Hematopoietic loss of Y chromosome and its impact on heart failure

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K20879
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0902:General internal medicine and related fields
• Research Institution: National Cardiovascular Center Research Institute (2023); Osaka Metropolitan University (2022); Osaka City University (2021)
• Principal Investigator: Sano Soichi 国立研究開発法人国立循環器病研究センター, 研究所, 室長 (80647884)
• Project Period (FY): 2021-08-30 – 2024-03-31
• Keywords: 後天的Y染色体喪失 / クローン性造血 / バイオバンク / 心不全モデル / マクロファージ / CRISPR/Cas9 / シングルセル解析

Outline of Final Research Achievements

Hematopoietic mosaic loss of Y chromosome (mLOY) is associated with increased risk of mortality and age-related diseases in men, but the causal and mechanistic relationships have yet to be established. Here, we show that male mice reconstituted with bone marrow cells lacking the Y chromosome display increased mortality and age-related profibrotic pathologies including reduced cardiac function. Cardiac macrophages lacking the Y chromosome exhibited polarization toward a more fibrotic phenotype, and treatment with a transforming growth factor-beta (TGF-beta) neutralizing antibody ameliorated cardiac dysfunction in mLOY mice. A prospective study revealed that mLOY in blood is associated with an increased risk for cardiovascular disease and heart failure-associated mortality. Together, these results indicate that hematopoietic mLOY causally contributes to fibrosis, cardiac dysfunction, and mortality in men.

Free Research Field

循環器内科学

Academic Significance and Societal Importance of the Research Achievements

血液の後天的Y染色体喪失は、生物学的男性にのみ見られる現象であり、疾患における性差を考える上で重要です。この研究では、臨床研究と動物実験を組み合わせることで、Y染色体を喪失した血液細胞が男性の心臓病を悪化させることやその仕組みについて解明しました。特に、Y染色体を失ったマクロファージという免疫細胞が心臓の線維化を引き起こし、心臓の機能を障害することが分かりました。本研究により、性差に基づく新たな心臓病治療法の開発に向けた第一歩が踏み出されたと考えられます。