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Toghani, D.* ; Gupte, S.C.* ; Zeng, S.* ; Mahammadov, E. ; Crosse, E.I.* ; Seyedhassantehrani, N.* ; Burns, C.* ; Gravano, D.* ; Radtke, S.* ; Kiem, H.P.* ; Rodriguez, S.* ; Carlesso, N.* ; Pradeep, A.* ; Georgiades, A.* ; Lucas, F.* ; Wilson, N.K.* ; Kinston, S.J.* ; Göttgens, B.* ; Zong, L.* ; Beerman, I.* ; Park, B.* ; Janssens, D.H.* ; Jones, D.* ; Toghani, A.* ; Nerlov, C.* ; Pietras, E.M.* ; Mesnieres, M.* ; Maes, C.* ; Kumanogoh, A.* ; Worzfeld, T.* ; Cheong, J.G.* ; Josefowicz, S.Z.* ; Kharchenko, P.V.* ; Scadden, D.T.* ; Scialdone, A. ; Spencer, J.A.* ; Silberstein, L.*

Niche-derived Semaphorin 4A safeguards functional identity of myeloid-biased hematopoietic stem cells.

Nature Aging, DOI: 10.1038/s43587-024-00798-7 (2025)
Postprint Forschungsdaten DOI PMC
Open Access Green
Somatic stem cell pools comprise diverse, highly specialized subsets whose individual contribution is critical for the overall regenerative function. In the bone marrow, myeloid-biased hematopoietic stem cells (myHSCs) are indispensable for replenishment of myeloid cells and platelets during inflammatory response but, at the same time, become irreversibly damaged during inflammation and aging. Here we identify an extrinsic factor, semaphorin 4A (Sema4A), which non-cell-autonomously confers myHSC resilience to inflammatory stress. We show that, in the absence of Sema4A, myHSC inflammatory hyper-responsiveness in young mice drives excessive myHSC expansion, myeloid bias and profound loss of regenerative function with age. Mechanistically, Sema4A is mainly produced by neutrophils, signals via a cell surface receptor, plexin D1, and safeguards the myHSC epigenetic state. Our study shows that, by selectively protecting a distinct stem cell subset, an extrinsic factor preserves functional diversity of somatic stem cell pool throughout organismal lifespan.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Gene-expression; Progenitors; Proliferation; Activation; Quiescence; Differentiation; Identification; Heterogeneity; Transcriptome; Organization
Sprache englisch
Veröffentlichungsjahr 2025
HGF-Berichtsjahr 2025
ISSN (print) / ISBN 2662-8465
e-ISSN 2662-8465
Zeitschrift Nature Aging
Verlag Springer
Verlagsort Campus, 4 Crinan St, London, N1 9xw, England
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Epigenetics and Stem Cells (IES)
POF Topic(s) 30204 - Cell Programming and Repair
Forschungsfeld(er) Stem Cell and Neuroscience
PSP-Element(e) G-506290-001
Förderungen U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)
National Institutes of Health
Fred Hutchinson Cancer Center
Leukemia and Lymphoma Society Translational Research Program
DOI 10.1038/s43587-024-00798-7
WOS ID 001408546400001
Scopus ID 85217176392
PubMed ID 39881190
Erfassungsdatum 2025-03-26
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