Pathogenesis of epithelial-mesenchymal transition relating to progressing fibrosis and its clinical significance

2013 Fiscal Year Final Research Report

• Project/Area Number: 23658265
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Clinical veterinary science
• Research Institution: Osaka Prefecture University
• Principal Investigator: YAMATE Jyoji 大阪府立大学, 生命環境科学研究科(系), 教授 (50150115)
• Co-Investigator(Kenkyū-buntansha): KUWAMURA Mitsuru 大阪府立大学, 生命環境科学研究科, 准教授 (20244668) ; TAKANAKA Shigeo 大阪府立大学, 生命環境科学研究科, 准教授 (10280067) ; IZAWA Takeshi 大阪府立大学, 生命環境科学研究科, 助教 (20580369)
• Project Period (FY): 2011 – 2013
• Keywords: 上皮－間葉転換 / 線維化 / 尿細管上皮 / 胆管上皮 / 毛嚢上皮 / 体性幹細胞

Research Abstract

Epithelial-mesenchymal transition (EMT) is a phenomenon in which injured epithelia acquire myofibroblastic properties, leading to progressive fibrosis. EMT was analyzed in renal epithelia, bile duct epithelia and follicular epithelia in renal fibrosis, peribiliary fibrosis and cutaneous fibrosis, respectively. The acquisition of myofibroblastic properties of incomplete renal regeneration in renal fibrosis was demonstrated; this EMT was inhibited by PGE2 and NGAL, but promoted by osteopontin. Since nephric blastema showed myofibroblastic properties, suggesting that renal EMT is a retroactive phenomenon towards renal blastema. Evident EMT was not shown in the bile duct epithelia in peribiliary fibrosis or follicular epithelia in cutaneous fibrosis. Myofibroblasts may be derived from the mesenchymal stem cells such as pericytes and bone-marrow stem cells. The present study gives a novel concept (EMT theory), which would open clues of possible therapies for intractable fibrosis.

