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ToolsLuis, Tiago C., Barkas, Nikolaos, Carrelha, Joana, Giustacchini, Alice, Mazzi, Stefania, Norfo, Ruggiero, Wu, Bishan, Aliouat, Affaf, Guerrero, Jose A., Rodriguez-Meira, Alba, Bouriez-Jones, Tiphaine, Macaulay, Iain C., Jasztal, Maria, Zhu, Guangheng, Ni, Heyu, Robson, Matthew J., Blakely, Randy D., Mead, Adam J., Nerlov, Claus, Ghevaert, Cedric and Jacobsen, Sten Eirik W. (2023) Perivascular niche cells sense thrombocytopenia and activate hematopoietic stem cells in an IL-1 dependent manner. Nature Communications, 14. ISSN 2041-1723
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Abstract
Hematopoietic stem cells (HSCs) residing in specialized niches in the bone marrow are responsible for the balanced output of multiple short-lived blood cell lineages in steady-state and in response to different challenges. However, feedback mechanisms by which HSCs, through their niches, sense acute losses of specific blood cell lineages remain to be established. While all HSCs replenish platelets, previous studies have shown that a large fraction of HSCs are molecularly primed for the megakaryocyte-platelet lineage and are rapidly recruited into proliferation upon platelet depletion. Platelets normally turnover in an activation-dependent manner, herein mimicked by antibodies inducing platelet activation and depletion. Antibody-mediated platelet activation upregulates expression of Interleukin-1 (IL-1) in platelets, and in bone marrow extracellular fluid in vivo. Genetic experiments demonstrate that rather than IL-1 directly activating HSCs, activation of bone marrow Lepr+ perivascular niche cells expressing IL-1 receptor is critical for the optimal activation of quiescent HSCs upon platelet activation and depletion. These findings identify a feedback mechanism by which activation-induced depletion of a mature blood cell lineage leads to a niche-dependent activation of HSCs to reinstate its homeostasis.
| Item Type: | Article |
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| Additional Information: | Data availability statement: The RNA-Sequencing data generated in this study have been deposited in NCBI Gene Expression Omnibus (GEO) and are accessible through GSE121249 (NCBI tracking system #19505382). The source data for Figs. 1–6 and Supplementary Figs. 1-2, 4-6 are provided as a Source Data file. All other data that supports the findings of this study are available from the corresponding authors upon request. Source data are provided with this paper. Code availability statement: Code for the RNA sequencing analysis included in this study is available at https://zenodo.org/record/8283315. Funding Information: This work was supported by the following grants; a Kay Kendall Leukaemia Fund Junior Research Fellowship (KKL832) to T.C.L.; an EMBO-LTF (ALTF1228-2011) to T.C.L.; a Sir Henry Dale Fellowship from the Wellcome Trust and The Royal Society (210424/Z/18/Z) to T.C.L; the MRC UK (G0801073 and MC_UU_12009/5) to S.E.W.J.; the Swedish Research Council to S.E.W.J.; the Knut och Alice Wallenberg Foundation to S.E.W.J.; the Tobias Foundation to S.E.W.J.; StratRegen KI to S.E.W.J, and The Torsten Söderberg Professorial Chair in Medicine to S.E.W.J. Open access funding provided by Karolinska Institute. |
| Uncontrolled Keywords: | chemistry(all),biochemistry, genetics and molecular biology(all),physics and astronomy(all) ,/dk/atira/pure/subjectarea/asjc/1600 |
| Faculty \ School: | Faculty of Science > School of Biological Sciences |
| Related URLs: | |
| Depositing User: | LivePure Connector |
| Date Deposited: | 25 Oct 2024 14:30 |
| Last Modified: | 12 Nov 2024 13:30 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/97220 |
| DOI: | 10.1038/s41467-023-41691-y |
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