Therapeutic angiogenesis using autologous adipose-derived regenerative cells

• Project/Area Number: 26293184
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Nagoya University
• Principal Investigator: MUROHARA TOYOAKI 名古屋大学, 医学(系)研究科(研究院), 教授 (90299503)
• Co-Investigator(Kenkyū-buntansha): 新谷 理 名古屋大学, 医学(系)研究科(研究院), 寄附講座准教授 (20309777) ; 柴田 玲 名古屋大学, 医学(系)研究科(研究院), 寄附講座准教授 (70343689) ; 近藤 和久 名古屋大学, 医学(系)研究科(研究院), 助教 (90644659)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥16,640,000 (Direct Cost: ¥12,800,000、Indirect Cost: ¥3,840,000); Fiscal Year 2016: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2015: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2014: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
• Keywords: 再生医療 / 血管再生療法 / 幹細胞 / 四肢虚血 / 脂肪組織由来幹細胞 / 血管内皮細胞 / 皮下脂肪組織 / サイトカイン / 血管再生 / 皮下脂肪 / 間葉系幹細胞 / 虚血 / 細胞治療 / 重症四肢虚血 / 血管新生 / 脂肪組織由来再生細胞 / 心筋再生 / 細胞シート / 組織工学 / 心機能 / 虚血性心疾患 / 末梢動脈閉塞症 / 皮下脂肪由来間葉系前駆細胞 / 細胞シート工学

Outline of Final Research Achievements

Our final goal of this research series is to establish the clinical therapeutic angiogenesis in patients with critical limb ischemia manifestating rest pain and/or ischemic skin ulcer due to atherosclerotic disease, Burger's disease and connective tissue diseases such as scleroderma (PSS). To this end, we have established mouse, rat and rabbit model of hind limb ischemia, and we examined the effects of the implantation of autologous adipose-tissue derived regenerative cells (ADRCs), one of the mesenchymal stem cell class, on limb blood perfusion and angiogenesis in these animal models. We also tested the effects of combination of several drugs and ADRCs, H2S on angiogenesis in hind limb ischemia model. We have already performed clinical cases using ADRC injection to patients with critical limb ischemia, and examined the possible biomarkers that can predict the salutary efficacy of this procedure. For example, we are focusing on the role of VEGF-A165b and circulating CD34+ cells.

