Molecular Mechanism to Maintain Adipose-derived Stem Cells in an Undifferentiated and quiescent State

• Project/Area Number: 26860041
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Biological pharmacy
• Research Institution: University of Shizuoka
• Principal Investigator: Yamaguchi Masahiko 静岡県立大学, 薬学部, 助教 (00632639)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2015: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 組織幹細胞 / 脂肪組織 / 核内受容体 / GPCR / 脂肪分化 / Gpr3 / Nr4a / cAMP / 間葉系幹細胞

Outline of Final Research Achievements

Proliferation and differentiation of adipose-derived stem cells (ADSCs) into mature adipocytes associate with development of obesity. Nutritional stimulation induces ADSCs proliferation and differentiation, but molecular mechanisms to maintain ADSCs in an undifferentiated and quiescent state are largely unknown. To identify genes essential for the mechanism, microarray analysis was performed using freshly isolated murine ADSCs and 4-day cultured ADSCs (preadipocytes). In ADSCs, 312 probes of transcriptional factors were up-regulated and we focused on nuclear receptor 4a subfamily (Nr4a1, Nr4a2, and Nr4a3), which play diverse roles including metabolic processes. We overexpressed each Nr4a receptor into ADSCs to evaluate the functions of differentiation. Nr4a over-expression decreased marker of adipogenic factors, which is altered by application of cAMP analogue. These data suggested that Nr4a1/2/3 inhibited cell proliferation and adipogenesis in a cAMP-dependent manner.

Research Products

• [Journal Article] Hypotonic stress-induced down-regulation of claudin-1 and -2 mediated by dephosphorylation and clathrin-dependent endocytosis in renal tubular epithelial cells (2016)
  • Author(s): Fujii N, Matsuo Y, Matsunaga T, Endo S, Sakai H, Yamaguchi M, Yamazaki Y, Sugatani J, Ikari A
  • Journal Title: Journal of Biological Chemistry Volume: 291 Issue: 47 Pages: 24787-24799
  • DOI: 10.1074/jbc.m116.728196
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Claudin-18 inhibits cell proliferation and motility mediated by inhibition of phosphorylation of PDK1 and Akt in human lung adenocarcinoma A549 cells (2016)
  • Author(s): Shun Shimobaba, Saeko Taga, Risa Akizuki, Asami Hichino, Satoshi Endo, Toshiyuki Matsunaga, Ryo Watanabe, Masahiko Yamaguchi, Yasuhiro Yamazaki, Junko Sugatani, Akira Ikari
  • Journal Title: Biochimica et Biophysica Acta Volume: 1863 Issue: 6 Pages: 1170-1178
  • DOI: 10.1016/j.bbamcr.2016.02.015
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Calcitonin Receptor Signaling Inhibits Muscle Stem Cells from Escaping the Quiescent State and the Niche (2015)
  • Author(s): Yamaguchi M, Watanabe Y, Ohtani T, Uezumi A, Mikami N, Nakamura M, Sato T, Ikawa M, Hoshino M, Tsuchida K, Miyagoe-Suzuki Y, Tsujikawa K, Takeda S, Yamamoto H, Fukada S
  • Journal Title: Cell Rep Volume: 13(2) Issue: 2 Pages: 302-314
  • DOI: 10.1016/j.celrep.2015.08.083
  • NAID: 120006957413
  • Peer Reviewed / Open Access
• [Journal Article] Evidence of Notch-Hesr-Nrf2 Axis in Muscle Stem Cells, but Absence of Nrf2 Has No Effect on Their Quiescent and Undifferentiated Stat (2015)
  • Author(s): Yamaguchi M, Murakami S, Yoneda T, Nakamura M, Zhang L, Uezumi A, Fukuda S, Kokubo H, Tsujikawa K, Fukada S
  • Journal Title: PLoS One Volume: 10(9) Issue: 9 Pages: 138517-138531
  • DOI: 10.1371/journal.pone.0138517
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Doublecortin marks a new population of transiently amplifying muscle progenitor cells and is required for myofiber maturation during skeletal muscle regeneration (2015)
  • Author(s): Ogawa R, Ma Y, Yamaguchi M, Ito T, Watanabe Y, Ohtani T, Murakami S, Uchida S, De Gaspari P, Uezumi A, Nakamura M, Miyagoe-Suzuki Y, Tsujikawa K, Hashimoto N, Braun T, Tanaka T, Takeda S, Yamamoto H, Fukada S
  • Journal Title: Development Volume: 142 Issue: 1 Pages: 51-61
  • DOI: 10.1242/dev.112557
  • Peer Reviewed / Open Access
• [Journal Article] A platelet-activating factor (PAF) receptor deficiency exacerbates diet-induced obesity but PAF/PAF receptor signaling does not contribute to the development of obesity-induced chronic inflammation. (2015)
  • Author(s): Yamaguchi, M., Matsui, M., Higa, R., Yamazaki, Y., Ikari, A., Miyake, M., Miwa, M., Ishii, S., Sugatani, J., and Shimizu, T.
