The DOI matches its Crossref record; 38 of the 38 references it cites were found in a registry or an index.
Clonal analysis reveals multiple functional defects of aged murine hematopoietic stem cells
Open accessAbstract
Hematopoietic stem cell (HSC) populations change with aging, but the extent to which this is caused by qualitative versus quantitative alterations in HSC subtypes is unclear. Using clonal assays, in this study we show that the aging HSC compartment undergoes both quantitative and qualitative changes. We observed a variable increase of HSC pool size with age, accompanied by the accumulation of predominantly myeloid-biased HSCs that regenerate substantially fewer mature progeny than young myeloid-biased HSCs and exhibit reduced self-renewal activity as measured by long-term secondary transplantation. Old HSCs had a twofold reduction in marrow-homing efficiency and a similar decrease in functional frequency as measured using long-term transplantation assays. Similarly, old HSCs had a twofold reduced seeding efficiency and a significantly delayed proliferative response compared with young HSCs in long-term stromal cell co-cultures but were indistinguishable in suspension cultures. We show that these functional defects are characteristics of most or all old HSCs and are not indicative of a nonfunctional subset of cells that express HSC markers. Furthermore, we demonstrate that cells with functional properties of old HSCs can be generated directly from young HSCs by extended serial transplantation, which is consistent with the possibility that they arise through a process of cellular aging.
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In the citing paper
“Despite the increase in their number, myeloid-biased stem cells are not as robust as their young counterparts (24)”
From Causes, consequences, and reversal of immune system aging (2013) · cites this paper as [24]
In the citing paper
“That aged HSC are functionally impaired compared with their young counterparts upon transplantation in young mice”
From Aging of hematopoietic stem cells (2018) · cites this paper as [10]
In the citing paper
“the functional heterogeneity of the HSC population increases with age.”
From Aging of hematopoietic stem cells (2018) · cites this paper as [10]
In the citing paper
“in aged mice that display an overall increase in HSC pool size”
From Aging of hematopoietic stem cells (2018) · cites this paper as [10]
In the citing paper
“individual HSCs behave very differently.”
From Aging of hematopoietic stem cells (2018) · cites this paper as [10]
In the citing paper
“mice in which blood cell production is derived from even a single stem cell, are not necessarily prone to develop leukemia.”
From Aging of hematopoietic stem cells (2018) · cites this paper as [10]
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Citations
Cites
Hu, Y., & Smyth, G. K. (2009) · Journal of Immunological Methods · doi:10.1016/j.jim.2009.06.008 · Cited by 2,084 · cited 1×
“…to Gr-1+SSChi cells at 24 wk after transplant were considered to be repopulated with HSCs and were counted as positive for the purposes of the limiting dilution calculation, performed using the Web-based calculator provided at http://bioinf.wehi.edu .au/software/elda/ (Hu and Smyth, 2009).”
MethodWilson, 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 · cited 1×
“To confirm the utility of this measurement, we sorted three LSK subpopulations from young BM: LSK4834E+150+, LSK4834+150, and LSK48+34+150, which are known to contain HSCs, more primitive multipotent progenitors (MPPs), and less primitive MPPs, respectively (Wilson et al., 2008).”
MethodCell intrinsic alterations underlie hematopoietic stem cell aging
Rossi, D. J., Bryder, D., Zahn, J. M., Ahlenius, H., Sonu, R., Wagers, A. J., & Weissman, I. L. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0503280102 · Cited by 1,152 · cited 2×
“…of these differences is that upon transplantation; old HSCs tend to have a myeloid-skewed blood cell production caused by a decreased ability to produce lymphoid cells (Sudo et al., 2000; Kim et al., 2003; Liang et al., 2005; Rossi et al., 2005; Cho et al., 2008; Beerman et al., 2010a).”
BackgroundDeficiencies in DNA damage repair limit the function of haematopoietic stem cells with age
Rossi, D. J., Bryder, D., Seita, J., Nussenzweig, A., Hoeijmakers, J., & Weissman, I. L. (2007) · Nature · doi:10.1038/nature05862 · Cited by 1,115 · cited 5×
“Consistent with earlier studies (Morrison et al., 1996; Sudo et al., 2000; Rossi et al., 2007b), the median proportion of LinloSca1+cKit+ (LSK) cells within the BM increased 1.9-fold in old mice (Fig.”
BackgroundResultInfluentialIsolation of Single Human Hematopoietic Stem Cells Capable of Long-Term Multilineage Engraftment
Notta, F., Doulatov, S., Laurenti, E., Poeppl, A., Jurisica, I., & Dick, J. E. (2011) · Science · doi:10.1126/science.1201219 · Cited by 919 · cited 1×
“Exciting recent developments in purification and assays for human HSCs (Notta et al., 2011) finally open up the possibility for similar interrogation of the aged human HSC pool at a clonal level.”
BackgroundIn vivo labeling with 2H2O reveals a human neutrophil lifespan of 5.4 days
Pillay, J., den Braber, I., Vrisekoop, N., Kwast, L. M., de Boer, R. J., Borghans, J. A. M., Tesselaar, K., & Koenderman, L. (2010) · Blood · doi:10.1182/blood-2010-01-259028 · Cited by 873 · cited 1×
“As a strict measure for long-term, active hematopoiesis, we considered a mouse to be transplanted with an HSC only if there was a minimum 1% donor contribution to the short-lived (Pillay et al., 2010) granulocyte population (defined as Gr-1+SSChi) at 24 wk after transplant.”
