Hematopoietic stem cell exhaustion impacted by p18INK4C and p21Cip1/Waf1 in opposite manners
Open accessAbstract
Transplantation-associated stress can compromise the hematopoietic potential of hematopoietic stem cells (HSCs). As a consequence, HSCs may undergo "exhaustion" in serial transplant recipients, for which the cellular and molecular bases are not well understood. Hematopoietic exhaustion appears to be accelerated in the absence of p21(Cip1/Waf1) (p21), a cyclin-dependent kinase inhibitor (CKI) in irradiated hosts. Our recent study demonstrated that unlike loss of p21, deletion of p18(INK4C) (p18), a distinct CKI, results in improved long-term engraftment, largely because of increased self-renewing divisions of HSCs in vivo. We show here that HSCs deficient in p18 sustained their competitiveness to wild-type HSCs from unmanipulated young mice, and retained multilineage differentiation potential after multiple rounds of serial bone marrow transfer over a period of more than 3 years. Further, p18 absence significantly decelerated hematopoietic exhaustion caused by p21 deficiency. Such an effect was shown to occur at the stem cell level, likely by a counteracting mechanism against the cellular senescence outcome. Our current study provides new insights into the distinct impacts of these cell-cycle regulators on HSC exhaustion and possibly HSC aging as well under proliferative stress, thereby offering potential pharmacologic targets for sustaining the durability of stressed HSCs in transplantation or elderly patients.
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p18 can negatively regulate HSC self-renewal.
“p18 can also negatively regulate HSC self-renewal.49”
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 [49]
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Self-citation
- Authors
- Yu, H., Yuan, Y., Shen, H., & Cheng, T.
- Affiliations
- University of Pittsburgh (US)
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2006-02-01
- Volume
- 107
- Issue
- 3
- Pages
- 1200-1206
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC1895913
- OpenAlex
- W2146707026
- Cited by
- 127
- References
- 42
- Citations by year
- 2025: 3 · 2024: 1 · 2023: 2 · 2022: 7 · 2021: 6 · 2020: 7 · 2019: 4 · 2018: 4 · 2017: 1 · 2016: 5 · 2015: 5 · 2014: 8 · 2013: 8 · 2012: 6
- FWCI
- 6.69
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Blood (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL70561, R01HL070561)
- National Institute of Diabetes and Digestive and Kidney Diseases (K08DK002761, DK 02761)
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Reproductive Biology and Fertility
- Keywords
- p18INK4c, p21, cyclin-dependent kinase inhibitors, serial transplantation, hematopoietic stem cell aging, cellular senescence, multilineage differentiation, self-renewal, engraftment
- MeSH terms
- Aged, Aged, 80 and over, Aging, Animals, Graft Survival, Hematopoiesis, Hematopoietic Stem Cells, Humans, Bone Marrow Transplantation, Cellular Senescence, Mice, Knockout, Cyclin-Dependent Kinase Inhibitor p21, Cyclin-Dependent Kinase Inhibitor p18, Mice
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