Haematopoietic stem cells do not asymmetrically segregate chromosomes or retain BrdU
Open accessAbstract
Stem cells are proposed to segregate chromosomes asymmetrically during self-renewing divisions so that older ('immortal') DNA strands are retained in daughter stem cells whereas newly synthesized strands segregate to differentiating cells. Stem cells are also proposed to retain DNA labels, such as 5-bromo-2-deoxyuridine (BrdU), either because they segregate chromosomes asymmetrically or because they divide slowly. However, the purity of stem cells among BrdU-label-retaining cells has not been documented in any tissue, and the 'immortal strand hypothesis' has not been tested in a system with definitive stem cell markers. Here we tested these hypotheses in haematopoietic stem cells (HSCs), which can be highly purified using well characterized markers. We administered BrdU to newborn mice, mice treated with cyclophosphamide and granulocyte colony-stimulating factor, and normal adult mice for 4 to 10 days, followed by 70 days without BrdU. In each case, less than 6% of HSCs retained BrdU and less than 0.5% of all BrdU-retaining haematopoietic cells were HSCs, revealing that BrdU has poor specificity and poor sensitivity as an HSC marker. Sequential administration of 5-chloro-2-deoxyuridine and 5-iodo-2-deoxyuridine indicated that all HSCs segregate their chromosomes randomly. Division of individual HSCs in culture revealed no asymmetric segregation of the label. Thus, HSCs cannot be identified on the basis of BrdU-label retention and do not retain older DNA strands during division, indicating that these are not general properties of stem cells.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
During normal tissue homeostasis, neither template strand segregation nor label retention was observed in one study of HSCs.
“During normal tissue homeostasis, neither template strand segregation nor label retention was observed in one study of HSCs135.”
From Molecular regulation of stem cell quiescence (2013) · cites this paper as [135]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Kiel, M. J., Yilmaz, Ö. H., Iwashita, T., Yilmaz, O. H., Terhorst, C., & Morrison, S. J. (2005) · Cell · doi:10.1016/j.cell.2005.05.026 · Cited by 3,168 · see citing works
Self-citationIdentification of the haematopoietic stem cell niche and control of the niche size
Zhang, J., Niu, C. S., Ye, L., Huang, H., He, X. C., Tong, W.-G., Ross, J., Haug, J., Johnson, T. J., Feng, J. Q., et al. (2003) · Nature · doi:10.1038/nature02041 · Cited by 2,948 · see citing works
Cotsarelis, G., Sun, T.-T., & Lavker, R. M. (1990) · Cell · doi:10.1016/0092-8674(90)90696-c · Cited by 2,276 · see citing works
Defining the Epithelial Stem Cell Niche in Skin
Tumbar, T., Guasch, G., Greco, V., Blanpain, C., Lowry, W. E., Rendl, M., & Fuchs, E. (2004) · Science · doi:10.1126/science.1092436 · Cited by 2,031 · see citing works
Tie2/Angiopoietin-1 Signaling Regulates Hematopoietic Stem Cell Quiescence in the Bone Marrow Niche
Arai, F., Hirao, A., Ohmura, M., Sato, H., Matsuoka, S., Takubo, K., Ito, K., Koh, G. Y., & Suda, T. (2004) · Cell · doi:10.1016/j.cell.2004.07.004 · Cited by 1,958 · see citing works
Mutation selection and the natural history of cancer
Cairns, J. (1975) · Nature · doi:10.1038/255197a0 · Cited by 1,592 · see citing works
Involvement of Follicular Stem Cells in Forming Not Only the Follicle but Also the Epidermis
Taylor, G., Lehrer, M. S., Jensen, P. J., Sun, T.-T., & Lavker, R. M. (2000) · Cell · doi:10.1016/s0092-8674(00)00050-7 · Cited by 1,070 · see citing works
Cheshier, S. H., Morrison, S. J., Liao, X., & Weissman, I. L. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.6.3120 · Cited by 858 · see citing works
Intestinal stem cells protect their genome by selective segregation of template DNA strands
Potten, C. S., Owen, G., & Booth, D. (2002) · Journal of Cell Science · doi:10.1242/jcs.115.11.2381 · Cited by 633 · see citing works
Sca-1pos Cells in the Mouse Mammary Gland Represent an Enriched Progenitor Cell Population