Research Products

• [Journal Article] Calponin expression in renal tubuolointerstitial fibrosis induced in rats by cisplatin (2014)
  • Author(s): Yuasa, T., Yano, R., Izawa, T., Kuwamura, M., Yamate, J
  • Journal Title: J Toxicol Pathol Volume: 27 Pages: 97-103
  • DOI: 10.1293/tox.2013-0048
  • Peer Reviewed
• [Journal Article] Characterization of glial fibrillary acidic protein (GFAP)-expressing hepatic stellate cells and myofibroblasts in thioacetamide (TAA)-induced rat liver injury (2013)
  • Author(s): Tennakoon, A.H., Izawa, T., Wijesundera, K.K., Golbar, H.M., Tanaka, M., Ichikawa, C., Kuwamura, M., Yamate, J
  • Journal Title: Exp Toxicol Pathol Volume: 65 Pages: 1159-1171
  • DOI: 10.1016/j.etp.2013.05.008
  • Peer Reviewed
• [Journal Article] Slowly progressive cholangiofibrosis induced in rats by alpha-naphthylisothiocyanate (ANIT), with particular references to characteristics of macrophages and myofibroblasts (2013)
  • Author(s): Golbar, H.M., Izawa, T., Ichikawa, C., Tanaka, M., Juniantito, V., Sawamoto, O., Kuwamura, M., Yamate, J
  • Journal Title: Exp Toxicol Pathol Volume: 65 Pages: 825-835
  • DOI: 10.1016/j.etp.2012.12.001
  • Peer Reviewed
• [Journal Article] Thy-1 expression, a possible marker of early myofibroblast development, in renal tubulointerstitial fibrosis induced in rats by cisplatin (2013)
  • Author(s): Yuasa, T., Juniantito, V., Ichikawa, C., Yano, R., Izawa, T., Kuwamura, M., Yamate, J
  • Journal Title: Exp Toxicol Pathol Volume: 65 Pages: 651-659
  • DOI: 10.1016/j.etp.2012.07.005
  • Peer Reviewed
• [Journal Article] Immunophenotypical analysis of myofibroblasts and mesenchymal cells in the bleomycin-induced rat scleroderma, with particular reference to their origin (2013)
  • Author(s): Juniantito, V., Izawa, T., Yuasa, T., Ichikawa, C., Tanaka, M., Kuwamura, M., Yamate, J
  • Journal Title: Exp Toxicol Pathol Volume: 65 Pages: 567-577
  • DOI: 10.1016/j.etp.2012.05.002
  • Peer Reviewed
• [Journal Article] Distribution of cells labelled by a novel somatic stem cell-recognizing antibody (A3) in pulmonary genesis and bleomycin induced pulmonary fibrosis in rats (2013)
  • Author(s): Hori, M., Juniantito, V., Izawa, T., Ichikawa, C., Tanaka, M., Tanaka, K., Takenaka, S., Kuwamura, M., Yamate, J
  • Journal Title: J Comp Pathol Volume: 148 Pages: 385-395
  • DOI: 10.1016/j.jcpa.2012.09.003
  • Peer Reviewed
• [Journal Article] Rat hair follicle-constituting cells labeled by a newly-developed somatic stem cell-recognizing antibody : a possible marker of hair follicle development (2013)
  • Author(s): Ichikawa, C., Izawa, T., Juniantito, V., Tanaka, M., Hori, M., Tanaka, K., Takenaka, S., Kuwamura, M., Yamate, J
  • Journal Title: Histol Histopathol Volume: 28 Pages: 257-268
  • Peer Reviewed
• [Journal Article] Amelioration of cisplatin-induced rat renal lesions by a cyclooxygenase (COX)-2 selective inhibitor (2012)
  • Author(s): Yamamato, E., Izawa, T., Sawamoto, O., Juniantito, V., Kuwamura, M., Yamate, J
  • Journal Title: Exp Toxicol Pathol Volume: 64 Pages: 625-631
  • DOI: 10.1016/j.etp.2010.12.005
  • Peer Reviewed
• [Journal Article] Immunophenotypical analyses of myofibroblasts in rat excisional wound healing : possible transdifferentiation of blood vessel pericytes and perifollicular dermal sheath cells into myofibroblasts (2012)
  • Author(s): Juniantito, V., Izawa, T., Yuasa, T., Ichikawa, C., Yamamoto, E., Kuwamura, M., Yamate, J
  • Journal Title: Histol Histopathol Volume: 27 Pages: 515-527
  • Peer Reviewed
• [Journal Article] Immunohistochemical analyses of the kinetics and distribution of macrophages, hepatic stellate cells and bile duct epithelia in the developing rat liver (2012)
  • Author(s): Golbar, H.M., Izawa, T., Murai, F., Kuwamura, M., Yamate, J
