Hematopoietic loss of Y chromosome and its impact on heart failure

• 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
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000); Fiscal Year 2022: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• 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 / 心不全 / マウス骨髄移植法 / 心臓マクロファージ / 線維化 / Loss of Y chromosome / UKバイオバンク / 動物実験 / 血液細胞の後天的Y染色体喪失 / 加齢

Outline of Research at the Start

男性では、加齢にともなってY染色体を失った血液細胞が増加することが知られている。この現象は後天的Y染色体喪失（Mosaic loss of chromosome Y：mLOY）と呼ばれ、近年、男性の生命予後や、心不全など様々な加齢性疾患の発症と関連していることが明らかとなった。そこで本研究では、申請者がこれまでに確立したmLOYの動物実験モデルを用いて、mLOYが心不全の経過を悪化させる機序を解明する。

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.

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。

Research Products

• [Int'l Joint Research] University of Virginia(米国)
• [Int'l Joint Research] Uppsala University(スウェーデン)
• [Int'l Joint Research] University of Virginia/CVRC(米国)
• [Journal Article] A Novel Method for Acquired Sex Chromosome Mosaicism (2024)
  • Author(s): Tsuchiya Junichi、Maki Yoshinori、Ayano Madoka、Kikuchi Taiki、Watanabe Yosuke、Ohtake Kiyoshi、Fujita Rumi、Hayashi Masaru、Yamamoto Junji、Wang Ying、Anzai Atsushi、Kubo Tomohiro、Sano Soichi
  • Journal Title: Advanced Biology Volume: - Issue: 7
  • DOI: 10.1002/adbi.202300512
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Dirsuption of the Uty epigenetic regulator locus in hemtopoietic cells phenocopies the profibrotic attributes of Y chromosome loss in heart failure. (2024)
  • Author(s): Horitani K, Chavkin NW, Arai Y, Wang Y, Ogawa H, Yura Y, Evans MA, Cochran JD, Thel MC, Polizio AH, Sano M, Miura-Yura E, Arai Y, Doviak H, Arnold AP, Gelfand BD, Hirschi KK, Sano S, Walsh
  • Journal Title: Nat Cardiovasc Res. Volume: 3 Pages: 343-355
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Why Y matters? The implication of loss of Y chromosome in blood and cancer (2024)
  • Author(s): Wang Ying、Sano Soichi
  • Journal Title: Cancer Science Volume: 115 Issue: 3 Pages: 706-714
  • DOI: 10.1111/cas.16072
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mosaic loss of chromosome Y and cardiovascular disease (2023)
  • Author(s): Sano Soichi、Walsh Kenneth
  • Journal Title: Nature Reviews Cardiology Volume: 21 Issue: 3 Pages: 151-152
  • DOI: 10.1038/s41569-023-00976-x
  • Int'l Joint Research
• [Journal Article] Clonal Hematopoiesis in Clinical and Experimental Heart Failure With Preserved Ejection Fraction (2023)
  • Author(s): Cochran JD, Yura Y, Thel MC, Doviak H, Polizio AH, Arai Y, Arai Y, Horitani K, Park E, Chavkin NW, Kour A, Sano S, Mahajan N, Evans M, Huba M, Naya NM, Sun H, Ban YH, Hirschi KK, Toldo S, Abbate A, Druley TE, Ruberg FL, Maurer MS, Ezekowitz JA, Dyck JRB, Walsh K.
  • Journal Title: Circulation Volume: 148 Issue: 15 Pages: 1165-1178
  • DOI: 10.1161/circulationaha.123.064170
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Development of a Mouse Model of Hematopoietic Loss of Y Chromosome (2023)
  • Author(s): Sano Soichi、Walsh Kenneth
  • Journal Title: BIO-PROTOCOL Volume: 13 Issue: 15
  • DOI: 10.21769/bioprotoc.4729
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mosaic Loss of Y Chromosome in White Blood Cells: Its Impact on Men's Health (2023)
  • Author(s): Sano Soichi、Thel Mark C.、Walsh Kenneth
