Nerve regeneration promoting effect of adipose-derived

• Project/Area Number: 19K09072
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55010:General surgery and pediatric surgery-related
• Research Institution: The University of Tokushima
• Principal Investigator: TOKUNAGA Takuya 徳島大学, 病院, 特任准教授 (30448328)
• Co-Investigator(Kenkyū-buntansha): 柏原 秀也 徳島大学, 病院, 助教 (10548738) ; 齋藤 裕 徳島大学, 病院, 講師 (50548675) ; 西 正暁 徳島大学, 病院, 助教 (70464344) ; 吉川 幸造 徳島大学, 大学院医歯薬学研究部(医学域), 特任教授 (80448331)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 神経再生 / 術後排尿障害 / ADSC / HMGB1 / 脂肪由来幹細胞 / Schwann細胞 / 排尿障害 / mTORC1 / HGGB1

Outline of Research at the Start

今回我々は転写因子を調節するHigh morbidity group box 1(HMGB1)に着目した。部分酸化型HMGB1は傷害局所への炎症・免疫担当細胞の集積を誘導する一方、還元型HMGB1は幹細胞の細胞周期を進行させ組織再生に寄与する可能性が報告されている。今回、還元型HMGB1がmTORC1シグナルを介してADSCの神経再生効果を促進させるとの着想に至り、骨盤内臓神経損傷モデルにおける、臨床応用を目指した還元型HMGB1・ADSC投与による神経再生促進および排尿障害改善効果を確立する目的で本研究計画を立案した。

Outline of Final Research Achievements

In rectal surgery, postoperative dysuria due to pelvic nerve injury contributes to a decrease in quality of life. Although the nerve regeneration effect using adipose-derived mesenchymal stem cells (ADSC) has been reported, the differentiation process of ADSC is still unclear.
We succeeded in enhancing the expression of markers in Schwann cells and increasing the secretion of nerve growth factor by adding folic acid to the protocol for differentiation of ADSC into Schwann cells. Moreover, we newly generated three-dimensional (3D) SLC spheroids from ADSCs. The differentiation efficiency and the secretion of neurotrophic factors were enhanced in 3D SLCs compared with conventional SLCs. 3D SLCs had a better therapeutic effect on nerve regeneration after transplantation into the sciatic nerve injury mouse model. these cells have great potential and can be used in the clinical treatment of peripheral nerve injury.

Academic Significance and Societal Importance of the Research Achievements

進行下部直腸癌では根治性を保ちつつ、自律神経を温存する術式が普及している。しかし、腫瘍浸潤などにより神経合併切除を余儀なくされることがあり、根治性を確保すると弛緩性神経因性膀胱による排尿障害が起こり術後のQOLが著しく低下する。神経を完全切離した場合、有効な治療方法が乏しく幹細胞を用いた神経再生治療が確立され臨床応用されれば、画期的な治療法となる。

