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

Nat Commun. 2015 Nov 25;6:8928. doi: 10.1038/ncomms9928.

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.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation / genetics
  • Flow Cytometry
  • Hematopoiesis / genetics*
  • Hematopoietic Stem Cells / metabolism*
  • Mice
  • Mice, Knockout
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Proto-Oncogene Proteins c-kit / metabolism*
  • Receptors, Cytokine / metabolism
  • Receptors, Thrombopoietin / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • STAT5 Transcription Factor / metabolism*
  • Thrombopoietin / metabolism*
  • Time-Lapse Imaging

Substances

  • MIRN193 microRNA, mouse
  • MicroRNAs
  • Mpl protein, mouse
  • Receptors, Cytokine
  • Receptors, Thrombopoietin
  • STAT5 Transcription Factor
  • Thrombopoietin
  • Proto-Oncogene Proteins c-kit

Associated data

  • BioProject/PRJNA267041