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FOXP1 controls mesenchymal stem cell commitment and senescence during skeletal aging
Open accessAbstract
A hallmark of aged mesenchymal stem/progenitor cells (MSCs) in bone marrow is the pivot of differentiation potency from osteoblast to adipocyte coupled with a decrease in self-renewal capacity. However, how these cellular events are orchestrated in the aging progress is not fully understood. In this study, we have used molecular and genetic approaches to investigate the role of forkhead box P1 (FOXP1) in transcriptional control of MSC senescence. In bone marrow MSCs, FOXP1 expression levels declined with age in an inverse manner with those of the senescence marker p16INK4A. Conditional depletion of Foxp1 in bone marrow MSCs led to premature aging characteristics, including increased bone marrow adiposity, decreased bone mass, and impaired MSC self-renewal capacity in mice. At the molecular level, FOXP1 regulated cell-fate choice of MSCs through interactions with the CEBPβ/δ complex and recombination signal binding protein for immunoglobulin κ J region (RBPjκ), key modulators of adipogenesis and osteogenesis, respectively. Loss of p16INK4A in Foxp1-deficient MSCs partially rescued the defects in replication capacity and bone mass accrual. Promoter occupancy analyses revealed that FOXP1 directly represses transcription of p16INK4A. These results indicate that FOXP1 attenuates MSC senescence by orchestrating their cell-fate switch while maintaining their replicative capacity in a dose- and age-dependent manner.
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“Ageing and genotoxic stress induce cellular senescence of these stem cells 96,97 and osteoprogenitor cells, 98,99 with subsequent decline in the functions of these cells in both mice and humans.100”
From The costs and benefits of senotherapeutics for human health (2022) · cites this paper as [98]
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Metadata
- Authors
- Li, H., Liu, P., Xu, S., Li, Y., Dekker, J. D., Li, B., Fan, Y., Zhang, Z., Hong, Y., Yang, G., Tang, T., Ren, Y., Tucker, H. O., Yao, Z., & Guo, X.
- Affiliations
- Shanghai Jiao Tong University (CN)
- Fudan University (CN)
- The University of Texas at Austin (US)
- Shanghai Sixth People's Hospital (CN)
- Nanjing First Hospital (CN)
- Corresponding author
- Guo, Xizhi
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2017-02-27
- Volume
- 127
- Issue
- 4
- Pages
- 1241-1253
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC5373872
- OpenAlex
- W2591050028
- Cited by
- 180
- References
- 74
- Citations by year
- 2026: 8 · 2025: 22 · 2024: 24 · 2023: 33 · 2022: 27 · 2021: 18 · 2020: 18 · 2019: 9 · 2018: 18 · 2017: 3
- FWCI
- 7.54
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Lymphoma Research Foundation (300463)
- Cancer Prevention and Research Institute of Texas (RP120459, RP120348 and RP120459, RP120348)
- National Natural Science Foundation of China (973 Program, 31171396, 31100624, 2012CB966903, 31271553, 81421061, 81200586, 2014CB942902, R01CA31534)
- National Institutes of Health (31100624, 31271553, 2014CB942902, 31171396, 81421061, 2012CB966903)
- National Key Research and Development Program of China (31271553, 2012CB966903, R01CA31534, 31100624, 31171396, 2014CB942902, 81421061)
- National Cancer Institute (R01CA031534)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Mesenchymal stem cell research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Keywords
- FOXP1, mesenchymal stem cells, skeletal aging, cellular senescence, p16INK4a, bone marrow adiposity, bone formation, adipogenesis, lineage commitment, transcriptional repression, replicative capacity, bone mass
- MeSH terms
- Animals, Bone Marrow Cells, Cell Line, Humans, Osteogenesis, Repressor Proteins, Cellular Senescence, Mice, Knockout, Cyclin-Dependent Kinase Inhibitor p16, CCAAT-Enhancer-Binding Protein-beta, Adipogenesis, Mice, CCAAT-Enhancer-Binding Protein-delta, Forkhead Transcription Factors, Mesenchymal Stem Cells
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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 ›
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