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Chronic inflammation decreases HSC fitness by activating the druggable Jak/Stat3 signaling pathway
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SYSNO ASEP 0566133 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Chronic inflammation decreases HSC fitness by activating the druggable Jak/Stat3 signaling pathway Author(s) Grušanovič, Srdjan (UMG-J)
Daněk, Petr (UMG-J)
Kuzmina, Maria (UMG-J)
Adamcová, Miroslava Kari (UMG-J)
Burocziová, Monika (UMG-J)
Mikyšková, Romana (UMG-J) RID
Vaníčková, Karolína (UMG-J)
Kosanovič, Slaďana (UMG-J)
Pokorná, Jana (UMG-J)
Reiniš, Milan (UMG-J) RID
Brdička, Tomáš (UMG-J) RID
Alberich-Jorda, Meritxell (UMG-J) RIDNumber of authors 12 Article number e54729 Source Title Embo Reports - ISSN 1469-221X
Roč. 24, č. 1 (2023)Number of pages 19 s. Publication form Online - E Language eng - English Country US - United States Keywords chronic inflammation ; chronic multifocal osteomyelitis ; hematopoietic stem cells ; il-6 ; Jak ; Stat3 ; niche Subject RIV EB - Genetics ; Molecular Biology OECD category Biochemistry and molecular biology R&D Projects GA20-03380S GA ČR - Czech Science Foundation (CSF) NV18-05-00562 GA MZd - Ministry of Health (MZ) LX22NPO5102 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Method of publishing Open access Institutional support UMG-J - RVO:68378050 UT WOS 000879363600001 DOI 10.15252/embr.202254729 Annotation Chronic inflammation represents a major threat to human health since long-term systemic inflammation is known to affect distinct tissues and organs. Recently, solid evidence demonstrated that chronic inflammation affects hematopoiesis, however, how chronic inflammation affects hematopoietic stem cells (HSCs) on the mechanistic level is poorly understood. Here, we employ a mouse model of chronic multifocal osteomyelitis (CMO) to assess the effects of a spontaneously developed inflammatory condition on HSCs. We demonstrate that hematopoietic and nonhematopoietic compartments in CMO BM contribute to HSC expansion and impair their function. Remarkably, our results suggest that the typical features of murine multifocal osteomyelitis and the HSC phenotype are mechanistically decoupled. We show that the CMO environment imprints a myeloid gene signature and imposes a pro-inflammatory profile on HSCs. We identify IL-6 and the Jak/Stat3 signaling pathway as critical mediators. However, while IL-6 and Stat3 blockage reduce HSC numbers in CMO mice, only inhibition of Stat3 activity significantly rescues their fitness. Our data emphasize the detrimental effects of chronic inflammation on stem cell function, opening new venues for treatment. Workplace Institute of Molecular Genetics Contact Nikol Škňouřilová, nikol.sknourilova@img.cas.cz, Tel.: 241 063 217 Year of Publishing 2023 Electronic address https://www.embopress.org/doi/full/10.15252/embr.202254729
Number of the records: 1