BackgroundThe aging of hematopoietic stem cells
Morrison, S. J., Wandycz, A. M., Akashi, K., Globerson, A., & Weissman, I. L. (1996) · Nature Medicine · doi:10.1038/nm0996-1011 · Cited by 853 · cited 5×
“…expressing HSC-associated markers is contaminated with primitive progenitors that are detected by in vitro assays but lack repopulating ability in vivo (Sudo et al., 2000) or that HSCs from old mice have a homing and/or engraftment defect and therefore remain undetected (Morrison et al., 1996).”
BackgroundResultInfluentialAging Hematopoietic Stem Cells Decline in Function and Exhibit Epigenetic Dysregulation
Chambers, S. M., Shaw, C. A., Gatza, C. E., Fisk, C. J., Donehower, L. A., & Goodell, M. A. (2007) · PLoS Biology · doi:10.1371/journal.pbio.0050201 · Cited by 799
Age-Associated Characteristics of Murine Hematopoietic Stem Cells
Sudo, K., Ema, H., Morita, Y., & Nakauchi, H. (2000) · The Journal of Experimental Medicine · doi:10.1084/jem.192.9.1273 · Cited by 722 · cited 8×
“…expressing HSC-associated markers is contaminated with primitive progenitors that are detected by in vitro assays but lack repopulating ability in vivo (Sudo et al., 2000) or that HSCs from old mice have a homing and/or engraftment defect and therefore remain undetected (Morrison et al., 1996).”
BackgroundResultInfluentialBeerman, I., Bhattacharya, D., Zandi, S., Sigvardsson, M., Weissman, I. L., Bryder, D., & Rossi, D. J. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1000834107 · Cited by 711
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Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice
Chang, J., Wang, Y., Shao, L., Laberge, R.-M., Demaria, M., Campisi, J., Janakiraman, K., Sharpless, N. E., Ding, S., Feng, W., et al. (2016) · Nature Medicine · doi:10.1038/nm.4010 · Cited by 1,819
Age-dependent dysregulation of innate immunity
Shaw, A. C., Goldstein, D. R., & Montgomery, R. R. (2013) · Nature Reviews Immunology · doi:10.1038/nri3547 · Cited by 1,061
Haematopoietic stem cell activity and interactions with the niche
Pinho, S., & Frenette, P. S. (2019) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-019-0103-9 · Cited by 1,064
Kowalczyk, M. S., Tirosh, I., Heckl, D., Rao, T. N., Dixit, A., Haas, B. J., Schneider, R. K., Wagers, A. J., Ebert, B. L., & Regev, A. (2015) · Genome Research · doi:10.1101/gr.192237.115 · Cited by 778
“…et al. 2000; Rossi et al. 2005) that shows decreased regenerative potential (Morrison et al. 1996; Sudo et al. 2000; Kim et al. 2003; Rossi et al. 2005; Dykstra et al. 2011) and a myeloid-skewed differentiation potential (Sudo et al. 2000; Kim et al. 2003; Liang et al. 2005; Rossi et al. 2005).”
BackgroundCauses, consequences, and reversal of immune system aging
Montecino-Rodriguez, E., Berent-Maoz, B., & Dorshkind, K. (2013) · Journal of Clinical Investigation · doi:10.1172/jci64096 · Cited by 793
“Despite the increase in their number, myeloid-biased stem cells are not as robust as their young counterparts (24), which in turn could underlie the numerous age-related deficiencies observed in mature myeloid cells such as neutrophils and macrophages (25, 26).”
Metadata
- Authors
- Dykstra, B., Olthof, S., Schreuder, J., Ritsema, M., & de Haan, G.
- Affiliations
- University Medical Center Groningen (NL)
- Department of Cell Biology 1 ; and 2
- Corresponding author
- Dykstra, Brad
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2011-11-21
- Volume
- 208
- Issue
- 13
- Pages
- 2691-2703
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC3244040
- OpenAlex
- W2103911902
- Cited by
- 494
- References
- 38
- Citations by year
- 2026: 26 · 2025: 34 · 2024: 35 · 2023: 42 · 2022: 38 · 2021: 42 · 2020: 41 · 2019: 36 · 2018: 40 · 2017: 26 · 2016: 36 · 2015: 25 · 2014: 29 · 2013: 29 · 2012: 15
- FWCI
- 15.97
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- other-oa
- Locations
- The Journal of Experimental Medicine (publishedVersion, other-oa)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by-nc-sa)
- Funders
- Ministry of Earth Sciences
- Universitair Medisch Centrum Groningen
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Mesenchymal stem cell research
- Health Sciences › Medicine › Hematology › Blood disorders and treatments
- Keywords
- hematopoietic stem cells, aging, clonal analysis, HSC self-renewal, stromal co-culture, serial transplantation, cellular aging
- MeSH terms
- Animals, Antigens, Differentiation, Colony-Forming Units Assay, Hematopoietic Stem Cells, Mice, Transgenic, Transplantation, Homologous, Cellular Senescence, Hematopoietic Stem Cell Transplantation, Cell Proliferation, Mice
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