Researchers Database

teratani takumi

    Assistant Professor
Last Updated :2021/12/04

Researcher Information


J-Global ID

Research Interests

  • 機能性食品   細胞移植   糖尿病   再生医療   間葉系幹細胞   Annexin II   S100蛋白   腎癌   脳型脂肪酸結合蛋白   TdRPase   エネルギー産生   S100A10   腎がん   バイオマーカー   B-FABP   脳型遊離脂肪酸結合蛋白   FABP7   低酸素バイオロジー   腫瘍学   

Research Areas

  • Life sciences / Food sciences
  • Life sciences / Environmental and pharmaceutical development resources
  • Life sciences / Biomaterials
  • Life sciences / General surgery, pediatric surgery
  • Life sciences / Urology

Academic & Professional Experience

  • 2011  Jichi Medical UniversitySchool of Medicine講師

Published Papers

  • Takumi Teratani, Naoya Kasahara, Tetsuo Ijichi, Yasuhiro Fujimoto, Yasunaru Sakuma, Naohiro Sata, Joji Kitayama
    Amino Acids 0939-4451 2021/10 [Refereed]
    AbstractPolyamines are important to the survival and activation of organs and tissues via a homeostatic cell-metabolic process, and the polyamine content in cytoplasm decreases with aging. Decreases in cellular polyamine have been known to augment mutagenesis and cell death. Thus, supplementary polyamine in food is important to the prevention of aging. Here we show the anti-aging effects of oral intake of polyamine using luciferase-transgenic rats. Healthy rats, 10–12 weeks old, were given foods containing 0.01% and 0.1% (w/w) of polyamine, as compared a control food without polyamine, for 4 weeks. Using a bioimaging system, the photon intensities seen in the whole bodies and livers of rats consuming 0.1% of polyamine in food were stronger than those in rats consuming 0.01% and 0% of polyamine. However, there were no differences between groups in other characteristics, such as liver damage and body weight. In conclusion, we found that polyamine intake can activate cells throughout the whole body, providing an anti-aging effect.
  • Yoshihiko Kono, Ryo Inoue, Takumi Teratani, Mineyuki Tojo, Yuko Kumagai, So Morishima, Koji Koinuma, Alan Kawarai Lefor, Joji Kitayama, Naohiro Sata, Hisanaga Horie
    Digestion 1 - 9 0012-2823 2021/10 [Refereed]
    <b><i>Background/Aims:</i></b> Recent studies have demonstrated that the populations of several microbes are significantly increased in fecal samples from patients with colorectal cancer (CRC), suggesting their involvement in the development of CRC. The aim of this study was to identify microbes which are increased in distal CRCs and to identify the specific location of microbes increased in mucosal tissue around the tumor. <b><i>Methods:</i></b> Tissue specimens were collected from surgical resections of 28 distal CRCs. Five samples were collected from each specimen (location A: tumor, B: adjacent normal mucosa, C: normal mucosa 1 cm proximal to the tumor, D: normal mucosa 3 cm proximally, and E: normal mucosa 6 cm proximally). The microbiota in the sample were analyzed using 16S rRNA gene amplicon sequencing and the relative abundance (RA) of microbiota compared among the 5 locations. <b><i>Results:</i></b> At the genus level, the RA of <i>Fusobacterium</i> and <i>Streptococcus</i> at location A was the highest among the 5 locations, significantly different from that in location E. The dominant species of each genus was <i>Fusobacterium nucleatum</i> and <i>Streptococcus anginosus.</i> The RAs of these species gradually decreased from locations B to E with a statistically significant difference in <i>F. nucleatum</i>. The genus <i>Peptostreptococcus</i> also showed a similar trend, and the RA of <i>Peptostreptococcus stomatis</i> in location A was significantly associated with depth of tumor invasion and tumor size. <b><i>Conclusion:</i></b> Although the clinical relevance is not clear yet, these results suggest that <i>F. nucleatum, S. anginosus</i>, and <i>P. stomatis</i> can spread to the adjacent normal tissues and may change the surrounding microenvironment to support the progression of CRC.
