Role of Vascular Niche in Stem Cell Aging

2018 Fiscal Year Final Research Report

• Project Area: Establishing a new paradigm of the pathogenesis of diseases through the understanding of stem cell aging
• Project/Area Number: 26115008
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Niigata University
• Principal Investigator: Tohru Minamino 新潟大学, 医歯学系, 教授 (90328063)
• Project Period (FY): 2014-07-10 – 2019-03-31
• Keywords: 細胞老化 / 血管ニッチ

Outline of Final Research Achievements

We have previously reported that p53 is activated in blood vessels by various stresses and contributes to tissue dysfunction and metabolic abnormalities. We hypothesized that hematopoietic insults also affect bone marrow vascular niche. We herein demonstrated 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 induced 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) failed to maintain dormancy, mobilized to the periphery, and were significantly depleted. Our results indicate that various hematopoietic insults affect HSCs not only directly, but also indirectly by altering vascular integrity.

Free Research Field

循環器内科

Academic Significance and Societal Importance of the Research Achievements

血管特異的p53/Mdm遺伝子改変マウスを用いた血管ニッチと幹細胞システムの検討によって、血管ニッチにおける老化シグナルの活性化がステムセルエイジングに大きなインパクトを与えていることが明らかとなった。一方、老化シグナルを直接標的とする抗老化治療はがん化の危険があり臨床応用が困難である。これに対して、本研究で同定したSeno-metaboliteやSeno-antigenを標的とした治療は、がん化の懸念がなく、様々な加齢関連疾患（アルツハイマー病やFrailty、サルコペニア、慢性腎臓病、肺疾患、循環器疾患、代謝疾患など）への臨床応用が見込まれる。