  • Journal Title: Biochem. Pharmacol. Volume: 93 Issue: 4 Pages: 482-495
  • DOI: 10.1016/j.bcp.2014.12.022
  • Peer Reviewed / Open Access
• [Journal Article] Antiobese function of platelet-activating factor : increased adiposity in platelet-activating factor receptor-deficient mice with age (2014)
  • Author(s): Sugatani, J., Sadamitsu, S., Yamaguchi, M., Yamazaki, Y., Higa, R., Hattori, Y., Uchida, T., Ikari, A., Sugiyama, W., Watanabe, T., Ishii, S., Miwa, M., and Shimizu, T
  • Journal Title: FASEB J Volume: 28 Issue: 1 Pages: 440-452
  • DOI: 10.1096/fj.13-233262
  • Peer Reviewed / Open Access
• [Presentation] ヒトiPS細胞とセルモーションイメージングを用いた心臓部位特異的な薬効評価法の基盤技術の開発 (2017)
  • Author(s): 鈴木 結衣、高橋 健太郎、児玉 昌美、諫田 泰成、山口 賢彦、早川 智広、松井 恵理子、古川 哲史、黒川 洵子
  • Organizer: 第137回 日本薬学会年会
  • Place of Presentation: 仙台
  • Year and Date: 2017-03-27
• [Presentation] Roles of nuclear receptor 4a family in maintenance of murine adipose-derived stem cells. (2017)
  • Author(s): Masahiko Yamaguchi, Hiroki Ishimura, Kenta Ito, Yui Shuzuki, Yasuhiro Yamazaki, Junko Sugatani, and Junko Kurokawa.
  • Organizer: 第90回日本薬理学会大会
  • Place of Presentation: 長崎
  • Year and Date: 2017-03-17
• [Presentation] セルモーションイメージングを用いたヒトiPS細胞由来心筋細胞における心臓部位特異的な薬効評価 (2017)
  • Author(s): 鈴木 結衣, 高橋 健太郎,児玉 昌美, 諌田 泰成, 山口 賢彦, 早川 智広, 松井 恵理子, 古川 哲史, 黒川 洵子
  • Organizer: 日本安全性薬理研究会
  • Place of Presentation: 東京
  • Year and Date: 2017-02-06
• [Presentation] Nuclear receptor 4a familyによる脂肪幹細胞の未分化性および静止期維持機構の解明 (2016)
  • Author(s): 山口賢彦、須山大輔、石村裕樹、鈴木結衣、嘉山節子、内山瑛美、山崎泰広、五十里彰、菅谷純子
  • Organizer: 第39回日本分子生物学会
  • Place of Presentation: 横浜
  • Year and Date: 2016-11-30
• [Presentation] A cAMP-dependent signaling pathway is involved in the canalicular trafficking of the ATP-binding cassette (ABC) transporter g5/g8 in mice liver. (2016)
  • Author(s): Masashi Aono, Yasuhiro Yamazaki, Masahiko Yamaguchi, Junko Sugatani
  • Organizer: The 3rd International Conference on Pharma and Food
  • Place of Presentation: 静岡
  • Year and Date: 2016-11-18
  • Int'l Joint Research
• [Presentation] The roles of nuclear receptor 4a family in maintenance of adipose-derived stem cells. (2016)
  • Author(s): Masahiko Yamaguchi, Daisuke Suyama, Setuko Kayama, Yasuhiro Yamazaki
  • Organizer: The 3rd International Conference on Pharma and Food
  • Place of Presentation: 静岡
  • Year and Date: 2016-11-18
  • Int'l Joint Research
• [Presentation] The molecular mechanism to maintain adipo-derived stem cell homeostasis through G-protein-coupled receptors. (2016)