  • Akira Fujisaki, Tatsuya Takayama, Takumi Teratani, Taro Kubo, Jun Kamei, Toru Sugihara, Satoshi Ando, Tatsuo Morita, Tetsuya Fujimura
    International Journal of Urology 0919-8172 2021/08 [Refereed]
  • Akira Fujisaki, Tatsuya Takayama, Motofumi Suzuki, Taro Kubo, Takumi Teratani, Shinsuke Kurokawa, Tomohiro Kameda, Maiko Komatsubara, Tatsuo Morita, Tetsuya Fujimura
    International Journal of Urology 28 (5) 598 - 604 0919-8172 2021/05 [Refereed]
    OBJECTIVE: To elucidate the mechanism of hypertensive crisis during energy device ablation of the adrenal gland. METHODS: Electrocoagulation on the adrenal glands of six pigs was carried out with the same energy device (VIO300D) using four methods: (i) monopolar coagulation; (ii) monopolar soft coagulation using IO-advanced ball-type electrodes; (iii) bipolar soft coagulation by pinching; and (iv) bipolar soft coagulation by non-pinching (surface contact) using Bipolar forceps Premium. After electrocoagulation for 5 s, blood pressure and pulse changes were monitored, and adrenal hormones were measured from a central vein. The adrenal glands were removed, and the degree of tissue damage was scored histologically. RESULTS: Hypertensive crisis occurred with electrocoagulation of the adrenal gland by the monopolar coagulation, monopolar soft coagulation and bipolar soft coagulation pinching methods. Blood pressure did not change with the bipolar soft coagulation non-pinching method. Pathologically, tissue damage to the adrenal medulla was associated with elevated blood pressure and adrenaline and noradrenaline release. CONCLUSIONS: Hypertensive crisis caused by energy device ablation to the adrenal gland is caused by the release of catecholamines due to heat damage to the adrenal medulla rather than the type of energy device. Proper use of an energy device that does not cause thermal degeneration of the medulla is required to prevent hypertensive crisis.
  • Shinji Kawaguchi, Yusuke Soma, Kazuaki Nakajima, Hideaki Kanazawa, Shugo Tohyama, Ryota Tabei, Akinori Hirano, Noriko Handa, Yoshitake Yamada, Shigeo Okuda, Shuji Hishikawa, Takumi Teratani, Satoshi Kunita, Yoshikazu Kishino, Marina Okada, Sho Tanosaki, Shota Someya, Yuika Morita, Hidenori Tani, Yujiro Kawai, Masataka Yamazaki, Akira Ito, Rei Shibata, Toyoaki Murohara, Yasuhiko Tabata, Eiji Kobayashi, Hideyuki Shimizu, Keiichi Fukuda, Jun Fujita
    JACC: Basic to Translational Science 6 (3) 239 - 254 2452-302X 2021/03 [Refereed]
    The severe shortage of donor hearts hampered the cardiac transplantation to patients with advanced heart failure. Therefore, cardiac regenerative therapies are eagerly awaited as a substitution. Human induced pluripotent stem cells (hiPSCs) are realistic cell source for regenerative cardiomyocytes. The hiPSC-derived cardiomyocytes are highly expected to help the recovery of heart. Avoidance of teratoma formation and large-scale culture of cardiomyocytes are definitely necessary for clinical setting. The combination of pure cardiac spheroids and gelatin hydrogel succeeded to recover reduced ejection fraction. The feasible transplantation strategy including transplantation device for regenerative cardiomyocytes are established in this study.
  • 寺谷 工, 笠原 尚哉, 浦橋 泰然, 藤本 康弘, 小林 英司, 後藤 昌史, 佐田 尚宏, 北山 丈二
    Organ Biology (一社)日本臓器保存生物医学会 26 (3) 120 - 120 1340-5152 2019/10 [Refereed][Not invited]
  • Satomi Shiba, Atsushi Miki, Hideyuki Ohzawa, Takumi Teratani, Yasunaru Sakuma, Alan Kawarai Lefor, Joji Kitayama, Naohiro Sata
    The Journal of surgical research 238 79 - 89 2019/06 [Refereed]
