Expansion of multipotent and lymphoid-committed human progenitors through intracellular dimerization of Mpl.
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.
Abdel-Azim
Hisham
H
Division of Research Immunology/Bone Marrow Transplantation, Childrens Hospital Los Angeles, MS no. 62, 4650 Sunset Blvd, Los Angeles, CA 90027, USA.
Zhu
Yuhua
Y
Hollis
Roger
R
Wang
Xiuli
X
Ge
Shundi
S
Hao
Qian-Lin
QL
Smbatyan
Goar
G
Kohn
Donald B
DB
Rosol
Michael
M
Crooks
Gay M
GM
D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D019070:Cell Lineage / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019281:Dimerization; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D016130:Immunophenotyping; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism*; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008214:Lymphocytes / Q000166:cytology* / Q000187:drug effects; D051379:Mice; D039902:Multipotent Stem Cells / Q000166:cytology* / Q000187:drug effects; D053628:Receptors, Thrombopoietin / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D033581:Stem Cell Transplantation; D016559:Tacrolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D014161:Transduction, Genetic; D014470:Umbilical Cord / Q000166:cytology / Q000187:drug effects
C463061:AP20187; D018952:Antigens, CD34; D053628:Receptors, Thrombopoietin; D011993:Recombinant Fusion Proteins; C082218:MPL protein, human; D017493:Leukocyte Common Antigens; D016559:Tacrolimus