Jak1 Integrates Cytokine Sensing to Regulate Hematopoietic Stem Cell Function and Stress Hematopoiesis

Cell Stem Cell. 2017 Oct 5;21(4):489-501.e7. doi: 10.1016/j.stem.2017.08.011. Epub 2017 Sep 28.

Abstract

JAK1 is a critical effector of pro-inflammatory cytokine signaling and plays important roles in immune function, while abnormal JAK1 activity has been linked to immunological and neoplastic diseases. Specific functions of JAK1 in the context of hematopoiesis, and specifically within hematopoietic stem cells (HSCs), have not clearly been delineated. Here, we show that conditional Jak1 loss in HSCs reduces their self-renewal and markedly alters lymphoid/myeloid differentiation in vivo. Jak1-deficient HSCs exhibit decreased competitiveness in vivo and are unable to rescue hematopoiesis in the setting of myelosuppression. They exhibit increased quiescence, an inability to enter the cell cycle in response to hematopoietic stress, and a marked reduction in cytokine sensing, including in response to type I interferons and IL-3. Moreover, Jak1 loss is not fully rescued by expression of a constitutively active Jak2 allele. Together, these data highlight an essential role for Jak1 in HSC homeostasis and stress responses.

Keywords: Jak1; cytokine signaling; hematopoietic stem cells; stress hematopoiesis.

Publication types

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

MeSH terms

  • Alleles
  • Animals
  • Bone Marrow Transplantation
  • Cell Cycle
  • Cell Differentiation
  • Enzyme Activation
  • Gene Expression Regulation
  • Hematopoiesis*
  • Hematopoietic Stem Cells / cytology
  • Hematopoietic Stem Cells / metabolism*
  • Immunosuppression
  • Interferon Type I / metabolism
  • Interleukin-3 / metabolism*
  • Janus Kinase 1 / metabolism*
  • Mice, Knockout
  • Myeloid Cells / metabolism
  • Signal Transduction
  • Stress, Physiological*

Substances

  • Interferon Type I
  • Interleukin-3
  • Janus Kinase 1