    OBJECTIVE: Mucin1 (MUC1), a member of the mucin family, is a glycoprotein which is often expressed in malignant cells. However, the expression and function of MUC1 in human duodenal adenocarcinoma (DAC) has not yet been characterized because of its low frequency. Here, we examined the functional roles of core protein (MUC1-C) in DAC. MATERIALS AND METHODS: Using a human duodenal cancer cell line, HuTu80, proliferation, migration, invasion, ALDH activity was assessed by cell counting kit-8, scratch wound healing, matrigel invasion, and ALDEFUOR assays, respectively. The function of MUC1 protein was evaluated with knockdown using specific siRNA as well as anti-MUC1-C peptide, GO203. MUC1 expression in human DAC was evaluated immunohistochemically in surgically resected tumors. RESULTS: The positive expression of MUC1 in HuTu80 was confirmed by RT-PCR and flow cytometry. In vitro cell growth was inhibited by the addition of 50-100 μM GO203 as well as treatment with siRNA for MUC1-C. Silencing of MUC1-C also significantly reduced migration, invasion, ALDH activity. Local injection of GO-203 (14 mg/kg) significantly suppressed the growth of subcutaneous HuTu80 tumors in nude mice. Immunohistochemically, MUC1 was strongly detected in seven DAC cases, but not in 11 others. The outcome of patients with high MUC1 expression was significantly worse than those without MUC1 expression. CONCLUSIONS: These results suggest that MUC1 is functionally associated with the malignant potential of DAC and could be a novel therapeutic target for this rare tumor.
  • Ryota Tabei, Shinji Kawaguchi, Hideaki Kanazawa, Shugo Tohyama, Akinori Hirano, Noriko Handa, Shuji Hishikawa, Takumi Teratani, Satoshi Kunita, Junichi Fukuda, Yoshihiro Mugishima, Tsuneyoshi Suzuki, Kazuaki Nakajima, Tomohisa Seki, Yoshikazu Kishino, Marina Okada, Masataka Yamazaki, Kazuma Okamoto, Hideyuki Shimizu, Eiji Kobayashi, Yasuhiko Tabata, Jun Fujita, Keiichi Fukuda
    The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation 38 (2) 203 - 214 2019/02 [Refereed]
    BACKGROUND: Induced pluripotent stem cell (iPSC)‒based regenerative therapy is a promising strategy for cardiovascular disease treatment; however, the method is limited by the myocardial retention of grafted iPSCs. Thus, an injection protocol that efficiently introduces and retains human iPSC-derived cardiomyocytes (hiPSC-CMs) within the myocardium is urgently needed. The objective of the present study was to develop a method to improve the retention of hiPSCs in the myocardium for cardiac therapy. METHODS: We efficiently produced hiPSC-CM spheroids in 3-dimensional (3D) culture using microwell plates, and developed an injection device for optimal 3D distribution of the spheroids in the myocardial layer. Device biocompatibility was assessed with purified hiPSC-CM spheroids. Device effectiveness was evaluated in 10- to 15-month-old farm pigs (n = 15) and 5- to 24-month-old micro-minipigs (n = 20). The pigs were euthanized after injection, and tissues were harvested for retention and histologic analysis. RESULTS: We demonstrated an injection device for direct intramyocardial transplantation of hiPSC-CM spheroids from large-scale culture. The device had no detrimental effects on cell viability, spheroid shape, or size. Direct epicardial injection of spheroids mixed with gelatin hydrogel into beating porcine hearts using this device resulted in better distribution and retention of transplanted spheroids in a layer within the myocardium than did conventional needle injection procedures. CONCLUSIONS: The combination of the newly developed transplant device and spheroid formation promotes the retention of transplanted CMs. These findings support the clinical application of hiPSC-CM spheroid‒based cardiac regenerative therapy in patients with heart failure.
  • Junshi Doi, Yasuhiro Fujimoto, Takumi Teratani, Naoya Kasahara, Masashi Maeda, Tatsuaki Tsuruyama, Taku Iida, Shintaro Yagi, Shinji Uemoto
    European surgical research. Europaische chirurgische Forschung. Recherches chirurgicales europeennes 60 (1-2) 63 - 73 2019 
