The role of hematopoietic lineage cells marked by smooth muscle-targeted Cre mice in cardiovascular diseases

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K17622
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: National Cardiovascular Center Research Institute
• Principal Investigator: Ishibashi Tomohiko 国立研究開発法人国立循環器病研究センター, 研究所, 上級研究員 (30722285)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: 肺動脈性肺高血圧症 / 平滑筋細胞 / gp130 / IL-6 / リンパ球

Outline of Final Research Achievements

Smooth muscle protein 22 alpha (SM22α)-Cre mouse are widely used as smooth muscle cell (SMC)-specific Cre recombination mice for the study of vascular biology. We found that SM22α-Cre mice showed unexpected Cre recombination in hematopoietic lineage cells. Deletion of gp130, which constitutes the interleukin-6 (IL-6) receptor, using SM22α-Cre mice improved the phenotype of hypoxia-induced pulmonary hypertension (HPH). It was suggested that this improvement was the result of nonspecific deletion of gp130 in CD4-positive T cells. In fact, CD4-positive cell-specific gp130 deletion by crossing gp130 flox mice with CD4-Cre mice ameliorated right ventricular systolic pressure in HPH mouse. These findings suggest that gp130-mediated signaling in CD4-positive cells plays an important role in the pathogenesis of PAH. Besides, careful attention should be paid when using SMC-targeted Cre recombination mice for the purpose of SMC-specific gene knockout and lineage tracing studies.

Free Research Field

血液内科学、血管生物学

Academic Significance and Societal Importance of the Research Achievements

平滑筋細胞特異的Creマウスとして広く研究に使用されているSM22α-Creマウスで、実際には血液細胞のすべての系統でCreリコンビネーションが生じることを明らかにした。SM22α-Creを用いた実験結果は慎重に解釈する必要があることを示すものであり、学術的に意義がある。また、指定難病である肺動脈性肺高血圧症の病態形成にIL-6が重要であることはこれまでも報告されてきたが、本研究の成果は、その標的としてCD4陽性T細胞が重要であることを示すものであり、新規治療法の開発などの臨床応用へ向けた基盤となると考えられる。