Research Products

• [Journal Article] The correlation of immunoscore and frailty in colorectal cancer. (2022)
  • Author(s): Nakao T, Shimada M, Yoshikawa K, Tokunaga T, Nishi M, Kashihara H, Takasu C, Wada Y, Yoshimoto T, Yamashita S, Iwakawa Y.
  • Journal Title: Int J Clin Oncol. Volume: 27 Pages: 528-537
  • Peer Reviewed
• [Journal Article] Usefulness of a stepwise training program for laparoscopic gastrectomy. (2022)
  • Author(s): Nishi M, Shimada M, Yoshikawa K, Tokunaga T, Kashihara H, Takasu C, Yoshimoto T, Iwahashi S.
  • Journal Title: Asian J Endosc Surg. Volume: 15 Pages: 121-127
  • Peer Reviewed
• [Journal Article] Strategy for laparoscopic repair of inguinal hernia after robot-assisted radical prostatectomy. (2022)
  • Author(s): Eto S, Yoshikawa K, Yoshimoto T, Takasu C, Kashihara H, Nishi M, Tokunaga T, Nakao T, Higashijima J, Iwata T, Shimada M.
  • Journal Title: Asian J Endosc Surg. Volume: 15 Pages: 155-161
  • Peer Reviewed
• [Journal Article] Epigallocatechin-gallate hinders metabolic coupling to suppress colorectal cancer malignancy through targeting aerobic glycolysis in cancer-associated fibroblasts. (2022)
  • Author(s): Chen S, Nishi M, Morine Y, Shimada M, Tokunaga T, Kashihara H, Takasu C, Yamada S, Wada Y.
  • Journal Title: Int J Oncol. Volume: 60 Pages: 19-19
  • Peer Reviewed
• [Journal Article] Propensity Score-Matched Analysis of the Short- and Long-Term Outcomes of Robotic Versus Laparoscopic Gastrectomy for Gastric Cancer (2022)
  • Author(s): Nishi M, Shimada M, Yoshikawa K, Takasu C, Wada Y, Tokunaga T, Nakao T, Kashihara H, Yoshimoto T, Yamashita S.
  • Journal Title: Ann Surg Oncol. Volume: -
  • Peer Reviewed
• [Journal Article] A Transabdominal Robotic Purse-String Suture Technique for Transanal Total Mesorectal Excision. (2021)
  • Author(s): Tokunaga T, Kashihara H, Higashijima J, Yoshikawa K, Nishi M, Takasu C, Eto S, Yoshimoto T, Shimada M.
  • Journal Title: Laparoendosc Adv Surg Tech A. Volume: 31 Pages: 937-941
  • Peer Reviewed
• [Journal Article] The influence and countermeasure of obesity in laparoscopic colorectal resection. (2021)
  • Author(s): Kashihara H, Shimada M, Yoshikawa K, Higashijima J, Tokunaga T, Nishi M, Takasu C, Yoshimoto T.
  • Journal Title: Ann Gastroenterol Surg. Volume: 5 Pages: 677-682
  • Peer Reviewed
• [Journal Article] The role of the immunoescape in colorectal cancer liver metastasis. (2021)
  • Author(s): Takasu C, Yamashita S, Morine Y, Yoshikawa K, Tokunaga T, Nishi M, Kashihara H, Yoshimoto T, Shimada M.
  • Journal Title: PLoS One. Volume: 16
  • Peer Reviewed
• [Journal Article] Usefulness of Diagnostic Staging Laparoscopy for Advanced Gastric Cancer. (2021)
  • Author(s): Yoshikawa K, Shimada M, Higashijima J, Tokunaga T, Nishi M, Takasu C, Kashihara H, Eto S, Yoshimoto T.
  • Journal Title: Am Surg. Volume: -
  • Peer Reviewed
• [Journal Article] Effect of TU-100 on Peyer's patches in a bacterial translocation rat model. (2021)
  • Author(s): Takasu C, Miyazaki K, Yoshikawa K, Nishi M, Tokunaga T, Kashihara H, Yoshimoto T, Ogawa H, Morine Y, Shimada M.
  • Journal Title: Ann Gastroenterol Surg. Volume: 5 Pages: 683-691
  • Peer Reviewed
• [Journal Article] Clinical analysis of postoperative venous thromboembolism in Japanese patients after colorectal cancer surgery. (2021)