Welm, B. E., Tepera, S. B., Bowman, T. V., Graubert, T. A., Rosen, J. M., & Goodell, M. A. (2002) · Developmental Biology · doi:10.1006/dbio.2002.0625 · Cited by 521 · see citing works
Asymmetric division and cosegregation of template DNA strands in adult muscle satellite cells
Shinin, V., Gayraud-Morel, B., Gomès, D., & Tajbakhsh, S. (2006) · Nature Cell Biology · doi:10.1038/ncb1425 · Cited by 504 · see citing works
Stem cell niches in the adult mouse heart
Urbanek, K., Cesselli, D., Rota, M., et al. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0600635103 · Cited by 433 · see citing works
Morrison, S. J., CSETE, M. E., Groves, A. K., Melega, W. P., Wold, B. J., & Anderson, D. J. (2000) · Journal of Neuroscience · doi:10.1523/jneurosci.20-19-07370.2000 · Cited by 403 · see citing works
Self-citationBowie, M. B., McKnight, K. D., Kent, D. G., McCaffrey, L., Hoodless, P. A., & Eaves, C. J. (2006) · Journal of Clinical Investigation · doi:10.1172/jci28310 · Cited by 380 · see citing works
Morrison, S. J., Wright, D. E., & Weissman, I. L. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.5.1908 · Cited by 314 · see citing works
Self-citationThe segregation of DNA in epithelial stem cells
Potten, C. S., Hume, W. J., Reid, P. J., & Cairns, J. (1978) · Cell · doi:10.1016/0092-8674(78)90274-x · Cited by 313 · see citing works
Smith, G. H. (2005) · Development · doi:10.1242/dev.01609 · Cited by 288 · see citing works
Conboy, M. J., Karasov, A. O., & Rando, T. A. (2007) · PLoS Biology · doi:10.1371/journal.pbio.0050102 · Cited by 287 · see citing works
Asymmetric Division and Lineage Commitment at the Level of Hematopoietic Stem Cells
Takano, H., Ema, H., Sudo, K., & Nakauchi, H. (2004) · The Journal of Experimental Medicine · doi:10.1084/jem.20030929 · Cited by 208 · see citing works
Support for the immortal strand hypothesis: neural stem cells partition DNA asymmetrically in vitro
Karpowicz, P. A., Morshead, C. M., Kam, A., Jervis, E., Ramunas, J., Cheng, V. Y. S., & van der Kooy, D. (2005) · The Journal of Cell Biology · doi:10.1083/jcb.200502073 · Cited by 191 · see citing works
Cell Type Regulates Selective Segregation of Mouse Chromosome 7 DNA Strands in Mitosis
Armakolas, A., & Klar, A. J. S. (2006) · Science · doi:10.1126/science.1120519 · Cited by 111 · see citing works
Quantification of Cell Turnover Kinetics Using 5-Bromo-2′-deoxyuridine
Bonhoeffer, S., Mohri, H., Ho, D. D., & Perelson, A. S. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.164.10.5049 · Cited by 98 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Gurtner, G. C., Werner, S., Barrandon, Y., & Longaker, M. T. (2008) · Nature · doi:10.1038/nature07039 · Cited by 6,542 · see citing works
The bone marrow niche for haematopoietic stem cells
Morrison, S. J., & Scadden, D. T. (2014) · Nature · doi:10.1038/nature12984 · Cited by 2,451 · see citing works
Self-citationThe role of m6A modification in the biological functions and diseases
Jiang, X., Liu, B., Nie, Z., Duan, L., Xiong, Q., Jin, Z., Yang, C., & Chen, Y. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-00450-x · Cited by 2,335 · see citing works
Variation in cancer risk among tissues can be explained by the number of stem cell divisions
Tomasetti, C., & Vogelstein, B. (2015) · Science · doi:10.1126/science.1260825 · Cited by 1,927 · see citing works
Wilson, A., Laurenti, E., Oser, G., van der Wath, R. C., Blanco-Bose, W., Jaworski, M., Offner, S., Dunant, C. F., Eshkind, L., Bockamp, E., et al. (2008) · Cell · doi:10.1016/j.cell.2008.10.048 · Cited by 1,908 · see citing works
Coexistence of Quiescent and Active Adult Stem Cells in Mammals
Li, L., & Clevers, H. (2010) · Science · doi:10.1126/science.1180794 · Cited by 1,247 · see citing works
Molecular regulation of stem cell quiescence
Cheung, T. H., & Rando, T. A. (2013) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3591 · Cited by 1,148 · see citing works
Hematopoiesis: a human perspective
Doulatov, S., Notta, F., Laurenti, E., & Dick, J. E. (2012) · Cell stem cell · doi:10.1016/j.stem.2012.01.006 · Cited by 895 · see citing works
