Steroid complement by the steroidogenic cell transplantation

• Project/Area Number: 16K09815
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Endocrinology
• Research Institution: Fukuoka University
• Principal Investigator: Tanaka Tomoko 福岡大学, 医学部, 助教 (10380528)
• Co-Investigator(Kenkyū-buntansha): 柳瀬 敏彦 福岡大学, 医学部, 教授 (30239818) ; 小玉 正太 福岡大学, 医学部, 教授 (90549338)
• Research Collaborator: Fukuda Takashi ; Muta Yoshimi
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2017: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: ステロイドホルモン補充 / 副腎不全 / NR5A1 / 分化誘導 / 移植療法 / ステロイドホルモン / 副腎皮質 / 細胞療法 / 再生医療 / 補充 / 移植・再生医療 / 内分泌学 / 分子生物学

Outline of Final Research Achievements

Hormone replacement therapy by cell transplantation is expected for replacement in response to physiological stimuli.We succeeded in generating steroid-producing cells from mesenchymal cells in vitro, and as a result of transplanting cells to adrenal insufficiency mice, survival time was extended and steroids in blood were detected. The mouse-derived cells did not induce the ACTH receptor by SF-1, and ACTH responsiveness of the transplanted mouse was not observed. Unlike in mice, ACTH responsiveness was observed when human-derived mesenchymal stem cells were used as the source, and in this study, MSCs were generated that turned on SF-1 expression in a drug-induced manner in order to implant them in immunodeficient adrenal insufficiency mice. It has become possible to adjust the required amount of transplanted cells. The hormone replacement effect by transplantation is under investigation.

Academic Significance and Societal Importance of the Research Achievements

副腎不全に対するステロイド補充療法は確立された療法であるが、一生涯の補充、生理的な補充は実現できない、副作用等といった問題点がある。細胞療法の利点の一つは、生体内の刺激に応答したホルモン補充である。動物実験で、副腎組織そのものの移植によるホルモン補充効果は報告されている。近年、体性幹細胞、ES細胞、iPS細胞をソースとしたステロイド産生細胞の誘導が細胞培養では成功しているが、これらの細胞を移植し、生体内での補充効果を検討した研究はない。我々は、マウス副腎不全モデルにおいて、ステロイド産生細胞の移植によるホルモン補充効果を証明し、今後の細胞療法開発の基盤となるデータを提供した。

Research Products

• [Journal Article] Circular IRE-type RNAs of the NR5A1 gene are formed in adrenocortical cells (2019)
  • Author(s): Ohe Kenji、Tanaka Tomoko、Horita Yuta、Harada Yoshihiro、Yamasaki Takafumi、Abe Ichiro、Tanabe Makito、Nomiyama Takashi、Kobayashi Kunihisa、Enjoji Munechika、Yanase Toshihiko
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 512 Issue: 1 Pages: 1-6
  • DOI: 10.1016/j.bbrc.2019.02.151
  • Peer Reviewed
• [Journal Article] Selective androgen receptor modulator, S42 has anabolic and anti-catabolic effects on cultured myotubes (2019)
  • Author(s): Muta Yoshimi、Tanaka Tomoko、Hamaguchi Yuriko、Hamanoue Nobuya、Motonaga Ryoko、Tanabe Makito、Nomiyama Takashi、Nawata Hajime、Yanase Toshihiko
  • Journal Title: Biochemistry and Biophysics Reports Volume: 17 Pages: 177-181
  • DOI: 10.1016/j.bbrep.2019.01.006
  • Peer Reviewed
• [Journal Article] Clinical Investigation of Adrenal Incidentalomas in Japanese Patients of the Fukuoka Region with Updated Diagnostic Criteria for Sub-clinical Cushing's Syndrome (2018)
  • Author(s): Abe, I., Sugimoto, K., Miyajima, T., Ide, T., Minezaki, M., Takeshita, K., Takahara, S., Nakagawa, M., Fujimura, Y., Kudo, T., et al.