  • Author(s): Mana Takahashi, Emi Uchiyama, Daisuke Suyama, Yasuhiro Yamazaki, and Masahiko Yamaguchi
  • Organizer: The 3rd International Conference on Pharma and Food
  • Place of Presentation: 静岡
  • Year and Date: 2016-11-18
  • Int'l Joint Research
• [Presentation] 脂肪組織由来間葉系幹細胞を維持するNuclear receptor 4a familyの機能解析 (2016)
  • Author(s): 須山大輔、山口賢彦、石村裕樹、鈴木結衣、内山瑛美、嘉山節子、山崎泰広、五十里彰、菅谷純子
  • Organizer: 第63回中部日本生理学会
  • Place of Presentation: 岡崎
  • Year and Date: 2016-11-04
• [Presentation] 高脂肪食負荷マウスの薬物代謝酵素/トランスポーター発現変動におけるPXR-シャペロン蛋白質経路の作用解析 (2016)
  • Author(s): 宮武将之、山口賢彦、山崎泰広、五十里彰、菅谷純子
  • Organizer: 第63回中部日本生理学会
  • Place of Presentation: 岡崎
  • Year and Date: 2016-11-04
• [Presentation] Protein kinase A が関与するABCトランスポーターの肝毛細胆管膜移行メカニズムの解析 (2016)
  • Author(s): 山崎泰広、青野雅士、小野千夏、上野歩美、山口賢彦、五十里彰、菅谷純子
  • Organizer: 第89回日本生化学会大会
  • Place of Presentation: 仙台
  • Year and Date: 2016-09-25
• [Presentation] 高脂肪食摂餌マウスの肝臓・腸管薬物代謝酵素/トランスポーターの発現変動とその機序について (2016)
  • Author(s): 宮武将之、山口賢彦、山崎泰広、菅谷純子
  • Organizer: 内外環境応答・代謝酵素研究会
  • Place of Presentation: 静岡
  • Year and Date: 2016-09-18
• [Presentation] 脂肪組織由来間葉系幹細胞の脂肪分化におけるGpr3の機能解析 (2016)
  • Author(s): 須山大輔、内山瑛美、石村裕樹、山口賢彦、山崎泰広、五十里彰、菅谷純子
  • Organizer: 第62回日本薬学会東海支部総会・大会
  • Place of Presentation: 愛知
  • Year and Date: 2016-07-09
• [Presentation] 脂肪組織由来間葉系幹細胞を維持する遺伝子の解析 (2016)
  • Author(s): 山口賢彦、須山大輔、内山瑛美、嘉山節子、山崎泰広、五十里彰、菅谷純子
  • Organizer: 第62回日本薬学会東海支部総会・大会
  • Place of Presentation: 愛知
  • Year and Date: 2016-07-09
• [Presentation] 肝臓へのコレステロール蓄積はコレステロールトランスポーターAbcg5/Abcg8の毛細胆管膜への移行を促進させる (2016)
  • Author(s): 山崎泰広、村田柚季、青野雅士、山口賢彦、五十里彰、菅谷純子
  • Organizer: 第11回トランスポーター研究会年会
  • Place of Presentation: 京都
  • Year and Date: 2016-07-02
• [Presentation] コレステロールトランスポーターの毛細胆管膜局在化機構の解析 (2016)
  • Author(s): 青野雅士、山崎泰広、村田柚季、小野千夏、上野歩美、山口賢彦、五十里彰、菅谷純子
  • Organizer: 第80回日本生化学会中部支部例会・シンポジウム
  • Place of Presentation: 岐阜
  • Year and Date: 2016-05-21
• [Presentation] 新規in vivo解析系を用いたLiver X receptorの動態解析 (2016)
  • Author(s): 佐々木里菜、山崎泰広、佐野一生、山口賢彦、五十里彰、菅谷純子
  • Organizer: 第80回日本生化学会中部支部例会・シンポジウム
  • Place of Presentation: 岐阜
  • Year and Date: 2016-05-21
• [Presentation] 脂肪組織由来間葉系幹細胞で高発現する Nr4a1/2/3 の機能解析 (2016)
  • Author(s): 山口 賢彦、嘉山 節子、内山 瑛美、須山 大輔、高橋 茉那、石村 裕樹、山崎 泰広、五十里 彰、菅谷 純子
  • Organizer: 日本薬学会第136年会
  • Place of Presentation: 横浜
  • Year and Date: 2016-03-27
• [Presentation] Nuclear receptor 4a familyが関わる脂肪幹細胞の細胞分化進行抑制機構の解析 (2015)
  • Author(s): 嘉山節子、山口賢彦、山崎泰広、五十里彰、菅谷純子
