Roles of Girdin in organ fibrosis and cancer associated fibrosis

• Project/Area Number: 18K07042
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49030:Experimental pathology-related
• Research Institution: Fujita Health University (2019-2020); Nagoya University (2018)
• Principal Investigator: Asai Naoya 藤田医科大学, 医学部, 教授 (80273233)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 臓器線維症 / 癌関連線維芽細胞 / 間葉系幹細胞 / 遺伝子改変動物 / 細胞運動 / 線維化症 / 臓器線維化症 / 強皮症

Outline of Final Research Achievements

Fibrosis can affect any organs and cancers, which lead poor prognosis in patients. To reveal mechanisms of fibrosis, we studied on Girdin and Meflin. With two mutant mice of Girdin S1416A and Girdin Y1764/1798F, we checked the importance of Girdin phosphorylation in fibrosis. Both Girdin mutant mice showed no significant impact of fibrotic status in organ fibrosis models in lung, liver and cancers. Meflin is a novel mesenchymal stem cell marker, and Meflin deficient mice show skin fibrosis, which is similar to systemic sclerosis in humans. By lineage trace experiment, we identified new subpopulation of kidney mesenchymal cells, which express Meflin and can differentiate into renin producing cells. Meflin-positive mesenchymal cells in kidney have important roles in kidney fibrosis, and patients of IgA nephropathy with many Meflin-positive cells show poor prognosis.

Academic Significance and Societal Importance of the Research Achievements

本研究により、Meflin欠損マウスにはヒト疾患の強皮症に類似した皮膚線維症の病態が生じることが判明したことから、疾患モデルとしての有効利用が期待される。
腎臓においてMeflin陽性細胞は血圧を制御するレニン産生細胞への分化を介して腎性高血圧へ関与すること、Mefliny陽性細胞の数がIgA腎症の予後不良因子となるとともに、腎間質線維症への関与することから、Meflin遺伝子が腎疾患における新たな治療ターゲットとなる可能性が期待される。

Research Products

• [Int'l Joint Research] University of Adelaide(オーストラリア)
• [Journal Article] Meflin defines mesenchymal stem cells and/or their early progenitors with multilineage differentiation capacity (2021)
  • Author(s): Hara A, Kato K, Ishihara T, Kobayashi H, Asai N, Mii S, Shiraki Y, Miyai Y, Ando R, Mizutani Y, Iida T, Takefuji M, Murohara T, Takahashi M, Enomoto A.
  • Journal Title: Genes Cells Volume: - Issue: 7 Pages: 495-512
  • DOI: 10.1111/gtc.12855
  • Peer Reviewed / Open Access
• [Journal Article] The balance of stromal BMP signaling mediated by GREM1 and ISLR drives colorectal carcinogenesis. (2021)
  • Author(s): Kobayashi H, Gieniec KA, Wright JA, Wang T, Asai N, Mizutani Y, Iida T, Ando R, Suzuki N, Lannagan TR, Ng JQ, Hara A, Shiraki Y, Mii S (14番目/36人中), ..., Enomoto A, Takahashi M, Worthley DL, Woods SL.
  • Journal Title: Gastroenterology. Volume: 160 Issue: 4 Pages: 1224-1239
  • DOI: 10.1053/j.gastro.2020.11.011
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Meflin-Positive Cancer-Associated Fibroblasts Inhibit Pancreatic Carcinogenesis. (2019)
  • Author(s): Mizutani Y, Kobayashi H, Iida T, Asai N, Masamune A, Hara A, Yamaguchi J, Wang T, Woods SL, Worthley D, Shimamura T, Fujishiro M, Hirooka Y, Enomoto A, Takahashi M. et al.
  • Journal Title: Cancer Res. Volume: 79 Issue: 20 Pages: 5367-5381
  • DOI: 10.1158/0008-5472.can-19-0454
  • NAID: 120006786261
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Roles of the Mesenchymal Stromal/Stem Cell Marker Meflin in Cardiac Tissue Repair and the Development of Diastolic Dysfunction. (2019)
  • Author(s): Hara A, Kobayashi H, Asai N, Saito S, Higuchi T, Kato K, Okumura T, Bando YK, Takefuji M, Mizutani Y, Miyai Y, Saito S, Maruyama S, Maeda K, Ouchi N, Nagasaka A, Miyata T, Mii S, Kioka N, Worthley DL, Murohara T, Takahashi M, Enomoto A.
  • Journal Title: Circ. Res. Volume: 125 Issue: 4 Pages: 414-430
  • DOI: 10.1161/circresaha.119.314806
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Remarks] 名古屋大学医学部 腫瘍病理学・分子病理学分野
  • URL: https://www.med.nagoya-u.ac.jp/patho2/