  • Journal Title: Internal Medicine Volume: 57 Issue: 17 Pages: 2467-2472
  • DOI: 10.2169/internalmedicine.0550-17
  • NAID: 130007480015
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2018-09-01
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Selective Androgen Receptor Modulator S42 Suppresses Prostate Cancer Cell Proliferation. (2018)
  • Author(s): Kawanami, T., Tanaka, T., Hamaguchi, Y., Nomiyama, T., Nawata, H., and Yanase, T.
  • Journal Title: Endocrinology Volume: 159 Issue: 4 Pages: 1774-1792
  • DOI: 10.1210/en.2018-00099
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Expansion of transplanted islets in mice by co-transplantation with adipose tissue-derived mesenchymal stem cells (2018)
  • Author(s): Tanaka Tomoko、Kojima Daibo、Mera Toshiyuki、Matsumoto Masahito、Yasunami Yohichi、Yanase Toshihiko
  • Journal Title: Heliyon Volume: 4 Issue: 5 Pages: e00632-e00632
  • DOI: 10.1016/j.heliyon.2018.e00632
  • Peer Reviewed / Open Access
• [Journal Article] HMGA1a Induces Alternative Splicing of the Estrogen Receptor-αlpha Gene by Trapping U1 snRNP to an Upstream Pseudo-5′ Splice Site (2018)
  • Author(s): Ohe Kenji、Miyajima Shinsuke、Tanaka Tomoko et al.
  • Journal Title: Frontiers in Molecular Biosciences Volume: 5 Pages: 1-8
  • DOI: 10.3389/fmolb.2018.00052
  • Peer Reviewed
• [Journal Article] HMGA1a induces alternative splicing of estrogen receptor alpha in MCF-7 human breast cancer cells. (2018)
  • Author(s): Ohe, K., Miyajima, S., Abe, I., Tanaka, T., Hamaguchi, Y., Harada, Y., Horita, Y., Beppu, Y., Ito, F., Yamasaki, T., et al.
  • Journal Title: J Steroid Biochem Mol Biol Volume: 印刷中 Pages: 21-26
  • DOI: 10.1016/j.jsbmb.2018.04.007
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Asynchronous Rhythm of Ad4BP/SF-1 and Per2 Expression in Adrenal Tumors of Cushing’s Syndrome (2018)
  • Author(s): Ohe Kenji
  • Journal Title: Biomedical Journal of Scientific & Technical Research Volume: 7 Issue: 1 Pages: 1-7
  • DOI: 10.26717/bjstr.2018.07.001459
  • Peer Reviewed / Open Access
• [Journal Article] Prevalence of Cardiovascular Disease and Its Risk Factors in Primary Aldosteronism: A Multicenter Study in Japan. (2018)
  • Author(s): Ohno, Y., Sone, M., Inagaki, N., Yamasaki, T., Ogawa, O., Takeda, Y., Kurihara, I., Itoh, H., Umakoshi, H., Tsuiki, M., et al.
  • Journal Title: Hypertension Volume: 71 Issue: 3 Pages: 530-537
  • DOI: 10.1161/hypertensionaha.117.10263
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Spleen as an Optimal Site for Islet Transplantation and a Source of Mesenchymal Stem Cells. (2018)
  • Author(s): Sakata, N., Yoshimatsu, G., and Kodama, S.
  • Journal Title: Int J Mol Sci Volume: 19 Issue: 5 Pages: 1391-1391
  • DOI: 10.3390/ijms19051391
  • Peer Reviewed / Open Access
• [Journal Article] Accuracy of adrenal computed tomography in predicting the unilateral subtype in young patients with hypokalaemia and elevation of aldosterone in primary aldosteronism. (2018)
  • Author(s): Umakoshi, H., Ogasawara, T., Takeda, Y., Kurihara, I., Itoh, H., Katabami, T., Ichijo, T., Wada, N., Shibayama, Y., Yoshimoto, T., et al.