  • Author(s): Yamashita S, Nishi M, Ikemoto T, Yoshikawa K, Higashijima J, Tokunaga T, Takasu C, Kashihara H, Eto S, Yoshimoto T, Shimada M.
  • Journal Title: Surg Today. Volume: 51 Pages: 1022-1027
  • Peer Reviewed
• [Journal Article] Lymphocyte to C-reactive protein ratio predicts long-term outcomes for patients with lower rectal cancer. (2021)
  • Author(s): Nishi M, Shimada M, Tokunaga T, Higashijima J, Yoshikawa K, Kashihara H, Takasu C, Ishikawa D, Wada Y, Eto S, Yoshimoto T.
  • Journal Title: World J Surg Oncol. Volume: 19 Pages: 201-201
  • Peer Reviewed
• [Journal Article] High Ligation of the Inferior Mesenteric Artery Induces Hypoperfusion of the Sigmoid Colon Stump During Anterior Resection. (2021)
  • Author(s): Higashijima J, Kono T, Shimada M, Sugitani A, Kashihara H, Takasu C, Nishi M, Tokunaga T, Yoshikawa K.
  • Journal Title: Front Surg. Volume: 8
  • Peer Reviewed
• [Journal Article] Robotic-assisted total gastrectomy in a patient with gastric cancer associated with situs inversus totalis: With video. (2021)
  • Author(s): Yoshimoto T, Yoshikawa K, Tokunaga T, Nishi M, Takasu C, Kashihara H, Nakasu C, Shimada M.
  • Journal Title: Asian J Endosc Surg. Volume: 14 Pages: 297-300
  • Peer Reviewed
• [Journal Article] The usefulness of intraoperative X-ray fluoroscopy in avoiding urethral injury during transanal total mesorectal excision. (2020)
  • Author(s): Tokunaga T, Higashijima J, Yoshikawa K, Nishi M, Kashihara H, Takasu C, Shimada M.
  • Journal Title: Asian J Endosc Surg. Volume: 13 Issue: 2 Pages: 242-245
  • DOI: 10.1111/ases.12717
  • Peer Reviewed
• [Journal Article] Intraoperative Thermal Imaging for Evaluating Blood Perfusion During Laparoscopic Colorectal Surgery. (2020)
  • Author(s): Tokunaga T, Shimada M, Higashijima J, Yoshikawa K, Nishi M, Kashihara H, Takasu C, Ishikawa D, Yoshimoto T.
  • Journal Title: Surg Laparosc Endosc Percutan Tech. Volume: - Issue: 3 Pages: 281-284
  • DOI: 10.1097/sle.0000000000000893
  • Peer Reviewed
• [Journal Article] The Role of Neutrophil-to-lymphocyte Ratio on the Effect of CRT for Patients With Rectal Cancer (2020)
  • Author(s): ISHIKAWA DAICHI、NISHI MASAAKI、TAKASU CHIE、KASHIHARA HIDEYA、TOKUNAGA TAKUYA、HIGASHIJIMA JUN、YOSHIKAWA KOZO、SHIMADA MITSUO
  • Journal Title: In Vivo Volume: 34 Issue: 2 Pages: 863-868
  • DOI: 10.21873/invivo.11850
  • Peer Reviewed
• [Journal Article] Bevacizumab-associated intestinal perforation and perioperative complications in patients receiving bevacizumab. (2020)
  • Author(s): Yoshimoto T, Yoshikawa K, Higashijima J, Miyatani T, Tokunaga T, Nishi M, Takasu C, Kashihara H, Takehara Y, Shimada M.
  • Journal Title: Ann Gastroenterol Surg. Volume: 4 Issue: 2 Pages: 151-155
  • DOI: 10.1002/ags3.12312
  • NAID: 120007174417
  • Peer Reviewed
• [Journal Article] Establishment of an evaluation system for non-technical skills in surgery : Surgeon and paramedical staff assessments (2020)
  • Author(s): Yoshikawa K, Shimada M, Higashijima J, Miyatani T, Tokunaga T, Nishi M, Takasu C, Kashihara H, Yoshimoto T, Iwata T.
  • Journal Title: The Journal of Medical Investigation Volume: 67 Issue: 1.2 Pages: 83-86
  • DOI: 10.2152/jmi.67.83
  • NAID: 130007839960
  • ISSN: 1343-1420, 1349-6867
  • Peer Reviewed
• [Journal Article] Impact of sidedness of colorectal cancer on tumor immunity. (2020)
