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Hellmich, Charlotte, Wojtowicz, Edyta, Moore, Jamie A., Mistry, Jayna J., Jibril, Aisha, Johnson, Benjamin B., Smith, James G.W. 
ORCID: https://orcid.org/0000-0003-0427-8678, Beraza, Naiara, Bowles, Kristian M. ORCID: https://orcid.org/0000-0003-1334-4526 and Rushworth, Stuart A.
(2023)
p16INK4A-dependent senescence in the bone marrow niche drives age-related metabolic changes of hematopoietic progenitors.
Blood Advances, 7 (2).
pp. 256-268.
ISSN 2473-9529
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Abstract
Rapid and effective leukocyte response to infection is a fundamental function of the bone marrow (BM). However, with increasing age, this response becomes impaired, resulting in an increased burden of infectious diseases. Here, we investigate how aging changes the metabolism and function of hematopoietic progenitor cells (HPCs) and the impact of the BM niche on this phenotype. We found that, in response to lipopolysaccharide-induced stress, HPC mitochondrial function is impaired, and there is a failure to upregulate the TCA cycle in progenitor populations in aged animals compared with young animals. Furthermore, aged mesenchymal stromal cells (MSCs) of the BM niche, but not HPCs, exhibit a senescent phenotype, and selective depletion of senescent cells from the BM niche, as well as treatment with the senolytic drug ABT-263, improves mitochondrial function of HPCs when stressed with lipopolysaccharide. In summary, age-related HPC metabolic dysfunction occurs indirectly as a “bystander phenomenon” in the aging BM niche and can be restored by targeting senescent MSCs.
| Item Type: | Article |
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| Additional Information: | Funding Information: C.H. is funded by a Wellcome Trust Clinical Research Fellowship (220534/Z/20/Z). C.H. and J.A.M. are funded by Norfolk and Norwich University Hospitals Charity Grant (51100/F049). The work was supported from the MRC project grant SAR (MR/ T02934X/1). E.W. is supported by a Sir Henry Welcome Postdoctoral Fellowship (213731/Z/18/Z). J.A.M. is funded by the Rosetrees Trust (M742), A.J. is funded by the Big C (18-11R). J.G.W.S. is supported by the Academy of Medical Sciences/the Wellcome Trust/the Government Department of Business, Energy, and Industrial Strategy/the British Heart Foundation/Diabetes UK Springboard Award (SBF005\1057). N.B. is supported by the Biotechnology and Biological Sciences Research Council (BBSRC) Institute’s Strategic Programme Gut Microbes and Health (BB/R012490/1: BBS/E/F/000P R10355). The author(s) acknowledge support from the Biotechnology and Biological Sciences Research Council (BBSRC), part of UK Research and Innovation, Core Capability Grant BB/CCG1720/1 and the National Capability (BBS/E/T/000P R9816). Publisher Copyright: © 2023 by The American Society of Hematology. |
| Uncontrolled Keywords: | hematology,sdg 3 - good health and well-being ,/dk/atira/pure/subjectarea/asjc/2700/2720 |
| Faculty \ School: | Faculty of Medicine and Health Sciences > Norwich Medical School Faculty of Science > School of Biological Sciences |
| UEA Research Groups: | Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health Faculty of Medicine and Health Sciences > Research Groups > Cardiovascular and Metabolic Health Faculty of Medicine and Health Sciences > Research Centres > Norwich Institute for Healthy Aging Faculty of Medicine and Health Sciences > Research Groups > Cancer Studies |
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| Depositing User: | LivePure Connector |
| Date Deposited: | 25 Mar 2024 13:30 |
| Last Modified: | 25 Mar 2024 13:31 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/94745 |
| DOI: | 10.1182/bloodadvances.2022007033 |
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