Research Products

• [Journal Article] Diallyl Trisulfide Augments Ischemia-Induced Angiogenesis via an Endothelial Nitric Oxide Synthase-Dependent Mechanism (2017)
  • Author(s): Hayashida R, Kondo K, Morita S, Unno K, Shintani S, Shimizu Y, Calvert JW, Shibata R, Murohara T.
  • Journal Title: Circulation Journal Volume: 81 Issue: 6 Pages: 870-878
  • DOI: 10.1253/circj.CJ-16-1097
  • NAID: 130005679693
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A dipeptidyl peptidase-4 inhibitor ameliorates hypertensive cardiac remodeling via angiotensin-II/sodium-proton pump exchanger-1 axis. (2016)
  • Author(s): Kawase H, Bando YK, Nishimura K, Aoyama M, Monji A, Murohara T.
  • Journal Title: J. Mol. Cell. Cardiol. Volume: 98 Pages: 37-47
  • DOI: 10.1016/j.yjmcc.2016.06.066
  • NAID: 120005895207
  • Peer Reviewed / Open Access
• [Journal Article] Cathepsin S Activity Controls Injury-Related Vascular Repair in Mice via the p38MAPK and PI3K－Akt/p-HDAC6 Signaling Pathway. (2016)
  • Author(s): Wu H, Cheng XW, Hu L, Takeshita K, Chen H, Du Q, Li X, Zhu E, Huang Z, Yisireyili M, Zhao G, Piao L, Inoue A, Jiang H, Lei Y, Zhang X, Liu S, Dai Q, Kuzuya M, Shi GP, and Murohara T.
  • Journal Title: Arteriosclerosis, Thromobosis, and Vascular Biology. Volume: 36(8) Issue: 8 Pages: 1549-1557
  • DOI: 10.1161/atvbaha.115.307110
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Sodium Sulfide Attenuates Ischemic-Induced Heart Failure by Enhancing Proteasomal Function in an Nrf2-Dependent Manner. (2016)
  • Author(s): Shimizu Y, Nicholson CK, Lambert JP, Barr LA, Kuek N, Herszenhaut D, Tan L, Murohara T, Hansen JM, Husain A, Naqvi N, Calvert JW.
  • Journal Title: Circ. Heart Fail. Volume: 9 Issue: 4
  • DOI: 10.1161/circheartfailure.115.002368
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Wnt11 Gene Therapy with Adeno-associated Virus 9 Improves Recovery from Myocardial Infarction by Modulating the Inflammatory Response (2016)
  • Author(s): Morishita Y, Kobayashi K, Klyachko E, Jujo K, Maeda K, Losordo DW, Murohara T.
  • Journal Title: Scientific Report Volume: 6 Issue: 1 Pages: 21705-21705
  • DOI: 10.1038/srep21705
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Dipeptidyl Peptidase 4 Inhibition Alleviates Shortage of Circulating Glucagon-Like Peptide-1 in Heart Failure and Mitigates Myocardial Remodeling and Apoptosis via the Exchange Protein Directly Activated by Cyclic AMP 1/Ras-Related Protein 1 Axis (2016)
  • Author(s): Aoyama M, Kawase H, Bando YK, Monji A, Murohara T
  • Journal Title: Circulation Heart Failure Volume: 9 Issue: 1
  • DOI: 10.1161/circheartfailure.115.002081
  • Peer Reviewed
• [Journal Article] Akt-dependent Girdin phosphorylation regulates repair processes after acute myocardial infarction. (2015)
  • Author(s): Hayano S, Takefuji M, Maeda K, Noda T, Ichimiya H, Kobayashi K, Enomoto A, Asai N, Takahashi M, Murohara T.
  • Journal Title: J Mol Cell Cardiol. Volume: 88 Pages: 55-63
  • DOI: 10.1016/j.yjmcc.2015.09.012
  • Peer Reviewed / Open Access
• [Journal Article] Girdin/GIV regulates transendothelial permeability by controlling VE-cadherin trafficking through the small GTPase, R-Ras. (2015)
  • Author(s): Ichimiya H, Maeda K, Enomoto A, Weng L, Takahashi M, Murohara T.
  • Journal Title: Biochem Biophys Res Commun. Volume: 461 Issue: 2 Pages: 260-267
  • DOI: 10.1016/j.bbrc.2015.04.012
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] New endoplasmic reticulum stress regulator, gipie, regulates the survival of vascular smooth muscle cells and the neointima formation after vascular injury. (2015)
  • Author(s): Noda T, Maeda K, Hayano S, Asai N, Enomoto A, Takahashi M, Murohara T
  • Journal Title: Arterioscler Thromb Vasc Biol. Volume: 35 Issue: 5 Pages: 1246-1253
  • DOI: 10.1161/atvbaha.114.304923
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Therapeutic Angiogenesis by Autologous Adipose-Derived Regenerative Cells: Comparison With Bone Marrow Mononuclear Cells. (2014)
  • Author(s): 31.Hao CN, Shintani S, Shimizu Y, Kondo K, Ishii M, Wu H, Murohara T.
  • Journal Title: Am J Physiol Heart Circ Physiol. Volume: 307 Issue: 6 Pages: H869-H879
  • DOI: 10.1152/ajpheart.00310.2014
  • Peer Reviewed
• [Journal Article] Multilayered adipose-derived regenerative cell sheets created by a novel magnetic tissue engineering method for myocardial infarction. (2014)
  • Author(s): Ishii M, Shibata R, Shimizu Y, Yamamoto T, Kondo K, Inoue Y, Ouchi N, Tanigawa T, Kanemura N, Ito A, Honda H, Murohara T.
  • Journal Title: Int J Cardiol. Volume: 175 Issue: 3 Pages: 545-553
  • DOI: 10.1016/j.ijcard.2014.06.034
  • Peer Reviewed / Open Access
• [Journal Article] Neuron-derived neurotrophic factor functions as a novel modulator that enhances endothelial cell function and revascularization processes. (2014)
  • Author(s): Ohashi K, Enomoto T, Joki Y, Shibata R, Ogura Y, Kataoka Y, Shimizu Y, Kambara T, Uemura Y, Yuasa D, Matsuo K, Hayakawa S, Hiramatsu-Ito M, Murohara T, Ouchi N.
  • Journal Title: Journal of Biological Chemistry Volume: 289 Issue: 20 Pages: 14132-14144
