Telomerase is required to slow telomere shortening and extend replicative lifespan of HSCs during serial transplantation
Abstract
Telomere shortening ultimately limits the replicative life span of cultured human somatic cells. Telomeres also shorten during replicative aging in vivo in hematopoietic cells, including early hematopoietic progenitors and hematopoietic stem cells (HSCs), from humans and mice, despite readily detectable levels of telomerase in these cells. To assess the relevance of telomerase to the long-term replicative capacity of HSCs in vivo, we serially transplanted HSCs from wild-type and telomerase-deficient mice until exhaustion and monitored telomere length in HSCs during this process. Telomerase-deficient HSCs could be serially transplanted for only 2 rounds, whereas wild-type HSCs could be serially transplanted for at least 4 rounds. Furthermore, the rate of telomere shortening was increased approximately 2-fold during serial transplantation of telomerase-deficient HSCs. These findings suggest that one role for telomerase in the HSC is to partially counter the rate of telomere shortening during division of HSCs, thereby preventing premature loss of telomere function and providing added replicative capacity.
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Telomerase knockout mice have short dysfunctional telomeres that severely impair progenitor cell function in actively renewing tissues, causing atrophy and reduced regenerative potential, while quiescent low-turnover tissues such as muscle are unaffected.
“In agreement with these findings, studies of telomerase knockout mice revealed short dysfunctional telomeres that profoundly impaired progenitor cell function in actively renewing tissues leading to atrophy and reduced regenerative potential, whereas more quiescent low-turnover tissues such as muscle were unaffected (Allsopp et al., 2003; Lee et al., 1998; Rudolph et al., 1999).”
From Short Telomeres and Stem Cell Exhaustion Model Duchenne Muscular Dystrophy in mdx/mTR Mice (2010) · cites this paper as Allsopp et al., 2003
Telomerase plays a crucial role in self-renewal of adult stem cells in high-turnover tissues such as blood, liver, skin, and testis.
“The generation of mouse models lacking telomerase activity, TERT and Terc knockout mice (Blasco et al., 1997; Liu et al., 2000) previously resulted in the demonstration that telomerase plays a crucial role in self-renewal of adult stem cells in high turnover tissues such as blood, liver, skin and testis (Allsopp et al., 2003; Lee et al., 1998).”
From Short Telomeres and Stem Cell Exhaustion Model Duchenne Muscular Dystrophy in mdx/mTR Mice (2010) · cites this paper as Allsopp et al., 2003
The severe degenerative tissue defects in late-generation telomerase-knockout mice are linked to impaired proliferation and increased apoptosis in cycling progenitor cells and to a self-renewal defect in tissue stem cells.
“The severe degenerative tissue defects in the late-generation telomerase-knockout mice appear linked to impaired proliferation and increased apoptosis in cycling progenitor cells and to a selfrenewal defect in tissue stem cells.”
From Telomeres and telomerase in cancer (2010) · cites this paper as [64]
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- Authors
- Allsopp, R. C., Morin, G. B., DePinho, R., Harley, C. B., & Weissman, I. L.
- Affiliations
- Harvard University (US)
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2003-07-15
- Volume
- 102
- Issue
- 2
- Pages
- 517-520
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W2011221227
- Cited by
- 324
- References
- 24
- Citations by year
- 2026: 7 · 2025: 6 · 2024: 5 · 2023: 4 · 2022: 9 · 2021: 6 · 2020: 8 · 2019: 7 · 2018: 10 · 2017: 5 · 2016: 12 · 2015: 16 · 2014: 15 · 2013: 11 · 2012: 17
- FWCI
- 11.91
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Blood (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r35ca042551-13)
- National Cancer Institute (CA 42551)
- National Institute of Diabetes and Digestive and Kidney Diseases (P01DK053074, DK 53074)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- telomerase, telomere shortening, hematopoietic stem cells, replicative lifespan, serial transplantation, replicative senescence, hematopoietic progenitor cells, stem cell exhaustion
- MeSH terms
- Animals, Cell Division, Cell Survival, DNA Replication, DNA-Binding Proteins, Graft Survival, Hematopoietic Stem Cells, Telomere, In Situ Hybridization, Fluorescence, Mice, Knockout, Hematopoietic Stem Cell Transplantation, Telomerase, Mice
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