STAT5-regulated microRNA-193b controls haematopoietic stem and progenitor cell expansion by modulating cytokine receptor signalling

  • Haematopoietic stem cells (HSCs) require the right composition of microRNAs (miR) for proper life-long balanced blood regeneration. Here we show a regulatory circuit that prevents excessive HSC self-renewal by upregulation of miR-193b upon self-renewal promoting thrombopoietin (TPO)-MPL-STAT5 signalling. In turn, miR-193b restricts cytokine signalling, by targeting the receptor tyrosine kinase c-KIT. We generated a miR-193b knockout mouse model to unravel the physiological function of miR-193b in haematopoiesis. MiR-193b−/− mice show a selective gradual enrichment of functional HSCs, which are fully competent in multilineage blood reconstitution upon transplantation. The absence of miR-193b causes an accelerated expansion of HSCs, without altering cell cycle or survival, but by decelerating differentiation. Conversely, ectopic miR-193b expression restricts long-term repopulating HSC expansion and blood reconstitution. MiR-193b-deficient haematopoietic stem and progenitor cells exhibit increased basal and cytokine-induced STAT5 and AKT signalling. This STAT5-induced microRNA provides a negative feedback for excessive signalling to restrict uncontrolled HSC expansion.
Metadaten
Author:Nadine Hätscher, Yonatan Feuermann, Susanne WingertGND, Maike Rehage, Frederic Bastian ThalheimerORCiDGND, Christian Weiser, Hanibal BohnenbergerORCiD, Klaus Jung, Timm Schroeder, Hubert ServeORCiDGND, Thomas OellerichORCiD, Lothar HennighausenORCiD, Michael A. RiegerORCiDGND
URN:urn:nbn:de:hebis:30:3-506030
DOI:https://doi.org/10.1038/ncomms9928
ISSN:2041-1723
Parent Title (English):Nature Communications
Publisher:Nature Publishing Group UK
Place of publication:[London]
Document Type:Article
Language:English
Year of Completion:2015
Date of first Publication:2015/11/25
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2019/07/04
Tag:Cell signalling; Haematopoietic stem cells; Self-renewal; miRNAs
Volume:6
Issue:Art. 8928
Page Number:11
First Page:1
Last Page:11
Note:
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HeBIS-PPN:453520499
Institutes:Medizin / Medizin
Angeschlossene und kooperierende Institutionen / Georg-Speyer-Haus
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 4.0