ANGPTL2 controls intestinal homeostasis

• Project/Area Number: 15H06508
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Pathological medical chemistry
• Research Institution: Kumamoto University
• Principal Investigator: Horiguchi Haruki 熊本大学, 生命資源研究・支援センター, 特定事業研究員 (70755454)
• Project Period (FY): 2015-08-28 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 潰瘍性大腸炎 / アンジオポエチン様2 / アンジオポエチン様因子2

Outline of Final Research Achievements

We assessed ANGPTL2 function in intestinal physiology and disease in vivo. Although intestinal development proceeded normally in Angptl2-deficient mice, expression levels of the intestinal stem cell (ISC) marker gene Lgr5 decreased, which was associated with decreased transcriptional activity of β-catenin in Angptl2-deficient mice. Epithelial regeneration after injury was significantly impaired in Angptl2-deficient relative to wild-type mice. ANGPTL2 was expressed and functioned within the mesenchymal compartment cells known as intestinal subepithelial myofibroblasts (ISEMFs). ANGPTL2 derived from ISEMFs maintained the intestinal stem cell niche by modulating levels of competing signaling between bone morphogenetic protein (BMP) and β-catenin. These results support the importance of ANGPTL2 in the stem cell niche in regulating stemness and epithelial wound healing in the intestine.

Research Products

• [Journal Article] ANGPTL2 expression in intestinal stem cell niche controls epithelial regeneration and homeostasis. (2017)
  • Author(s): Horiguchi H, Endo M, Kawane K, Kadomatsu T, Terada K, Morinaga J, Araki K, Miyata K, Oike Y,
  • Journal Title: EMBO Journal Volume: 36 Issue: 4 Pages: 409-424
  • DOI: 10.15252/embj.201695690
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] ANGPTL2 activity in cardiac pathologies accelerates heart failure by perturbing cardiac function and energy metabolism. (2016)
  • Author(s): Tian Z, Miyata K, Kadomatsu T, Horiguchi H, Fukushima H, Tohyama S, Ujihara Y, Okumura T, Yamaguchi S, Zhao J, Endo M, Morinaga J, Sato M, Sugizaki T, Zhu S, Terada K, Sakaguchi H, Komohara Y, Takeya M, Takeda N, Araki K, Manabe I, Fukuda K, Otsu K, Wada J, Murohara T, Mohri S, Yamashita JK, Sano M, Oike Y.
  • Journal Title: Nature Communications Volume: 7 Issue: 1 Pages: 13016-13016
  • DOI: 10.1038/ncomms13016
  • NAID: 120006345014
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Interstitial pneumonia induced by bleomycin treatment is exacerbated in Angptl2-deficient mice (2016)
  • Author(s): Motokawa I, Endo M, Terada K, Horiguchi H, Miyata K, Kadomatsu T, Morinaga J, Sugizaki T, Ito T, Araki K, Morioka MS, Manabe I, Samukawa T, Watanabe M, Inoue H, Oike Y.
  • Journal Title: American Journal of Physiology. Lung Cellular and Molecular Physiology Volume: 311 Issue: 4 Pages: 704-713
  • DOI: 10.1152/ajplung.00005.2016
  • Peer Reviewed
• [Journal Article] Mice Deficient in Angiopoietin-like Protein 2 (Angptl2) Gene Show Increased Susceptibility to Bacterial Infection Due to Attenuated Macrophage Activity (2016)
  • Author(s): Yugami M, Odagiri H, Endo M, Tsutsuki H, Fujii S, Kadomatsu T, Masuda T, Miyata K, Terada K, Tanoue H, Ito H, Morinaga J, Horiguchi H, Sugizaki T, Akaike T, Gotoh T, Takai T, Sawa T, Mizuta H, Oike Y
  • Journal Title: Journal of Biological Chemistry Volume: 291 Issue: 36 Pages: 18843-18852
  • DOI: 10.1074/jbc.m116.720870
  • Peer Reviewed / Open Access / Acknowledgement Compliant