  • Organizer: 第38回日本分子生物学会年会・第88回日本生化学会大会合同大会
  • Place of Presentation: 神戸
  • Year and Date: 2015-12-01
• [Presentation] 脂肪組織由来間葉系幹細胞に高発現するGpr3を介した脂肪分化調節機構の解明 (2015)
  • Author(s): 内山瑛美、山口賢彦、須山大輔、山崎泰広、五十里彰、菅谷純子
  • Organizer: 第38回日本分子生物学会年会・第88回日本生化学会大会合同大会
  • Place of Presentation: 神戸
  • Year and Date: 2015-12-01
• [Presentation] 脂肪幹細胞において高発現する Nuclear receptor 4a family の機能解明 (2015)
  • Author(s): 嘉山節子、山口賢彦、内山瑛美、山崎泰広、五十里彰、菅谷純子
  • Organizer: 第79回日本生化学会中部支部例会・シンポジウム
  • Place of Presentation: 松本
  • Year and Date: 2015-05-23
• [Presentation] A platelet-activating factor (PAF) receptor deficiency exacerbates diet-induced obesity and PAF/PAF receptor signaling up-regulates an energy expenditure inducer in adipocytes. (2015)
  • Author(s): Masahiko Yamaguchi, Masakazu Matsui, Yasuhiro Yamazaki, Akira Ikari, Masao Miwa, Satoshi Ishii, Takao Shimizu, Junko Sugatani
  • Organizer: 6th International Conference on PLA2 and lipid mediators
  • Place of Presentation: 東京
  • Year and Date: 2015-02-10
• [Presentation] 間葉系幹細胞の未分化状態維持に関わる分子機構の解析 (2014)
  • Author(s): 山口賢彦、嘉山節子、内山瑛美、山崎泰広、五十里彰、菅谷純子
  • Organizer: 第37回日本分子生物学会
  • Place of Presentation: 横浜
  • Year and Date: 2014-11-27
• [Presentation] Platelet-Activating Factor Receptor Deficiency Exacerbates Diet-induced Obesity and Glucose Metabolism Disorders. (2014)
  • Author(s): Masahiko Yamaguchi, Masakazu Matsui, Yasuhiro Yamazaki, Akira Ikari and Junko Sugatani
  • Organizer: The 2nd International Conference on Pharma and Food
  • Place of Presentation: 静岡
  • Year and Date: 2014-11-06
• [Presentation] The role of G-protein-coupled receptors highly expressed in adipose-derived stem cells. (2014)
  • Author(s): Emi Uchiyama, Masahiko Yamaguchi, Yasuhiro Yamazaki, Akira Ikari and Junko Sugatani
  • Organizer: The 2nd International Conference on Pharma and Food
  • Place of Presentation: 静岡
  • Year and Date: 2014-11-06
• [Presentation] 未分化間葉系幹細胞機能維持に関わる分子機構の解析 (2014)
  • Author(s): 内山瑛美、山口賢彦、山崎泰広、五十里彰、菅谷純子
  • Organizer: 第60回日本薬学会東海支部 総会・大会
  • Place of Presentation: 三重
  • Year and Date: 2014-07-05
• [Presentation] 脂肪組織の慢性炎症化過程に関わる血小板活性化因子の機能解析 (2014)
  • Author(s): 山口賢彦、比嘉涼子、山崎泰広、五十里彰、石井聡、三輪匡男、清水孝雄、菅谷純子
  • Organizer: 第56回日本脂質生化学会
  • Place of Presentation: 大阪
  • Year and Date: 2014-06-07
• [Remarks] 静岡県立大学薬学部 生体情報分子解析学分野HP
  • URL: http://w3pharm.u-shizuoka-ken.ac.jp/rinsho/
• [Remarks] 静岡県立大学薬学部 医療薬学大講座 生体情報分子解析学分野
  • URL: http://w3pharm.u-shizuoka-ken.ac.jp/rinsho/