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

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)41-51.e1
JournalExperimental Hematology
Volume63
DOIs
Publication statusPublished - 2018 Jul 1

Fingerprint

Hematopoietic Stem Cells
Endothelial Cells
Bone Marrow
Blood Vessels
Inflammation
Cell Aging
p53 Genes
Mesenchymal Stromal Cells
Bone Marrow Cells
DNA Damage
Dilatation
Cell Count
Maintenance
Infection

ASJC Scopus subject areas

  • Molecular Biology
  • Hematology
  • Genetics
  • Cell Biology
  • Cancer Research

Cite this

Si, S., Nakajima-Takagi, Y., Iga, T., Tsuji, M., Hou, L., Oshima, M., ... Iwama, A. (2018). Hematopoietic insults damage bone marrow niche by activating p53 in vascular endothelial cells. Experimental Hematology, 63, 41-51.e1. https://doi.org/10.1016/j.exphem.2018.04.006

Hematopoietic insults damage bone marrow niche by activating p53 in vascular endothelial cells. / Si, Sha; Nakajima-Takagi, Yaeko; Iga, Takahito; Tsuji, Mayoko; Hou, Libo; Oshima, Motohiko; Koide, Shuhei; Saraya, Atsunori; Yamazaki, Satoshi; Takubo, Keiyo; Kubota, Yoshiaki; Minamino, Tohru; Iwama, Atsushi.

In: Experimental Hematology, Vol. 63, 01.07.2018, p. 41-51.e1.

Research output: Contribution to journalArticle

Si, S, Nakajima-Takagi, Y, Iga, T, Tsuji, M, Hou, L, Oshima, M, Koide, S, Saraya, A, Yamazaki, S, Takubo, K, Kubota, Y, Minamino, T & Iwama, A 2018, 'Hematopoietic insults damage bone marrow niche by activating p53 in vascular endothelial cells', Experimental Hematology, vol. 63, pp. 41-51.e1. https://doi.org/10.1016/j.exphem.2018.04.006
Si, Sha ; Nakajima-Takagi, Yaeko ; Iga, Takahito ; Tsuji, Mayoko ; Hou, Libo ; Oshima, Motohiko ; Koide, Shuhei ; Saraya, Atsunori ; Yamazaki, Satoshi ; Takubo, Keiyo ; Kubota, Yoshiaki ; Minamino, Tohru ; Iwama, Atsushi. / Hematopoietic insults damage bone marrow niche by activating p53 in vascular endothelial cells. In: Experimental Hematology. 2018 ; Vol. 63. pp. 41-51.e1.
@article{c8e62546ea1246759a69253e784bdd09,
title = "Hematopoietic insults damage bone marrow niche by activating p53 in vascular endothelial cells",
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.",
author = "Sha Si and Yaeko Nakajima-Takagi and Takahito Iga and Mayoko Tsuji and Libo Hou and Motohiko Oshima and Shuhei Koide and Atsunori Saraya and Satoshi Yamazaki and Keiyo Takubo and Yoshiaki Kubota and Tohru Minamino and Atsushi Iwama",
year = "2018",
month = "7",
day = "1",
doi = "10.1016/j.exphem.2018.04.006",
language = "English",
volume = "63",
pages = "41--51.e1",
journal = "Experimental Hematology",
issn = "0301-472X",
publisher = "Elsevier Inc.",

}

TY - JOUR

T1 - Hematopoietic insults damage bone marrow niche by activating p53 in vascular endothelial cells

AU - Si, Sha

AU - Nakajima-Takagi, Yaeko

AU - Iga, Takahito

AU - Tsuji, Mayoko

AU - Hou, Libo

AU - Oshima, Motohiko

AU - Koide, Shuhei

AU - Saraya, Atsunori

AU - Yamazaki, Satoshi

AU - Takubo, Keiyo

AU - Kubota, Yoshiaki

AU - Minamino, Tohru

AU - Iwama, Atsushi

PY - 2018/7/1

Y1 - 2018/7/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85048750661&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85048750661&partnerID=8YFLogxK

U2 - 10.1016/j.exphem.2018.04.006

DO - 10.1016/j.exphem.2018.04.006

M3 - Article

VL - 63

SP - 41-51.e1

JO - Experimental Hematology

JF - Experimental Hematology

SN - 0301-472X

ER -