Expansion of Multipotent and Lymphoid-committed Human Progenitors Through Intracellular Dimerization of Mpl

Overview

Journal Blood

Publisher Elsevier

Specialty Hematology

Date 2008 Jan 5

PMID 18174381

Citations 9

Authors

Hisham Abdel-Azim

Yuhua Zhu

Roger Hollis

Xiuli Wang

Shundi Ge

Qian-Lin Hao

Goar Smbatyan

Donald B Kohn

Michael Rosol

Gay M Crooks

Affiliations

Soon will be listed here.

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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