  • Journal Title: Physiology Volume: 2023 Issue: 4 Pages: 161-166
  • DOI: 10.1152/physiol.00008.2023
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Clonal hematopoiesis: the nonhereditary genetics of age-associated cardiovascular disease (2023)
  • Author(s): Sano Soichi、Thel Mark C.、Walsh Kenneth
  • Journal Title: Current Opinion in Cardiology Volume: 38 Pages: 201-206
  • DOI: 10.1097/hco.0000000000001032
  • Open Access / Int'l Joint Research
• [Journal Article] Hematopoietic loss of Y chromosome leads to cardiac fibrosis and heart failure mortality (2022)
  • Author(s): Sano Soichi、Mattisson Jonas、Hata Atsushi、Danielsson Marcus、Miura-Yura Emiri、Zaghlool Ammar、Evans Megan A.、Fall Tove、De Hoyos Henry N.、Forsberg Lars A.、Walsh Kenneth at al.
  • Journal Title: Science Volume: 377 Issue: 6603 Pages: 292-297
  • DOI: 10.1126/science.abn3100
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] ぼくらはモザイクにんげん (2024)
  • Author(s): 佐野宗一
  • Organizer: 第28回令和私塾共創の場
  • Invited
• [Presentation] 循環器内科臨床医として知らないわけにはいかないクローン性造血 Clonal Hematopoiesis and Cardiovascular Disease - Knowns and Unknowns (2024)
  • Author(s): 佐野宗一
  • Organizer: 第88回日本循環器学会学術集会、会長特別企画
  • Invited
• [Presentation] 血液の性染色体喪失 (2023)
  • Author(s): 佐野宗一
  • Organizer: 心血管代謝週間CVMW2023
  • Invited
• [Presentation] Y染色体喪失と個体老化 (2023)
  • Author(s): 佐野宗一
  • Organizer: 第46回日本分子生物学会年会
  • Invited
• [Presentation] Why Y matters? Loss of Y chromosome と疾患 (2023)
  • Author(s): 佐野宗一
  • Organizer: 第 18 回 Osaka Cardio‐Diabetes Conference
  • Invited
• [Presentation] 体細胞変異と生物学的老化 (2023)
  • Author(s): 佐野宗一
  • Organizer: 第2回日本抗加齢医学会 WEBメディアセミナー
  • Invited
• [Presentation] 男性のハートブレイク-Loss of Y chromosomeと心不全- (2023)
  • Author(s): 佐野宗一
  • Organizer: ABUS 2023(Atjerosclerosis/thrombosis and Biolipid Update Seminar）
  • Invited
• [Presentation] The Darkside of Hematology : Clonal Hematopoiesis and heart Failure (2023)
  • Author(s): 佐野宗一
  • Organizer: 第55回日本動脈硬化学会総会・学術集会
  • Invited
• [Presentation] When Heartbreak is Literal:the Link Between Loss of Y Chromosome in Leukocytes and Heart Failure in Men (2023)
  • Author(s): 佐野宗一
  • Organizer: 第55回日本動脈硬化学会総会・学術集会
  • Invited
• [Presentation] 男性のハートブレイク：Loss of Y chromosomeと心不全の因果関係 (2023)
  • Author(s): 佐野宗一
  • Organizer: 第8回JCVA（日本心血管協会）年次学術集会
  • Invited
• [Presentation] 男性にとってのハートブレイク：Loss of Y chromosomeと心不全の関連性 (2023)
  • Author(s): 佐野宗一
  • Organizer: 日本心血管内分泌代謝学会（CVEM）
  • Invited
• [Presentation] Why Y matters? 血液のY染色体喪失 (2022)
  • Author(s): 佐野宗一
  • Organizer: 第26回Science Cafe
  • Invited
• [Book] Medical Practice (2024)
  • Author(s): 牧貴紀、佐野宗一
  • Total Pages: 4
  • Publisher: 文光堂
• [Book] 検査と技術 (2024)
  • Author(s): 土屋純一、佐野宗一
  • Total Pages: 2
  • Publisher: 医学書院
• [Book] 日本臨牀 (2024)
  • Author(s): 安西淳、佐野宗一
  • Total Pages: 7
  • Publisher: 日本臨牀社
• [Book] 実験医学 (2023)
  • Author(s): 菊池太貴、佐野宗一
  • Total Pages: 5
  • Publisher: 羊土社
• [Book] 循環器病研究の進歩 (2023)
  • Author(s): 菊池太貴、佐野宗一
  • Total Pages: 8
  • Publisher: 協和企画
• [Book] BIO Clinica (2023)
  • Author(s): 佐野宗一
  • Total Pages: 8
  • Publisher: 北隆館 ニュー・サイエンス
• [Book] Japanese Scientists in Science 2022 (2023)
  • Author(s): 佐野宗一 他
  • Total Pages: 50
  • Publisher: American Association for the Advancement of Science
• [Remarks] 心血管モザイク研究室HP
  • URL: https://www.ncvc.go.jp/res/divisions/cvm/