Suppression of homeobox transcription factor VentX promotes expansion of human hematopoietic stem/multipotent progenitor cells.
Mechanisms that regulate proliferation and expansion of human hematopoietic stem/multipotent progenitor cells (HSC/MPPs) are targets of intensive investigations. Several cell intrinsic factors and signaling pathways have been implicated in the proliferation and differentiation of human HSC/MPPs. Nevertheless, expansion of human HSC/MPPs for clinical application remains a critical challenge. VentX is a human homeobox transcription factor that was recently identified as an anti-proliferation and pro-differentiation factor in human hematopoietic cells. Here, we report that VentX expression is up-regulated during ontogenesis of human hematopoietic cells. Strikingly, suppression of VentX expression led to significant expansion of HSC/MPPs ex vivo and a 20-fold increase in engraftment potential in the NOD/SCID/IL2Rγ2(null) mouse model. VentX suppression helped preserve the HSC/MPP pools and promote clonogenicity of hematopoietic progenitor cells. Mechanistically, we show that VentX regulates critical cell cycle regulators and Wnt downstream genes previously implicated in HSC/MPP proliferation and expansion.
Gastroenterology Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
Hong
H
Gao
Xiaoming
X
Wu
Yan
Y
Sun
Shuanhu
S
Zhou
Leslie E
LE
Silberstein
Zhenglun
Z
Zhu
D000818:Animals; D002453:Cell Cycle / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology*; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D039902:Multipotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014183:Transplantation, Heterologous; D015854:Up-Regulation / Q000502:physiology; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism
D018398:Homeodomain Proteins; D014157:Transcription Factors; C408346:VENTX protein, human; D051153:Wnt Proteins