  • Author(s): Takasu C, Nishi M, Yoshikawa K, Tokunaga T, Kashihara H, Yoshimoto T, Shimada M.
  • Journal Title: PLoS One. Volume: 15 Issue: 10 Pages: e0240408-e0240408
  • DOI: 10.1371/journal.pone.0240408
  • NAID: 120007001400
  • Peer Reviewed
• [Journal Article] Trans-abdominal Pre-peritoneal (TAPP) Inguinal Hernia Repair with Liquid-injection and Gauze Dissection (2020)
  • Author(s): Kashihara H, Shimada M, Yoshikawa K, Miyatani T, Tokunaga T, Nishi M, Takasu C, Yoshimoto T.
  • Journal Title: The Journal of Medical Investigation Volume: 67 Issue: 3.4 Pages: 271-273
  • DOI: 10.2152/jmi.67.271
  • NAID: 130007936859
  • ISSN: 1343-1420, 1349-6867
  • Peer Reviewed
• [Journal Article] Usefulness of an ICG fluorescence catheter system in TaTME for avoiding intraoperative urethral injury (2020)
  • Author(s): Ohta S, Nishi M, Tokunaga T, Yoshikawa K, Higashijima J, Miyatani T, Kashihara H, Takasu C, Ishikawa D, Shimada M.
  • Journal Title: The Journal of Medical Investigation Volume: 67 Issue: 3.4 Pages: 285-288
  • DOI: 10.2152/jmi.67.285
  • NAID: 130007936864
  • ISSN: 1343-1420, 1349-6867
  • Peer Reviewed
• [Journal Article] Transoral Anvil Delivery System With Tension-Free Method for Esophagojejunostomy After Laparoscopic Total Gastrectomy Prevents The Postoperative Stenosis. (2020)
  • Author(s): Yoshikawa K, Shimada M, Higashijima J, Tokunaga T, Nishi M, Takasu C, Kashihara H, Eto S, Yoshimoto T.
  • Journal Title: Am Surg. Volume: - Issue: 4 Pages: 1066-1068
  • DOI: 10.1177/0003134820973393
  • Peer Reviewed
• [Journal Article] Usefulness of blood flow evaluation by indocyanine green fluorescence system in laparoscopic anterior resection. (2019)
  • Author(s): Higashijima Jun、Shimada Mitsuo、Yoshikawa Kozo、Miyatani Tomohiko、Tokunaga Takuya、Nishi Masaaki、Kashihara Hideya、Takasu Chie
  • Journal Title: The Journal of Medical Investigation Volume: 66 Issue: 1.2 Pages: 65-69
  • DOI: 10.2152/jmi.66.65
  • NAID: 130007638729
  • ISSN: 1343-1420, 1349-6867
  • Year and Date: 2019-02-15
  • Peer Reviewed
• [Journal Article] Expression Level of MicroRNA-449a Predicts the Prognosis of Patients With Gastric Cancer (2019)
  • Author(s): ISHIKAWA DAICHI、YOSHIKAWA KOZO、TAKASU CHIE、KASHIHARA HIDEYA、NISHI MASAAKI、TOKUNAGA TAKUYA、HIGASHIJIMA JUN、SHIMADA MITSUO
  • Journal Title: Anticancer Research Volume: 40 Issue: 1 Pages: 239-244
  • DOI: 10.21873/anticanres.13945
  • Peer Reviewed
• [Journal Article] Usefulness of virtual three-dimensional image analysis in inguinal hernia as an educational tool (2019)
  • Author(s): Wada Y, Nishi M, Yoshikawa K, Higashijima J, Miyatani T, Tokunaga T, Takasu C, Kashihara H, Ishikawa D, Yoshimoto T, Shimada M
  • Journal Title: Surg Endosc. Volume: 34(5) Issue: 5 Pages: 1923-1928
  • DOI: 10.1007/s00464-019-06964-y
  • Peer Reviewed
• [Journal Article] The Effect of Laparoscopic Sleeve Gastrectomy on Obesity and Obesity-related Disease : the Results of 10 Initial Cases (2019)
  • Author(s): Kashihara Hideya、Shimada Mitsuo、Yoshikawa Kozo、Higashijima Jun、Miyatani Tomohiko、Tokunaga Takuya、Nishi Masaaki、Takasu Chie、Hamada Yasuhiro
  • Journal Title: The Journal of Medical Investigation Volume: 66 Issue: 3.4 Pages: 289-292
  • DOI: 10.2152/jmi.66.289
  • NAID: 130007733043
  • ISSN: 1343-1420, 1349-6867
  • Peer Reviewed