  • DOI: 10.1074/jbc.m114.555789
  • Peer Reviewed
• [Journal Article] Cathepsin K-mediated Notch1 activation contributes to neovascularization in response to hypoxia (2014)
  • Author(s): Jiang H, Cheng XW, Shi GP, Hu L, Inoue A, Yamamura Y, Wu H, Takeshita K, Li X, Huang Z, Song H, Asai M, Hao CN, Unno K, Koike T, Oshida Y, Okumura K, Murohara T, Kuzuya M
  • Journal Title: Nat Commun Volume: 5 Issue: 1 Pages: 3838-3838
  • DOI: 10.1038/ncomms4838
  • Peer Reviewed
• [Journal Article] An antiangiogenic isoform of VEGF-A contributes to impaired vascularization in peripheral artery disease. (2014)
  • Author(s): Kikuchi R, Nakamura K, MacLauchlan S, Ngo DT, Shimizu I, Fuster JJ, Katanasaka Y, Yoshida S, Qiu Y, Yamaguchi TP, Matsushita T, Murohara T, Gokce N, Bates DO, Hamburg NM, Walsh K
  • Journal Title: Nat Med Volume: 20(12) Issue: 12 Pages: 1464-71
  • DOI: 10.1038/nm.3703
  • Peer Reviewed
• [Presentation] Therapeutic angiogenesis by adipose tissue-derived regenerative cells. (2016)
  • Author(s): Kondo K, Shibata R, Hayashida R, Shintani S, Murohara T.
  • Organizer: Scientific Session, American Heart Association 2016
  • Place of Presentation: New Orleans, LA, USA
  • Year and Date: 2016-11-12
  • Int'l Joint Research
• [Presentation] Effect of the aging-accelerating Werner protein on glucose metabolism and myocardial remodeling (2016)
  • Author(s): Kawase H, Bando Y, Murohara T.
  • Organizer: European Society of Cardiology 2016
  • Place of Presentation: Roma, Italy
  • Year and Date: 2016-08-27
  • Int'l Joint Research
• [Presentation] Correlations between geriatric nutritional risk index and peripheral artery disease in elderly coronary artery disease patients (2016)
  • Author(s): Suzuki S, Ishii H, Murohara T.
  • Organizer: European Society of Cardiology 2016
  • Place of Presentation: Roma, Italy
  • Year and Date: 2016-08-27
  • Int'l Joint Research
• [Presentation] C1q/TNF-related protein 1 reduces vascular smooth muscle cell growth and meointimal thickening after vascular injury. (2016)
  • Author(s): Ogawa H, Shibata R, Murohara T, Ouchi N.
  • Organizer: European Society of Cardiology 2016
  • Place of Presentation: Roma, Italy
  • Year and Date: 2016-08-27
  • Int'l Joint Research
• [Presentation] Incretin ameliorates diabetic microangiopathy in heart via suppression of nonanoic acid, a naturally-occurring saturated fatty acid, via activation of AMPK pathway (2016)
  • Author(s): Nishimura K, Bando Y, Murohara T.
  • Organizer: European Society of Cardiology 2016
  • Place of Presentation: Roma, Italy
  • Year and Date: 2016-08-27
  • Int'l Joint Research
• [Presentation] The therapeutic potential of adipose-derived regenerative cell sheets created by a novel magnetite tissue engineering method (2016)
  • Author(s): Rei Shibata
  • Organizer: 第80回日本循環器学会総会
  • Place of Presentation: 仙台国際センター（宮城県仙台市 ）
  • Year and Date: 2016-03-18
  • Invited
• [Presentation] Therapeutic angiogenesis by iPS cells (2015)
  • Author(s): Rei Shibata, Toyoaki Murohara
  • Organizer: 第79回日本循環器学会総会
  • Place of Presentation: 大阪国際会議場（大阪府大阪市）
  • Year and Date: 2015-04-24
  • Invited
• [Presentation] Therapeutic angiogenesis by adipose-derived regenerative cells (2014)
  • Author(s): Rei Shibata, Kazuhisa Kondo, Satoshi Shintani, Toyoaki Murohara
  • Organizer: 第31回国際心臓研究学会（ISHR）日本部会
  • Place of Presentation: 愛知県名古屋市 愛知県産業労働 センター
  • Year and Date: 2014-11-28 – 2014-11-29
• [Presentation] Translational Research in Cardiovascular Medicine: Vascular regeneration therapy (2014)
  • Author(s): Toyoaki Murohara
  • Organizer: 第31回国際心臓研究学会（ISHR）日本部会
  • Place of Presentation: 愛知県名古屋市 愛知県産業労働 センター
  • Year and Date: 2014-11-28 – 2014-11-29
• [Presentation] Therapeutic Angiogenesis by Cell Transplantation (2014)
  • Author(s): Satoshi Shintani
  • Organizer: 第31回国際心臓研究学会（ISHR）日本部会
  • Place of Presentation: 愛知県名古屋市 愛知県産業労働 センター
  • Year and Date: 2014-11-28 – 2014-11-29
• [Presentation] The Comparison of Adipose Derived Regenerative Cells and Bone Marrow Mononuclear Cells as Transplanted Cells for Therapeutic Angiogenesis. (2014)
  • Author(s): Shintani S, Hao C, Shimizu Y, Kondo K, Murohara T.
  • Organizer: BCVS, American Heart Association
  • Place of Presentation: Las Vegas, Nevada, USA
  • Year and Date: 2014-07-14 – 2014-07-17
• [Presentation] Cell-based therapeutic angiogenesis for critical limb ischemia (2014)
  • Author(s): Toyoaki Murohara
  • Organizer: The 18th International Vascular Biology Meeting 2014 (IVBM 2014)
  • Place of Presentation: 京都府京都市 京都市勧業館
  • Year and Date: 2014-04-14 – 2014-04-17
• [Book] Therapeutic Angiogenesis (2017)
  • Author(s): Toyoaki Murohara, Kazuhisa Kondo
  • Publisher: Springer
• [Book] Annual Review 2015 循環器 (2015)
  • Author(s): 坂東泰子、室原豊明
  • Total Pages: 318
  • Publisher: 中外医学社
• [Book] EBM 循環器疾患の治療 (2015)
  • Author(s): 坂東泰子、室原豊明
  • Total Pages: 472
  • Publisher: 中外医学社
• [Book] 循環器疾患最新の治療2014-2015 (2014)
  • Author(s): 吉川大治、室原豊明
  • Total Pages: 528
  • Publisher: 南江堂
• [Book] 専門医のための循環器病学 (2014)
  • Author(s): 室原豊明
  • Total Pages: 582
  • Publisher: 医学書院