Activation of CCAAT/Enhancer-Binding Protein α or PU.1 in Hematopoietic Stem Cells Leads to Their Reduced Self-Renewal and Proliferation
Abstract
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.
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PU.1 can restrict proliferation in hematopoietic stem and progenitor cells (HSPCs), likely a mechanism to promote PU.1 accumulation during myeloid differentiation.
“Interestingly, PU.1 can also restrict proliferation in hematopoietic stem and progenitor cells (HSPCs), likely a mechanism to promote PU.1 accumulation during myeloid differentiation (Fukuchi et al., 2008; Kueh et al., 2013).”
From PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress (2021) · cites this paper as Fukuchi et al., 2008
PU.1 is commonly characterized as a lineage differentiation factor, and its role as a regulator of cell proliferation has also been extensively studied.
“while PU.1 is commonly characterized as a lineage differentiation factor, its role as a regulator of cell proliferation has also been extensively studied (Delestré et al., 2017; Fukuchi et al., 2008; Oikawa et al., 1999; Solomon et al., 2017; Ziliotto et al., 2014).”
From PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress (2021) · cites this paper as Fukuchi et al., 2008
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AML1–ETO downregulates the granulocytic differentiation factor C/EBPα in t(8;21) myeloid leukemia
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Dynamic regulation of PU.1 expression in multipotent hematopoietic progenitors
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PU.1 regulates the commitment of adult hematopoietic progenitors and restricts granulopoiesis
Dakic, A., Metcalf, D., Di Rago, L., Mifsud, S., Wu, L., & Nutt, S. L. (2005) · The Journal of Experimental Medicine · doi:10.1084/jem.20050075 · Cited by 297 · see citing works
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Staber, P. B., Zhang, P., Ye, M., Welner, R. S., Nombela-Arrieta, C., Bach, C., Kerenyi, M., Bartholdy, B. A., Zhang, H., Alberich-Jordà, M., et al. (2013) · Molecular Cell · doi:10.1016/j.molcel.2013.01.007 · Cited by 158 · see citing works
PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress
Chavez, J. S., Rabe, J. L., Loeffler, D., Higa, K. C., Hernandez, G., Mills, T. S., Ahmed, N., Gessner, R. L., Ke, Z., Idler, B. M., et al. (2021) · Journal of Experimental Medicine · doi:10.1084/jem.20201169 · Cited by 91 · see citing works
“1 accumulation during myeloid differentiation (Fukuchi et al., 2008; Kueh et al., 2013).”
BackgroundSelf-citationSenescence is a Spi1-induced anti-proliferative mechanism in primary hematopoietic cells
Delestré, L., Cui, H., Esposito, M., Quiveron, C., Mylonas, E., Penard-Lacronique, V., Bischof, O., & Guillouf, C. (2017) · Haematologica · doi:10.3324/haematol.2016.157636 · Cited by 32 · see citing works
Blood stem cell PU.1 upregulation is a consequence of differentiation without fast autoregulation
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Self-citation
- Authors
- Fukuchi, Y., Ito, M., Shibata, F., Kitamura, T., & Nakajima, H.
- Affiliations
- Institute of Medical Science, The University of Tokyo (JP)
- Corresponding author
- Nakajima, Hideaki
- Venue
- Stem Cells
- Publisher
- Oxford University Press (OUP)
- Published
- 2008-09-11
- Volume
- 26
- Issue
- 12
- Pages
- 3172-3181
- ISSN
- 1066-5099 (ISSN-L)
- 1549-4918
- OpenAlex
- W1889444666
- Cited by
- 20
- References
- 8
- Citations by year
- 2025: 2 · 2021: 2 · 2020: 1 · 2018: 1 · 2017: 2 · 2015: 2 · 2014: 2 · 2013: 1 · 2012: 1
- FWCI
- 1.29
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- Stem Cells (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Blood disorders and treatments
- Keywords
- hematopoietic stem cells, C/EBPα, PU.1, transcription factor activation, self-renewal, stem cell proliferation, megakaryopoiesis, HSC homeostasis, BMI1, HOXB4, conditional transgenic mice
- MeSH terms
- Proto-Oncogene Protein Spi-1, Animals, Bone Marrow Cells, Cell Differentiation, Hematopoiesis, Hematopoietic Stem Cells, Mice, Transgenic, Nuclear Proteins, Proto-Oncogene Proteins, Repressor Proteins, Transcription Factors, Trans-Activators, Apoptosis, Homeodomain Proteins, Cell Lineage, Transgenes, CCAAT-Enhancer-Binding Protein-alpha, Cell Proliferation, Mice, Polycomb Repressive Complex 1
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