title: STAT5-regulated microRNA-193b controls haematopoietic stem and progenitor cell expansion by modulating cytokine receptor signalling.
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.
authors.affiliation: LOEWE Center for Cell and Gene Therapy and Department of Medicine, Hematology/Oncology, Goethe University Frankfurt, Theodor-Stern-Kai 7, Frankfurt 60590, Germany.|Georg-Speyer-Haus, Paul-Ehrlich-Street 42-44, Frankfurt 60596, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Haetscher
authors.affiliation: LOEWE Center for Cell and Gene Therapy and Department of Medicine, Hematology/Oncology, Goethe University Frankfurt, Theodor-Stern-Kai 7, Frankfurt 60590, Germany.|Laboratory of Genetics and Physiology, NIDDK, National Institutes of Health, 9000 Rockville Pike, Bethesda, Maryland 20892, USA.
authors.forename: Yonatan
authors.initials: Y
authors.lastname: Feuermann
authors.affiliation: LOEWE Center for Cell and Gene Therapy and Department of Medicine, Hematology/Oncology, Goethe University Frankfurt, Theodor-Stern-Kai 7, Frankfurt 60590, Germany.|Georg-Speyer-Haus, Paul-Ehrlich-Street 42-44, Frankfurt 60596, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Wingert
authors.affiliation: LOEWE Center for Cell and Gene Therapy and Department of Medicine, Hematology/Oncology, Goethe University Frankfurt, Theodor-Stern-Kai 7, Frankfurt 60590, Germany.|Georg-Speyer-Haus, Paul-Ehrlich-Street 42-44, Frankfurt 60596, Germany.
authors.forename: Maike
authors.initials: M
authors.lastname: Rehage
authors.affiliation: LOEWE Center for Cell and Gene Therapy and Department of Medicine, Hematology/Oncology, Goethe University Frankfurt, Theodor-Stern-Kai 7, Frankfurt 60590, Germany.|Georg-Speyer-Haus, Paul-Ehrlich-Street 42-44, Frankfurt 60596, Germany.
authors.forename: Frederic B
authors.initials: FB
authors.lastname: Thalheimer
authors.affiliation: Georg-Speyer-Haus, Paul-Ehrlich-Street 42-44, Frankfurt 60596, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Weiser
authors.affiliation: Department of Pathology, University Medical Center Göttingen, Robert-Koch-Street 40, Goettingen 37075, Germany.
authors.forename: Hanibal
authors.initials: H
authors.lastname: Bohnenberger
authors.affiliation: Department of Medical Statistics, University Medical Center Göttingen, Humboldtallee 32, Goettingen 37073, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Jung
authors.affiliation: Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, Basel 4058, Switzerland.
authors.forename: Timm
authors.initials: T
authors.lastname: Schroeder
authors.affiliation: LOEWE Center for Cell and Gene Therapy and Department of Medicine, Hematology/Oncology, Goethe University Frankfurt, Theodor-Stern-Kai 7, Frankfurt 60590, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
authors.forename: Hubert
authors.initials: H
authors.lastname: Serve
authors.affiliation: LOEWE Center for Cell and Gene Therapy and Department of Medicine, Hematology/Oncology, Goethe University Frankfurt, Theodor-Stern-Kai 7, Frankfurt 60590, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Oellerich
authors.affiliation: Laboratory of Genetics and Physiology, NIDDK, National Institutes of Health, 9000 Rockville Pike, Bethesda, Maryland 20892, USA.
authors.forename: Lothar
authors.initials: L
authors.lastname: Hennighausen
authors.affiliation: LOEWE Center for Cell and Gene Therapy and Department of Medicine, Hematology/Oncology, Goethe University Frankfurt, Theodor-Stern-Kai 7, Frankfurt 60590, Germany.|Georg-Speyer-Haus, Paul-Ehrlich-Street 42-44, Frankfurt 60596, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Rieger
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000235:genetics; D005434:Flow Cytometry; D006410:Hematopoiesis / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*; D018121:Receptors, Cytokine / Q000378:metabolism; D053628:Receptors, Thrombopoietin / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D013926:Thrombopoietin / Q000378:metabolism*; D059008:Time-Lapse Imaging
chemical_list: C568257:MIRN193 microRNA, mouse; D035683:MicroRNAs; C481270:Mpl protein, mouse; D018121:Receptors, Cytokine; D053628:Receptors, Thrombopoietin; D050799:STAT5 Transcription Factor; D013926:Thrombopoietin; D019009:Proto-Oncogene Proteins c-kit