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 Blood, 15 April 2008, Vol. 111, No. 8, pp. 4064-4074.
Prepublished online as a Blood First Edition Paper on January 3, 2008; DOI 10.1182/blood-2007-08-107466.

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HEMATOPOIESIS AND STEM CELLS

Expansion of multipotent and lymphoid-committed human progenitors through intracellular dimerization of Mpl

Hisham Abdel-Azim1, Yuhua Zhu1, Roger Hollis1, Xiuli Wang1, Shundi Ge1, Qian-Lin Hao1, Goar Smbatyan2, Donald B. Kohn1, Michael Rosol2, and Gay M. Crooks1

1 Division of Research Immunology/Bone Marrow Transplantation, and 2 Department of Radiology, Childrens Hospital Los Angeles, Los Angeles, CA

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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Related Article in Blood Online:

Cell expansion and maintenance of stemness
Kenneth Kaushansky
Blood 2008 111: 3920-3921. [Full Text] [PDF]





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