    BACKGROUND: It was demonstrated that polyamines ameliorate ischemia-reperfusion injury (IRI) and promote regeneration in the liver. An optimal protocol of polyamine treatment remains unknown in the clinical setting. We examined 2 types of administration methods using rat models. METHODS: Experiment 1: evaluation of pharmacokinetics of polyamines. Experiment 2: for 3 days preoperatively and 5 days postoperatively, polyamines were given to male Lewis rats in the following three groups: the control group, no polyamine administration; the chow group, 0.05% polyamines mixed in chow; the bolus group, polyamines (200 μmol/kg) given by gastric tube once a day. All rats received 70% hepatectomy after 40 min of warm IRI. Postoperatively, IRI and regeneration were evaluated with assessment of serum levels of hepatic enzymes, histology and immunohistochemistry of liver tissue, and measurement of remnant liver weight. RESULTS: The blood concentrations of polyamines in the portal vein increased at 1 h of bolus administration, while they did not increase without the bolus. The bolus group was significantly associated with lower serum levels of aspartate/alanine aminotransferases (p < 0.05), decreased hepatocyte congestion, vacuolization and necrosis in histopathological scoring (p < 0.05), a lower number of TUNEL-positive hepatocytes (p < 0.05), higher remnant liver weight at 24, 48, and 168 h (p < 0.05), and a higher Ki-67 labeling index (24 h, p < 0.01) compared with the chow group. CONCLUSION: The bolus administration of polyamines was more effective in ameliorating IRI and promoting regeneration than chow administration. Perioperative bolus administration of polyamines might be an optimal treatment, when clinically applied.
  • Hideyuki Ohzawa, Atsushi Miki, Takumi Teratani, Satomi Shiba, Yasunaru Sakuma, Wataru Nishimura, Yasuko Noda, Noriyoshi Fukushima, Hirofumi Fujii, Yasuo Hozumi, Hirofumi Mukai, Yoshikazu Yasuda
    Oncology letters 13 (3) 1731 - 1740 2017/03 [Refereed]
    Pathological complete response (pCR) is considered to be a useful prognostic marker for neoadjuvant chemotherapy to improve the survival rate of patients with operable breast cancer. In the present study, we identified differentially expressed microRNAs (miRNAs) between pCR and non-pCR groups of patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer who received neoadjuvant chemotherapy with trastuzumab. Expression profiles were examined by miRNA microarrays using total RNA extracted from formalin-fixed, paraffin-embedded tissues from pretreatment biopsy specimens. Significant differences were observed in miRNAs associated with pCR between the luminal B-like (HER2-positive) and HER2-positive (nonluminal) subtypes, which were further classified according to their estrogen receptor (ER) status. Prediction models constructed with differentially expressed miRNAs performed well. In conclusion, the combination of miRNA profiles and ER status may improve the accuracy of pCR prediction in patients with HER2-positive breast cancer and enable the development of personalized treatment regimens.
  • Shinya Okumura, Takumi Teratani, Yasuhiro Fujimoto, Xiangdong Zhao, Tatsuaki Tsuruyama, Yuki Masano, Naoya Kasahara, Taku Iida, Shintaro Yagi, Tadahiro Uemura, Toshimi Kaido, Shinji Uemoto
    Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society 22 (9) 1231 - 44 2016/09 [Refereed]