• [Journal Article] Duodenal-Jejunal Bypass Maintains Gut Permeability by Suppressing Gut Inflammation. (2019)
  • Author(s): Kashihara H, Shimada M, Yoshikawa K, Higashijima J, Miyatani T, Tokunaga T, Nishi M, Takasu C.
  • Journal Title: Obes Surg. Volume: 29 Pages: 2745-2749
  • Peer Reviewed
• [Journal Article] The Significance of MicroRNA-449a and Its Potential Target HDAC1 in Patients With Colorectal Cancer (2019)
  • Author(s): ISHIKAWA DAICHI、TAKASU CHIE、KASHIHARA HIDEYA、NISHI MASAAKI、TOKUNAGA TAKUYA、HIGASHIJIMA JUN、YOSHIKAWA KOZO、YASUTOMO KOJI、SHIMADA MITSUO
  • Journal Title: Anticancer Research Volume: 39 Issue: 6 Pages: 2855-2860
  • DOI: 10.21873/anticanres.13414
  • Peer Reviewed
• [Journal Article] Utility of virtual three-dimensional image analysis for laparoscopic gastrectomy conducted by trainee surgeons (2019)
  • Author(s): Nishi Masaaki、Yoshikawa Kozo、Higashijima Jun、Tokunaga Takuya、Takasu Chie、Kashihara Hideya、Ishikawa Daichi、Shimada Mitsuo
  • Journal Title: The Journal of Medical Investigation Volume: 66 Issue: 3.4 Pages: 280-284
  • DOI: 10.2152/jmi.66.280
  • NAID: 130007733039
  • ISSN: 1343-1420, 1349-6867
  • Peer Reviewed
• [Presentation] ホログラムと術中尿道造影を駆使した経会陰的直腸切断術（TpAPR） (2021)
  • Author(s): 徳永 卓哉
  • Organizer: 第121回日本外科学会定期学術集会
• [Presentation] TaTMEの手術手技と治療成績 (2021)
  • Author(s): 徳永 卓哉
  • Organizer: 第76回日本消化器外科学会総会
• [Presentation] 当科におけるTaTME手術手技と治療成績 (2021)
  • Author(s): 徳永 卓哉
  • Organizer: 第59回日本癌治療学会学術集会
• [Presentation] 直腸切断術に対するTransperineal approachの有用性 (2021)
  • Author(s): 徳永 卓哉
  • Organizer: 第83回日本臨床外科学会総会
• [Presentation] 直腸癌に対する経肛門的アプローチにおけるホログラムと尿道造影を併用した術中ナビゲーション (2021)
  • Author(s): 徳永 卓哉
  • Organizer: 第30回日本コンピュータ外科学会大会
• [Presentation] 他臓器合併切除を要する直腸癌に対するTrasaperineal abdominoperineal resection (2021)
  • Author(s): 徳永 卓哉
  • Organizer: 第34回日本内視鏡外科学会総会
• [Presentation] 直腸切断術TpTMEにおける術前VR・MRシミュレーションと術中尿道造影ナビゲーションの有用性 (2020)
  • Author(s): 徳永卓哉, 島田光生, 吉川幸造, 宮谷知彦, 西正暁, 齋藤裕, 柏原秀也, 高須千絵, 良元俊昭, 武原悠花子, 杉本真樹
  • Organizer: 第120回日本外科学会定期学術集会
• [Presentation] 術中尿道造影を併用したTpAPR手術手技 (2020)
  • Author(s): 徳永卓哉, 島田光生, 吉川幸造, 東島潤, 西正暁, 柏原秀也, 高須千絵, 江藤祥平, 良元俊昭
  • Organizer: 第82回日本臨床外科学会総会
• [Presentation] 経会陰的全直腸間膜切除術（TpTME）のピットフォール～術中尿道損傷の有用性～ (2020)
  • Author(s): Tokunaga T, Shimada M, Higashijima J, Yoshikawa K, Nishi M, Kashihara H, Takasu C, Eto S, Yoshimoto T
  • Organizer: JDDW2020
• [Presentation] TpTMEにおける前壁側剥離の工夫 ～術中尿道造影の有用性～ (2020)
  • Author(s): 徳永卓哉, 島田光生, 吉川幸造, 宮谷知彦, 西正暁, 柏原秀也, 高須千絵, 吉川雅登, 良元俊昭, 武原悠花子
  • Organizer: 第75回日本消化器外科学会総会
• [Presentation] 直腸切断術におけるTaTMEの工夫～尿道損傷回避のための術中尿道造影の有用性～ (2019)
  • Author(s): 徳永 卓哉, 島田光生, 吉川幸造, 東島潤, 宮谷知彦, 西正暁, 柏原秀也, 高須千絵, 良元俊昭
  • Organizer: 第119回日本外科学会定期学術集会
• [Presentation] Urethrography navigationを用いたTpTME手術手技 (2019)
  • Author(s): 徳永卓哉, 島田光生, 吉川幸造, 東島潤, 西正暁, 柏原秀也, 髙須千絵, 良元俊昭
  • Organizer: 第74回日本消化器外科学会総会
• [Presentation] The Usefulness of Intraoperative X-ray Fluoroscopy for Avoiding Urethral Injury in Transperineal total Mesorectal Excision (2019)
  • Author(s): Tokunaga T, Yoshikawa K, Miyatani T, Nishi M, Kashihara H, Takasu C, Yoshimoto T, Takehara Y, Shimada M
  • Organizer: 第31回IASGO
  • Int'l Joint Research
• [Presentation] TpTMEを安全に行うために ～前壁剥離時の術中尿道造影の有用性～ (2019)
  • Author(s): 徳永卓哉, 島田光生, 吉川幸造, 宮谷知彦, 西正暁, 柏原秀也, 高須千絵, 良元俊昭, 武原悠花子
  • Organizer: 第32回日本内視鏡外科学会総会