Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells.
Open accessAbstract
A central issue in stem cell biology is to understand the mechanisms that regulate the self-renewal of haematopoietic stem cells (HSCs), which are required for haematopoiesis to persist for the lifetime of the animal. We found that adult and fetal mouse and adult human HSCs express the proto-oncogene Bmi-1. The number of HSCs in the fetal liver of Bmi-1-/- mice was normal. In postnatal Bmi-1-/- mice, the number of HSCs was markedly reduced. Transplanted fetal liver and bone marrow cells obtained from Bmi-1-/- mice were able to contribute only transiently to haematopoiesis. There was no detectable self-renewal of adult HSCs, indicating a cell autonomous defect in Bmi-1-/- mice. A gene expression analysis revealed that the expression of stem cell associated genes, cell survival genes, transcription factors, and genes modulating proliferation including p16Ink4a and p19Arf was altered in bone marrow cells of the Bmi-1-/- mice. Expression of p16Ink4a and p19Arf in normal HSCs resulted in proliferative arrest and p53-dependent cell death, respectively. Our results indicate that Bmi-1 is essential for the generation of self-renewing adult HSCs.
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Upregulation of p16 and Arf has been implicated in mediating the induction of cellular senescence in a variety of cells including HSCs.
“Upregulation of p16 and Arf has been implicated in mediating the induction of cellular senescence in a variety of cells including HSCs.”
From Total body irradiation causes long-term mouse BM injury via induction of HSC premature senescence in an Ink4a- and Arf-independent manner (2014) · cites this paper as [15]
p16, but not Arf, plays an important role in mediating induction of Bmi1−/− HSC senescence, whereas Arf mainly promotes HSC apoptosis.
“However, it appears that p16, but not Arf, plays an important role in mediating induction of Bmi1−/− HSC senescence, whereas Arf mainly promotes HSC apoptosis.15”
From Total body irradiation causes long-term mouse BM injury via induction of HSC premature senescence in an Ink4a- and Arf-independent manner (2014) · cites this paper as [15]
Increased expression of p16 and Arf was found in HSCs from Bmi1−/− mice.
“For example, increased expression of p16 and Arf was found in HSCs from Bmi1−/− mice.15”
From Total body irradiation causes long-term mouse BM injury via induction of HSC premature senescence in an Ink4a- and Arf-independent manner (2014) · cites this paper as [15]
ROS plays an important role in mediating induction of HSC senescence under various pathological conditions, such as mutation of ATM and various Fanconi anemia genes; deletion of Bmi1, FoxOs, Mdm2, and Tsc1; and aging.
“ROS plays an important role in mediating induction of HSC senescence under various pathological conditions, such as mutation of ATM and various Fanconi anemia genes; deletion of Bmi1, FoxOs, Mdm2, and Tsc1; and aging.15,19,20,35-38”
From Total body irradiation causes long-term mouse BM injury via induction of HSC premature senescence in an Ink4a- and Arf-independent manner (2014) · cites this paper as [15]
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- Authors
- Park, I.-K., Qian, D., Kiel, M., Becker, M. W., Pihalja, M., Weissman, I. L., Morrison, S. J., & Clarke, M. F.
- Affiliations
- University of Michigan (US)
- Howard Hughes Medical Institute (US)
- Stanford Medicine (US)
- Corresponding author
- Clarke, Michael F.
- ORCID
- Venue
- Nature
- Published
- 2003-04-20
- Volume
- 423
- Issue
- 6937
- Pages
- 302-305
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2021050536
- Cited by
- 1,871
- References
- 31
- Citations by year
- 2026: 16 · 2025: 19 · 2024: 15 · 2023: 29 · 2022: 50 · 2021: 48 · 2020: 45 · 2019: 51 · 2018: 52 · 2017: 68 · 2016: 79 · 2015: 81 · 2014: 97 · 2013: 100 · 2012: 127
- FWCI
- 55.81
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Deep Blue (University of Michigan) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- University of Michigan
- National Institutes of Health
- 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
- BMI1, hematopoietic stem cells, self-renewal, stem cell maintenance, p16INK4a, p19ARF, p53-dependent cell death, growth arrest, cell survival genes, hematopoiesis, bone marrow
- MeSH terms
- Proto-Oncogene Mas, Animals, Bone Marrow Cells, Cell Division, Gene Expression Regulation, Hematopoietic Stem Cells, Humans, Liver, Models, Biological, Nuclear Proteins, Proto-Oncogene Proteins, Repressor Proteins, RNA, Messenger, Bone Marrow Transplantation, Gene Deletion, Hematopoietic Stem Cell Transplantation, Cyclin-Dependent Kinase Inhibitor p16, Tumor Suppressor Protein p14ARF, Mice, Polycomb Repressive Complex 1
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