Hematopoietic insults damage bone marrow niche by activating p53 in vascular endothelial cells

Exp Hematol. 2018 Jul;63:41-51.e1. doi: 10.1016/j.exphem.2018.04.006. Epub 2018 Apr 27.

Abstract

Hematopoietic stem cells (HSCs) are exposed to various insults such as genotoxic stress, inflammation, and infection, which have a direct effect. These insults deplete, cause a functional decline in, and promote HSC aging and transformation. However, the impact of hematopoietic insults on niche cells remains largely unknown. We have reported previously that p53 is activated in blood vessels by various stresses, including hypoxia, inflammation, and aging, and contributes to tissue dysfunction and metabolic abnormalities. We hypothesized that hematopoietic insults also affect the bone marrow (BM) vascular niche. Here, we demonstrate that p53 becomes activated in BM endothelial cells upon hematopoietic stresses such as irradiation and chemotherapeutic treatments. The conditional activation of p53 in VE-cadherin+ vascular niche cells by deleting Mdm2 induces the expression of p53 target genes specifically in vascular endothelial cells, resulting in the dilation and collapse of vascular endothelial cells and reductions in perivascular mesenchymal stromal cell numbers. Consequently, hematopoietic stem cells (HSCs) fail to maintain dormancy, mobilize to the periphery, and are depleted significantly. Our results indicate that various hematopoietic insults affect HSCs, not only directly, but also indirectly by altering vascular integrity, which is critical for perivascular niche formation and maintenance of HSCs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Congenic
  • Blood Cell Count
  • Bone Marrow / drug effects*
  • Bone Marrow / radiation effects*
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism*
  • Endothelial Cells / radiation effects
  • Endothelium, Vascular / cytology*
  • Fluorouracil / toxicity
  • Gene Expression Regulation
  • Genes, p53
  • Hematopoietic Stem Cells / drug effects
  • Hematopoietic Stem Cells / metabolism
  • Hematopoietic Stem Cells / pathology*
  • Hematopoietic Stem Cells / radiation effects
  • Mesenchymal Stem Cells
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Proto-Oncogene Proteins c-mdm2 / deficiency
  • Radiation Injuries, Experimental / pathology
  • Stem Cell Niche
  • Tumor Suppressor Protein p53 / deficiency
  • Tumor Suppressor Protein p53 / physiology*

Substances

  • Trp53 protein, mouse
  • Tumor Suppressor Protein p53
  • Mdm2 protein, mouse
  • Proto-Oncogene Proteins c-mdm2
  • Fluorouracil