Activation of CCAAT/enhancer-binding protein alpha or PU.1 in hematopoietic stem cells leads to their reduced self-renewal and proliferation.
Previous studies using loss-of-function mutants revealed that CCAAT/enhancer-binding protein alpha (C/EBPalpha) and PU.1 are potential regulators for hematopoietic stem cells (HSCs). To gain further insight into the HSC regulation by C/EBPalpha or PU.1, we used transgenic mice expressing conditional forms of these transcription factors to examine whether their activation alone is sufficient for modulating HSC functions. The activation of C/EBPalpha or PU.1 in HSCs in vitro or in vivo led to their suppression of growth, decreased mixed colony formation, and impaired competitive repopulating activities because of their defective self-renewal. These effects were more prominently observed when C/EBPalpha was activated, and the differentiation capacity to megakaryocytic lineage was selectively impaired upon C/EBPalpha activation. Unexpectedly, the expression of Bmi-1 and HoxB4, well-known regulators for self-renewal of HSCs, was not affected by the activation of C/EBPalpha or PU.1, suggesting that they regulate HSC function through an as yet unknown mechanism. Our data suggest that the activation of C/EBPalpha or PU.1 is sufficient to repress stem cell capacities in HSCs, and their fine-tuned regulation is critical for HSC homeostasis.
Fukuchi
Yumi
Y
Center of Excellence, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
Ito
Miyuki
M
Shibata
Fumi
F
Kitamura
Toshio
T
Nakajima
Hideaki
H
D000818:Animals; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000166:cytology; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000378:metabolism*; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000378:metabolism; D063150:Polycomb Repressive Complex 1; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D019076:Transgenes; D000099232:Proto-Oncogene Protein Spi-1
D022763:CCAAT-Enhancer-Binding Protein-alpha; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D063150:Polycomb Repressive Complex 1; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000099232:Proto-Oncogene Protein Spi-1; C489421:Bmi1 protein, mouse; C513262:Hoxb4 protein, mouse