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

Sha Si, Yaeko Nakajima-Takagi, Takahito Iga, Mayoko Tsuji, Libo Hou, Motohiko Oshima, Shuhei Koide, Atsunori Saraya, Satoshi Yamazaki, Keiyo Takubo, Yoshiaki Kubota, Tohru Minamino, Atsushi Iwama

研究成果: Article査読

8 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)41-51.e1
ジャーナルExperimental Hematology
63
DOI
出版ステータスPublished - 2018 7月

ASJC Scopus subject areas

  • 分子生物学
  • 血液学
  • 遺伝学
  • 細胞生物学
  • 癌研究

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