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.

• Klíčová slova
• IL-6/Jak/Stat3, chronic inflammation, chronic multifocal osteomyelitis, hematopoietic stem cells, niche,
• MeSH
• hematopoetické kmenové buňky metabolismus   MeSH
• hematopoéza MeSH
• interleukin-6 * genetika   metabolismus   MeSH
• lidé MeSH
• myši MeSH
• osteomyelitida MeSH
• signální transdukce MeSH
• transkripční faktor STAT3 genetika   metabolismus   MeSH
• zánět * metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• interleukin-6 * MeSH
• STAT3 protein, human MeSH Prohlížeč
• transkripční faktor STAT3 MeSH

Hematopoiesis, the formation of blood cells from hematopoietic stem cells (HSC), is a highly regulated process. Since the discovery of microRNAs (miRNAs), several studies have shown their significant role in the regulation of the hematopoietic system. Impaired expression of miRNAs leads to disrupted cellular pathways and in particular causes loss of hematopoietic ability. Here, we report a previously unrecognized function of miR-143 in granulopoiesis. Hematopoietic cells undergoing granulocytic differentiation exhibited increased miR-143 expression. Overexpression or ablation of miR-143 expression resulted in accelerated granulocytic differentiation or block of differentiation, respectively. The absence of miR-143 in mice resulted in a reduced number of mature granulocytes in blood and bone marrow. Additionally, we observed an association of high miR-143 expression levels with a higher probability of survival in two different cohorts of patients with acute myeloid leukemia (AML). Overexpression of miR-143 in AML cells impaired cell growth, partially induced differentiation, and caused apoptosis. Argonaute2-RNA-Immunoprecipitation assay revealed ERK5, a member of the MAPK-family, as a target of miR-143 in myeloid cells. Further, we observed an inverse correlation of miR-143 and ERK5 in primary AML patient samples, and in CD34+ HSPCs undergoing granulocytic differentiation and we confirmed functional relevance of ERK5 in myeloid cells. In conclusion, our data describe miR-143 as a relevant factor in granulocyte differentiation, whose expression may be useful as a prognostic and therapeutic factor in AML therapy.

• MeSH
• 3' nepřekládaná oblast MeSH
• akutní myeloidní leukemie metabolismus   mortalita   patologie   MeSH
• antagomiry metabolismus   MeSH
• apoptóza MeSH
• buněčná diferenciace MeSH
• granulocyty cytologie   metabolismus   MeSH
• hematopoetické kmenové buňky cytologie   metabolismus   MeSH
• lidé MeSH
• mikro RNA antagonisté a inhibitory   genetika   metabolismus   MeSH
• míra přežití MeSH
• mitogenem aktivovaná proteinkinasa 7 chemie   genetika   metabolismus   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• prognóza MeSH
• proliferace buněk MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 3' nepřekládaná oblast MeSH
• antagomiry MeSH
• MAPK7 protein, human MeSH Prohlížeč
• mikro RNA MeSH
• MIRN143 microRNA, human MeSH Prohlížeč
• mitogenem aktivovaná proteinkinasa 7 MeSH