An ERK-Dependent Feedback Mechanism Prevents Hematopoietic Stem Cell Exhaustion

Cell Stem Cell. 2018 Jun 1;22(6):879-892.e6. doi: 10.1016/j.stem.2018.05.003. Epub 2018 May 24.


Hematopoietic stem cells (HSCs) sustain hematopoiesis throughout life. HSCs exit dormancy to restore hemostasis in response to stressful events, such as acute blood loss, and must return to a quiescent state to prevent their exhaustion and resulting bone marrow failure. HSC activation is driven in part through the phosphatidylinositol 3-kinase (PI3K)/AKT/mTORC1 signaling pathway, but less is known about the cell-intrinsic pathways that control HSC dormancy. Here, we delineate an ERK-dependent, rate-limiting feedback mechanism that controls HSC fitness and their re-entry into quiescence. We show that the MEK/ERK and PI3K pathways are synchronously activated in HSCs during emergency hematopoiesis and that feedback phosphorylation of MEK1 by activated ERK counterbalances AKT/mTORC1 activation. Genetic or chemical ablation of this feedback loop tilts the balance between HSC dormancy and activation, increasing differentiated cell output and accelerating HSC exhaustion. These results suggest that MEK inhibitors developed for cancer therapy may find additional utility in controlling HSC activation.

Keywords: AKT/mTORC1 pathway; ERK pathway; emergency hematopoiesis; feedback regulation of signaling; hematopoietic stem cell activation; hematopoietic stem cell exhaustion; hematopoietic stem cells; intracellular signaling; mitochondrial fitness; oxidative stress.

MeSH terms

  • Animals
  • Cells, Cultured
  • Coculture Techniques
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Female
  • Hematopoietic Stem Cells / cytology*
  • Hematopoietic Stem Cells / enzymology*
  • Humans
  • MAP Kinase Kinase 1 / deficiency
  • MAP Kinase Kinase 1 / metabolism
  • Male
  • Membrane Potential, Mitochondrial
  • Mice
  • Reactive Oxygen Species / metabolism


  • Reactive Oxygen Species
  • Extracellular Signal-Regulated MAP Kinases
  • MAP Kinase Kinase 1
  • Map2k1 protein, mouse