Barker, N., van de Wetering, M., & Clevers, H. (2008) · Genes & Development · doi:10.1101/gad.1674008 · Cited by 629 · see citing works
Analysis of histone 2B-GFP retention reveals slowly cycling hematopoietic stem cells
Foudi, A., Hochedlinger, K., Van Buren, D., Schindler, J. W., Jaenisch, R., Carey, V., & Hock, H. (2009) · Nature Biotechnology · doi:10.1038/nbt.1517 · Cited by 586 · see citing works
Niche Regulation of Muscle Satellite Cell Self-Renewal and Differentiation
Kuang, S., Gillespie, M. A., & Rudnicki, M. A. (2008) · Cell Stem Cell · doi:10.1016/j.stem.2007.12.012 · Cited by 507 · see citing works
Hematopoietic Stem Cells Are the Major Source of Multilineage Hematopoiesis in Adult Animals
Sawai, C. M., Babovic, S., Upadhaya, S., Knapp, D. J. H. F., Lavin, Y., Lau, C. M., Goloborodko, A., Feng, J., Fujisaki, J., Ding, L., et al. (2016) · Immunity · doi:10.1016/j.immuni.2016.08.007 · Cited by 381 · see citing works
The tortoise and the hair: slow-cycling cells in the stem cell race
Fuchs, E. (2009) · Cell · doi:10.1016/j.cell.2009.05.002 · Cited by 371 · see citing works
The replication rate of human hematopoietic stem cells in vivo
Catlin, S. N., Busque, L., Gale, R. E., Guttorp, P., & Abkowitz, J. L. (2011) · Blood · doi:10.1182/blood-2010-08-303537 · Cited by 259 · see citing works
Lgr5 intestinal stem cells have high telomerase activity and randomly segregate their chromosomes
Schepers, A. G., Vries, R., van den Born, M., van de Wetering, M., & Clevers, H. (2011) · The EMBO Journal · doi:10.1038/emboj.2011.26 · Cited by 217 · see citing works
Johnson, S. M., Torrice, C. D., Bell, J. F., Monahan, K. B., Jiang, Q., Wang, Y., Ramsey, M. R., Jin, J., Wong, K.-K., Su, L., et al. (2010) · Journal of Clinical Investigation · doi:10.1172/jci41402 · Cited by 168 · see citing works
Tang, D., Tao, S., Chen, Z., Koliesnik, I. O., Calmes, P. G., Hoerr, V., Han, B., Gebert, N., Zörnig, M., Löffler, B., et al. (2016) · Journal of Experimental Medicine · doi:10.1084/jem.20151100 · Cited by 133 · see citing works
Stem cells and aging in the hematopoietic system
Warren, L. A., & Rossi, D. J. (2009) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2008.03.010 · Cited by 128 · see citing works
Sotiropoulou, P. A., Candi, A., & Blanpain, C. (2008) · Stem Cells · doi:10.1634/stemcells.2008-0634 · Cited by 67 · see citing works
Stem cell ageing and non-random chromosome segregation
Charville, G. W., & Rando, T. A. (2011) · Philosophical Transactions of the Royal Society B: Biological Sciences · doi:10.1098/rstb.2010.0279 · Cited by 45 · see citing works
He, P., Staufenbiel, M., Li, R., & Shen, Y. (2014) · Human Molecular Genetics · doi:10.1093/hmg/ddu370 · Cited by 33 · see citing works
- Authors
- Kiel, M. J., He, S., Ashkenazi, R., Gentry, S. N., Teta, M., Kushner, J. A., Jackson, T. L., & Morrison, S. J.
- Affiliations
- Howard Hughes Medical Institute (US)
- University of Michigan (US)
- Children's Hospital of Philadelphia (US)
- Corresponding author
- Morrison, Sean J.
- Venue
- Nature
- Published
- 2007-08-29
- Volume
- 449
- Issue
- 7159
- Pages
- 238-242
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2633872
- OpenAlex
- W2162096092
- Cited by
- 417
- References
- 22
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 7 · 2023: 4 · 2022: 7 · 2021: 9 · 2020: 15 · 2019: 11 · 2018: 12 · 2017: 14 · 2016: 24 · 2015: 20 · 2014: 26 · 2013: 35 · 2012: 36
- FWCI
- 31.67
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Deep Blue (University of Michigan) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (R01AG024945)
- Army Research Laboratory
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- hematopoietic stem cells, stem cell markers, mutation accumulation, self-renewal, hematopoiesis, cyclophosphamide, granulocyte colony-stimulating factor, stem cell purification, DNA replication timing
- MeSH terms
- Aging, Animals, Animals, Newborn, Bone Marrow Cells, Bromodeoxyuridine, Cells, Cultured, Cyclophosphamide, Hematopoietic Stem Cells, Stochastic Processes, Time Factors, Granulocyte Colony-Stimulating Factor, Chromosome Segregation, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
