Chronic activation of endothelial MAPK disrupts hematopoiesis via NFKB dependent inflammatory stress reversible by SCGF

Nat Commun. 2020 Feb 3;11(1):666. doi: 10.1038/s41467-020-14478-8.


Inflammatory signals arising from the microenvironment have emerged as critical regulators of hematopoietic stem cell (HSC) function during diverse processes including embryonic development, infectious diseases, and myelosuppressive injuries caused by irradiation and chemotherapy. However, the contributions of cellular subsets within the microenvironment that elicit niche-driven inflammation remain poorly understood. Here, we identify endothelial cells as a crucial component in driving bone marrow (BM) inflammation and HSC dysfunction observed following myelosuppression. We demonstrate that sustained activation of endothelial MAPK causes NF-κB-dependent inflammatory stress response within the BM, leading to significant HSC dysfunction including loss of engraftment ability and a myeloid-biased output. These phenotypes are resolved upon inhibition of endothelial NF-κB signaling. We identify SCGF as a niche-derived factor that suppresses BM inflammation and enhances hematopoietic recovery following myelosuppression. Our findings demonstrate that chronic endothelial inflammation adversely impacts niche activity and HSC function which is reversible upon suppression of inflammation.

Publication types

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

MeSH terms

  • Animals
  • Antigens, CD
  • Bone Marrow
  • Cadherins
  • Endothelial Cells / metabolism*
  • Female
  • Hematopoiesis / physiology*
  • Hematopoietic Cell Growth Factors / metabolism*
  • Hematopoietic Stem Cell Transplantation
  • Hematopoietic Stem Cells
  • Inflammation
  • Lectins, C-Type / metabolism*
  • Male
  • Mice
  • Mitogen-Activated Protein Kinase Kinases / metabolism*
  • NF-kappa B / metabolism*
  • Signal Transduction
  • Transplantation, Autologous


  • Antigens, CD
  • Cadherins
  • Hematopoietic Cell Growth Factors
  • Lectins, C-Type
  • NF-kappa B
  • cadherin 5
  • Mitogen-Activated Protein Kinase Kinases