  • Journal Title: Clin Endocrinol (Oxf) Volume: 88 Issue: 5 Pages: 645-651
  • DOI: 10.1111/cen.13582
  • Peer Reviewed / Open Access
• [Journal Article] Significance of Computed Tomography and Serum Potassium in Predicting Subtype Diagnosis of Primary Aldosteronism. (2018)
  • Author(s): Umakoshi, H., Tsuiki, M., Takeda, Y., Kurihara, I., Itoh, H., Katabami, T., Ichijo, T., Wada, N., Yoshimoto, T., Ogawa, Y., et al.
  • Journal Title: J Clin Endocrinol Metab Volume: 103 Issue: 3 Pages: 900-908
  • DOI: 10.1210/jc.2017-01774
  • Peer Reviewed
• [Journal Article] Low glycated hemoglobin level is associated with severity of frailty in Japanese elderly diabetes patients. (2018)
  • Author(s): Yanagita, I., Fujihara, Y., Eda, T., Tajima, M., Yonemura, K., Kawajiri, T., Yamaguchi, N., Asakawa, H., Nei, Y., Kayashima, Y., et al.
  • Journal Title: J Diabetes Investig Volume: 9 Issue: 2 Pages: 419-425
  • DOI: 10.1111/jdi.12698
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] New diagnostic criteria of adrenal subclinical Cushing’s syndrome: opinion from the Japan Endocrine Society (2018)
  • Author(s): Yanase, T., Oki, Y., Katabami, T., Otsuki, M., Kageyama, K., Tanaka, T., Kawate, H., Tanabe, M., Doi, M., Akehi, Y., et al.
  • Journal Title: Endocrine Journal Volume: 65 Issue: 4 Pages: 383-393
  • DOI: 10.1507/endocrj.EJ17-0456
  • NAID: 130006727070
  • ISSN: 0918-8959, 1348-4540
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Frailty in elderly diabetes patients (2018)
  • Author(s): Yanase, T., Yanagita, I., Muta, K., and Nawata, H.
  • Journal Title: Endocrine Journal Volume: 65 Issue: 1 Pages: 1-11
  • DOI: 10.1507/endocrj.EJ17-0390
  • NAID: 130006321954
  • ISSN: 0918-8959, 1348-4540
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Postpartum hypothalamic adrenal insufficiency with remission: A rare case (2017)
  • Author(s): Akehi, Y., Hashimoto, Y., Meren, J., Tanabe, M., Nomiyama, T., and Yanase, T.
  • Journal Title: Endocrine Journal Volume: 64 Issue: 2 Pages: 157-162
  • DOI: 10.1507/endocrj.EJ16-0066
  • NAID: 130005397091
  • ISSN: 0918-8959, 1348-4540
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A higher score on the Aging Males’ Symptoms scale is associated with insulin resistance in middle-aged men (2017)
  • Author(s): Hamanoue, N., Tanabe, M., Tanaka, T., Akehi, Y., Murakami, J., Nomiyama, T., and Yanase, T.
  • Journal Title: Endocrine Journal Volume: 64 Issue: 5 Pages: 521-530
  • DOI: 10.1507/endocrj.EJ16-0619
  • NAID: 130005682812
  • ISSN: 0918-8959, 1348-4540
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Hepatectomy for Liver Metastases of Colorectal Cancer After Adoptive Chemoimmunotherapy Using Activated alphabeta T-cells. (2017)
  • Author(s): Ishii, F., Yoshida, Y., Yamauchi, Y., Aisu, N., Kojima, D., Mera, T., Kato, D., Tanaka, T., Naito, K., Yasumoto, K., et al.
