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

Nadine Haetscher, Yonatan Feuermann, Susanne Wingert, Maike Rehage, Frederic B. Thalheimer, Christian Weiser, Hanibal Bohnenberger, Klaus Jung, Timm Schroeder, Hubert Serve, Thomas Oellerich, Lothar Hennighausen and Michael A. Rieger ()
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Nadine Haetscher: Hematology/Oncology, Goethe University Frankfurt
Yonatan Feuermann: Hematology/Oncology, Goethe University Frankfurt
Susanne Wingert: Hematology/Oncology, Goethe University Frankfurt
Maike Rehage: Hematology/Oncology, Goethe University Frankfurt
Frederic B. Thalheimer: Hematology/Oncology, Goethe University Frankfurt
Christian Weiser: Georg-Speyer-Haus
Hanibal Bohnenberger: University Medical Center Göttingen
Klaus Jung: University Medical Center Göttingen
Timm Schroeder: ETH Zurich
Hubert Serve: Hematology/Oncology, Goethe University Frankfurt
Thomas Oellerich: Hematology/Oncology, Goethe University Frankfurt
Lothar Hennighausen: Laboratory of Genetics and Physiology, NIDDK, National Institutes of Health
Michael A. Rieger: Hematology/Oncology, Goethe University Frankfurt

Nature Communications, 2015, vol. 6, issue 1, 1-11

Abstract: Abstract 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.

Date: 2015
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DOI: 10.1038/ncomms9928

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