Comprehensive analysis of myeloid lineage conversion using mice expressing an inducible form of C/EBP alpha.
CCAAT/enhancer-binding protein (C/EBP) alpha is a critical regulator for early myeloid differentiation. Although C/EBPalpha has been shown to convert B cells into myeloid lineage, precise roles of C/EBPalpha in various hematopoietic progenitors and stem cells still remain obscure. To examine the consequence of C/EBPalpha activation in various progenitors and to address the underlying mechanism of lineage conversion in detail, we established transgenic mice expressing a conditional form of C/EBPalpha. Using these mice, we show that megakaryocyte/erythroid progenitors (MEPs) and common lymphoid progenitors (CLPs) could be redirected to functional macrophages in vitro by a short-term activation of C/EBPalpha, and the conversion occurred clonally through biphenotypic intermediate cells. Moreover, in vivo activation of C/EBPalpha in mice led to the increase of mature granulocytes and myeloid progenitors with a concomitant decrease of hematopoietic stem cells and nonmyeloid progenitors. Our study reveals that C/EBPalpha can activate the latent myeloid differentiation program of MEP and CLP and shows that its global activation affects multilineage homeostasis in vivo.
Fukuchi
Yumi
Y
Division of Cellular Therapy, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
Shibata
Fumi
F
Ito
Miyuki
M
Goto-Koshino
Yuko
Y
Sotomaru
Yusuke
Y
Ito
Mamoru
M
Kitamura
Toshio
T
Nakajima
Hideaki
H
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics*; D019070:Cell Lineage / Q000235:genetics*; D002478:Cells, Cultured; D018920:Coculture Techniques; D004912:Erythrocytes / Q000166:cytology / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D016131:Lymphocyte Subsets / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000166:cytology* / Q000378:metabolism*; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism
D022763:CCAAT-Enhancer-Binding Protein-alpha