  • Journal Title: Anticancer Res Volume: 37 Issue: 7 Pages: 3933-3939
  • DOI: 10.21873/anticanres.11776
  • Peer Reviewed
• [Journal Article] The spleen is an ideal site for inducing expansion of transplanted islet grafts in mice (2017)
  • Author(s): Itoh T, Nishinakamura H, Kumano K, Takahashi H, Kodama S.*
  • Journal Title: PLoS One Volume: 12(1) Issue: 1 Pages: e0170899-e0170899
  • DOI: 10.1371/journal.pone.0170899
  • Peer Reviewed / Open Access
• [Journal Article] Exendin-4, a Glucagonlike Peptide-1 Receptor Agonist, Attenuates Breast Cancer Growth by Inhibiting NF-kappaB Activation. (2017)
  • Author(s): Iwaya, C., Nomiyama, T., Komatsu, S., Kawanami, T., Tsutsumi, Y., Hamaguchi, Y., Horikawa, T., Yoshinaga, Y., Yamashita, S., Tanaka, T., et al.
  • Journal Title: Endocrinology Volume: 158 Issue: 12 Pages: 4218-4232
  • DOI: 10.1210/en.2017-00461
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] CD44 Promotes Inflammation and Extracellular Matrix Production During Arteriovenous Fistula Maturation. (2017)
  • Author(s): Kuwahara, G., Hashimoto, T., Tsuneki, M., Yamamoto, K., Assi, R., Foster, T.R., Hanisch, J.J., Bai, H., Hu, H., Protack, C.D., et al.
  • Journal Title: Arterioscler Thromb Vasc Biol Volume: 37 Issue: 6 Pages: 1147-1156
  • DOI: 10.1161/atvbaha.117.309385
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prolonged Inflation Technique Using a Scoring Balloon for Severe Calcified Lesion (2017)
  • Author(s): Otsuka, Y., Koyama, T., Imoto, Y., Katsuki, Y., Kawahara, M., Nakamura, K., Kodama, S., Noguchi, H., and Iwasaki, K.
  • Journal Title: International Heart Journal Volume: 58 Issue: 6 Pages: 982-987
  • DOI: 10.1536/ihj.16-605
  • NAID: 130006251711
  • ISSN: 1349-2365, 1349-3299
  • Peer Reviewed
• [Journal Article] Prescription of oral hypoglycemic agents for patients with type 2 diabetes mellitus: A retrospective cohort study using a Japanese hospital database. (2017)
  • Author(s): Tanabe, M., Motonaga, R., Terawaki, Y., Nomiyama, T., and Yanase, T.
  • Journal Title: J Diabetes Investig Volume: 8 Issue: 2 Pages: 227-234
  • DOI: 10.1111/jdi.12567
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A Modified Adenovirus Vector-Mediated Antibody Screening Method Identifies EphA2 as a Cancer Target. (2017)
  • Author(s): Tanaka, T., Yamada, H., Kuroki, M., Kodama, S., Tamura, K., and Takamatsu, Y.
  • Journal Title: Transl Oncol Volume: 10 Issue: 4 Pages: 476-484
  • DOI: 10.1016/j.tranon.2017.04.001
  • Peer Reviewed
• [Journal Article] Impact of metabolic disorders on prostate cancer growth: Androgen and insulin resistance perspectives. (2017)
  • Author(s): Yanase, T., Kawanami, T., Tanaka, T., Tanabe, M., and Nomiyama, T.
  • Journal Title: Reprod Med Biol Volume: 16 Issue: 3 Pages: 252-257
  • DOI: 10.1002/rmb2.12039
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Clinical Study on the Medical Value of Combination Therapy Involving Adoptive Immunotherapy and Chemotherapy for Stage IV Colorectal Cancer (COMVI Study). (2017)
  • Author(s): Yoshida, Y., Naito, M., Yamada, T., Aisu, N., Kojima, D., Mera, T., Tanaka, T., Naito, K., Yasumoto, K., Kamigaki, T., et al.
