed in populations enriched in human lymphomyeloid progenitor/stem cells (CD34+CD38?Lin?CD7?) and multilymphoid progenitors (CD34+CD38?Lin?CD7+). Intracellular dimerization of Mpl in target cells was induced by in vitro or in vivo administration of a diffusible synthetic ligand. In vitro, Mpl dimerization produced divisions of clonogenic, multilineage CD34+ cells able to engraft immunodeficient mice. When dimerization was induced in vivo after transplantation of either lymphomyeloid or multilymphoid progenitors, donor-derived hematopoiesis was sustained for at least 12 weeks and primitive CD34+Lin? progenitors were expanded more than 1000-fold. Lineage potential of progenitors was not altered and differentiation was not prevented by synthetically induced Mpl signaling. These data demonstrate that dimerization of a single cytokine receptor can deliver a profound expansion signal in both uncommitted and lymphoid-committed human hematopoietic progenitors.
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