Understanding of the Stem Cell Aging Regulation in Intestinal Stem Cells

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: 26115007
• 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: Keio University
• Principal Investigator: Sato Toshiro 慶應義塾大学, 医学部(信濃町), 教授 (70365245)
• Project Period (FY): 2014-07-10 – 2019-03-31
• Keywords: 大腸癌 / 炎症性腸疾患 / オルガノイド / 幹細胞 / 老化

Outline of Final Research Achievements

Intestinal epithelium is the highest proliferative tissue in our body, and its self-renewal is fueled by intestinal stem cells resided at crypt bottoms. Cell proliferation ensues inevitable genomic mutations, however, it remains unknown to what extent intestinal stem cells accumulate genomic mutations along with aging. In this study, using human intestinal organoid culture, Sato et al. determined the dynamics of genomic mutations in healthy and diseased epithelium in association with aging and its relationship with disease phenotype. As a result, the mutation rate was projected to be 40 mutations/year in single intestinal stem cell. Moreover, we demonstrated that mucosal inflammation of ulcerative colitis accelerated the mutation rate of intestinal stem cells and acquired genetic mutations related to the resistance against inflammation.

Free Research Field

内科学　消化器内科

Academic Significance and Societal Importance of the Research Achievements

本研究により，これまで不明であった，腸管上皮幹細胞の遺伝子変異蓄積が明らかにされた．また，本邦で増加している潰瘍性大腸炎患者の大腸上皮では，変異速度の加速と特異的な遺伝子変異の蓄積が確認された．本研究は，加齢による腸管上皮細胞の遺伝学的な変化と生物学的な形質への寄与を突き止めた学術的な意義の高い研究である．また，本研究で得られた成果は潰瘍性大腸炎の発がんリスク群の絞り込みに有効と考えられ，臨床的・社会的にも還元可能な優れた成果である．