  • Journal Title: Anticancer Res Volume: 37 Issue: 7 Pages: 3941-3946
  • DOI: 10.21873/anticanres.11777
  • Peer Reviewed
• [Journal Article] Impact of metabolic disorders on prostate cancer growth: androgen and insulin resistance perspective (2017)
  • Author(s): Yanase T, Kawanami T, Tanaka T, Tanabe M, Nomiyama T
  • Journal Title: Reproductive Medicine and Biology Volume: in press
• [Journal Article] Syndrome of inappropriate antidiuretic hormone secretion in a case of olfactory neuroblastoma without anti-diuretic hormone immunoreactivity: A case report and review of the literature. (2016)
  • Author(s): Nakano T, Motoshita J, Sawada F, Okabe M, Tamae A, Hiramatsu S, Kodama S, Shiratsuchi H, Yasumatsu R, Nakashima T, Nakagawa T.
  • Journal Title: Auris Nasus Larynx. Volume: 16 Issue: 6 Pages: 30362-5
  • DOI: 10.1016/j.anl.2016.11.012
  • Peer Reviewed / Open Access
• [Journal Article] Augmented GH secretion and Stat3 phosphorylation in an aryl hydrocarbon receptor interacting protein (AIP)-disrupted somatotroph cell line. (2016)
  • Author(s): Fukuda T, Tanaka T, Hamaguchi Y, Kawanami T, Nomiyama T, Yanase T
  • Journal Title: PLOS ONE Volume: 11(10) Issue: 10 Pages: e0164131-e0164131
  • DOI: 10.1371/journal.pone.0164131
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] CX-4945 as a Potential Drug for Adrenocortical Carcinoma That Induces Multiple Exon-Skipping and Circular RNA of NR5A1 (2019)
  • Author(s): Tomoko Tanaka, Kenji Ohe, MD, Takashi Nomiyama, Toshihiko Yanase
  • Organizer: ENDO2019
• [Presentation] SF-1/Ad4BP誘導性ステロイド産生細胞におけるKCNJ5過剰発現の影響について (2017)
  • Author(s): 田中智子、野見山 崇、柳瀬敏彦
  • Organizer: 第90回日本内分泌学会学術総会
• [Presentation] SF-1/Ad4BP誘導性ステロイド産生細胞におけるKCNJ5過剰発現の影響について (2017)
  • Author(s): 田中智子、野見山 崇、柳瀬敏彦
  • Organizer: 第25回日本ステロイドホルモン学会学術集会
• [Presentation] APAのアルドステロン産生におけるKCNJ5の役割について (2016)
  • Author(s): 田中智子、野見山崇、柳瀬敏彦
  • Organizer: 第89回日本内分泌学会学術総会
  • Place of Presentation: 京都国際会館（京都）
  • Year and Date: 2016-04-21
• [Presentation] Steroid complement by the transplantation of SF-1/Ad4BP-induced steroidogenic cells in mice with adrenal insufficiency (2016)
  • Author(s): Tomoko Tanaka, Shohta Kodama and Toshihiko Yanase
  • Organizer: The Endocrine Society's 98th Annual Meeting and Expo
  • Place of Presentation: Boston
  • Year and Date: 2016-04-01
  • Int'l Joint Research
• [Patent(Industrial Property Rights)] ＮＲ５Ａ１発現抑制剤および医薬組成物 (2018)
  • Inventor(s): 柳瀬敏彦、大江賢治、田中智子
  • Industrial Property Rights Holder: 柳瀬敏彦、大江賢治、田中智子
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2018-038982
  • Filing Date: 2018
• [Patent(Industrial Property Rights)] AIPノックアウト成長ホルモン産生細胞株 (2016)
  • Inventor(s): 柳瀬敏彦、福田高士、田中智子
  • Industrial Property Rights Holder: 学校法人福岡大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2016-138981
  • Filing Date: 2016-07-13