Physiological and pathological analysis of intestinal mucosa lymphatic endothelial cells.

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K22665
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 55:Surgery of the organs maintaining homeostasis and related fields
• Research Institution: Kumamoto University
• Principal Investigator: Kume Tsutomu 熊本大学, 生命資源研究・支援センター, 客員教授 (60786474)
• Project Period (FY): 2019-06-28 – 2023-03-31
• Keywords: リンパ管 / VEGF-C / 小腸虚血再灌流障害モデル / 虚血性腸疾患 / リンパ管内凝固

Outline of Final Research Achievements

The lymphatic endothelial cells (ECs) have critical roles in maintaining tissue homeostasis. To analyze the signals for lymphatic vessel formation, we have initially focused on the RASGAP family, Rasa4 and Rasal3, as the downstream of the FOXC transcription factor and have generated the Tamoxifen-inducible conditional these knockout mice, crossed with EC-specific VE-cadherin-CreERT2 transgenic line. Next, to study the correlation between coagulation systems in lymphatic ECs, we have verified the von Willebrand factor (vWF) expression in vivo and cultured cells. The vWF promoter activity and expression were predominantly observed in vascular but not lymphatic ECs in mice. However, in cultured conditions, vWF changed to express lymphatic ECs. The epigenetic status regulated such tissue-specific expression patterns since EZH2 inhibitor treatment leaked to vWF expression in cultured fibroblasts. Further analysis will uncover the lymphatic EC's specific signals and the expression machinery.

Free Research Field

血管生物学、循環器医学

Academic Significance and Societal Importance of the Research Achievements

血管やリンパ管内皮細胞は存在する微小環境、即ち存在する組織での異種細胞間での相互作用やサイトカイン、血流やリンパ流、酸素分圧の影響を受けて、主にエピゲノムレベルでの可逆的あるいは不可逆的な制御下、その微小環境に即した遺伝子発現やそれに伴う内皮細胞の構造変化を行うことが想定されている。今回 vWF を基に、in vivo と培養細胞での違いが顕著に示されたことで、この微小環境を考慮してリンパ管の解析を進める重要性とエピゲノムレベルでの今後の研究展開の重要性が明らかとなった。