  • Journal Title: Exp Toxicol Pathol Volume: 64 Pages: 1-8
  • DOI: 10.1016/j.etp.2010.05.011
  • Peer Reviewed
• [Presentation] ラット発生過程の膵とイヌの線維化膵における膵星細胞と筋線維芽細胞の免疫組織学的特性解析 (2014)
  • Author(s): 橋本 愛, 井澤武史, 田中美有, Golbar HM, Wijesundera K, 桑村 充, 山手丈至
  • Organizer: 第30回日本毒性病理学会学術集会
  • Place of Presentation: 徳島
  • Year and Date: 20140130-31
• [Presentation] 正常肝と肝硬変ラットにおける上皮-間葉転換の観点からの肝星細胞の特徴解析 (2014)
  • Author(s): Tennakoon A, 井澤武史, Wijesundera K, Golbar HM, 田中美有, 桑村 充, 山手丈至
  • Organizer: 第30回日本毒性病理学会学術集会
  • Place of Presentation: 徳島
  • Year and Date: 20140130-31
• [Presentation] Characterization of GFAP-expressing hepatic stellate cells (HSCs) and myofibroblasts (MFs) in thioacetamide (TAA)-induced rat liver injury (2013)
  • Author(s): Tennakoon A, 井澤武史, Wijesundera K, 村上 宙, Golbar HM, 田中美有, 市川智彩, 桑村 充, 山手丈至
  • Organizer: 第155回日本獣医学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 20130328-30
• [Presentation] Golbar HM, 井澤武史, 市川智彩, 田中美有, 桑村 充, 山手丈至 (2013)
  • Author(s): α-naphthylisothiocyanate(ANIT)により誘発したラットの急性と慢性胆管病変におけるマクロファージと筋線維芽細胞の特性比較
  • Organizer: 第29回日本毒性病理学会学術集会
  • Place of Presentation: つくば
  • Year and Date: 20130131-0201
• [Presentation] ラット体性幹細胞標識抗体A3 が認識する毛発生過程における上皮細胞の特性解明 (2012)
  • Author(s): 市川智彩, 井澤武史, 田中勝啓, 竹中重雄, 桑村 充, 山手丈至
  • Organizer: 第154回日本獣医学会学術集会
  • Place of Presentation: 盛岡
  • Year and Date: 20120914-16
• [Presentation] シスプラチン誘発ラット腎間質線維化におけるカルポニンの発現と筋線維芽細胞との関連 (2012)
  • Author(s): 湯浅隆弘, 井澤武史, 桑村 充, 山手丈至
  • Organizer: 第28回日本毒性病理学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 20120202-03
• [Presentation] Mechanisms of cutaneous wound healing, based on functional properties of macrophages and myofibroblasts (2012)
  • Author(s): Yamate J
  • Organizer: 第153回日本獣医学会学術集会.
  • Place of Presentation: 東京
  • Year and Date: 2012-03-29
  • Invited
• [Presentation] Immunohistochemical detection of macrophages and myofibroblasts in rat model of bleomycin-induced scleroderma (2011)
  • Author(s): Juniantito V, Ichikawa C, Izawa T, Kuwamura M, Yamate J
  • Organizer: The Joint Meeting of the 5th Conference and Congress of Asian Society of Veterinary Pathology (ASVP) 2011 and the 10th Scientific Symposium of Indonesia Society of Veterinary Pathology (ISVP) 2011
  • Place of Presentation: Bogor, Indonesia
  • Year and Date: 20111122-23
• [Presentation] Nestin expression in α-naphthylisocyanate (ANIT)-induced acute bile duct injury lesions in rats (2011)
  • Author(s): Golbar HM, 井澤武史, 市川智彩, 田中美有, 桑村 充, 山手丈至
  • Organizer: 第152回日本獣医学会学術集会
  • Place of Presentation: 堺
  • Year and Date: 20110919-21
• [Presentation] Involvement of macrophages and myofibroblasts in chronic alpha-naphthyl isothiocyanate (ANIT)-induced peribiliary fibrosis in rat model (2011)
  • Author(s): Golbar HM, 井澤武史, 矢野遼, 澤本修, 桑村 充, 山手丈至
  • Organizer: 第27回日本毒性病理学会学術集会
  • Place of Presentation: 大阪
  • Year and Date: 20110130-31
• [Presentation] シスプラチン誘発ラット腎傷害における内因性PGE2 の影響 (2011)
  • Author(s): 山本絵美, 増野功一, 藤澤可恵, 土屋紀子, 松嶋周一, 高須伸夫, 鳥井幹則, 井澤武史, Juniantito V, 桑村 充, 杉浦喜久弥, 竹内正吉, 山手丈至
  • Organizer: 第27回日本毒性病理学会学術集会
  • Place of Presentation: 大阪
  • Year and Date: 20110130-31
• [Presentation] ラット腎間質線維化におけるThy-1 免疫陽性細胞の動態, 特に筋線維芽細胞との関連について (2011)
  • Author(s): 湯浅隆弘, 井澤武史, 桑村 充, 山手丈至
  • Organizer: 第27回日本毒性病理学会学術集会
  • Place of Presentation: 大阪
  • Year and Date: 20110130-31
• [Presentation] Comparisons of properties of macrophages and myofibroblasts between two different cutaneous fibrosis rat models (2011)
  • Author(s): Juniantito V, 井澤武史, 矢野遼, 桑村 充, 山手丈至
  • Organizer: 第27回日本毒性病理学会学術集会
  • Place of Presentation: 大阪
  • Year and Date: 20110130-31
• [Book] 教科書:動物病理学総論(第3 版) 第5 章:細胞の増殖と分化およびその異常 6.線維化, 瘢痕形成. 日本獣医学会編 (2013)
  • Author(s): 山手丈至
  • Total Pages: 88-90
  • Publisher: 文永堂