    Polyamines are essential for cell growth and differentiation. They play important roles in protection from liver damage and promotion of liver regeneration. However, little is known about the effect of oral exogenous polyamine administration on liver damage and regeneration. This study investigated the impact of polyamines (spermidine and spermine) on ischemia/reperfusion injury (IRI) and liver regeneration. We used a rat model in which a 70% hepatectomy after 40 minutes of ischemia was performed to mimic the clinical condition of living donor partial liver transplantation (LT). Male Lewis rats were separated into 2 groups: a polyamine group given polyamines before and after operation as treatment and a vehicle group given distilled water as placebo. The levels of serum aspartate aminotransferase and alanine aminotransferase at 6, 24, and 48 hours after reperfusion were significantly lower in the polyamine group compared with those in the vehicle group. Polyamine treatment reduced the expression of several proinflammatory cytokines and chemokines at 6 hours after reperfusion. Histological analysis showed significantly less necrosis and apoptosis in the polyamine group at 6 hours after reperfusion. Sinusoidal endothelial cells were also well preserved in the polyamine group. In addition, the regeneration of the remnant liver at 24, 48, and 168 hours after reperfusion was significantly accelerated, and the Ki-67 labeling index and the expressions of proliferating cell nuclear antigen and phosphorylated retinoblastoma protein at 24 hours after reperfusion were significantly higher in the polyamine group compared with those in the vehicle group. In conclusion, perioperative oral polyamine administration attenuates liver IRI and promotes liver regeneration. It might be a new therapeutic option to improve the outcomes of partial LT. Liver Transplantation 22 1231-1244 2016 AASLD.
  • N. Okada, K. Mizuta, M. Oshima, N. Yamada, Y. Sanada, Y. Ihara, T. Urahashi, J. Ishikawa, T. Tsuji, S. Hishikawa, T. Teratani, E. Kobayashi
    Transplantation Proceedings 47 (2) 419 - 426 0041-1345 2015/03 [Refereed]
  • Shinji Uemoto, Yasuhiro Fujimoto, Takumi Teratani, Hiroyuki Kanazawa, Junji Iwasaki, Zhao Xiangdong, Yuki Masano, Shintaro Yagi, Koichiro Hata, Eiji Kobayashi
    281 - 293 2015 [Refereed]
    In liver transplantation, prolonged ischemia and/or a relatively small graft (living, split, reduced) are the risk factors for liver dysfunction. Novel measures to enhance liver function with a smaller graft can be a clue for safe partial or living-donor liver transplantation or safe hepatectomy for malignant disease. The therapeutic potential and immunomodulatory effects of mesenchymal stem cells (MSCs) have been reported. In this chapter, recent finding on the positive effect of MSCs for liver transplantation and hepatectomy are discussed. Our rat experiment revealed that introduction of MSCs provides trophic support to the I/R-injured liver by inhibiting hepatocellular apoptosis and by stimulating regeneration, which is shown with the pig model as well. In the rat liver transplantation model, portal transfusion of the MSCs ameliorates the injury of the liver graft after prolonged cold preservation and transplantation. Those findings together suggest a potential advantage with partial or living-donor liver transplantation. The most severe complication with cell therapy is embolus formation due to cell aggregation. However, with modification of the solution, we can keep cells in a suspended form for several hours, which secures safe administration of MSCs.
  • S. Iwai, I. Sakonju, S. Okano, T. Teratani, N. Kasahara, S. Yokote, T. Yokoo, E. Kobayash
    Transplantation Proceedings 46 (5) 1578 - 1584 0041-1345 2014/06 [Refereed]
  • J. Doi, T. Teratani, N. Kasahara, T. Kikuchi, Y. Fujimoto, S. Uemoto, E. Kobayashi
    Transplantation Proceedings 46 (1) 63 - 65 0041-1345 2014/01
  • Takumi Teratani, Eiji Kobayashi
    Cell medicine 5 (2-3) 45 - 51 2013/11 [Refereed]
    Research in the life sciences has been greatly advanced by the ability to directly visualize cells, tissues, and organs. Preclinical studies often involve many small and large animal experiments and, frequently, cell and organ transplantations. The rat is an excellent animal model for the development of transplantation and surgical techniques because of its small size and ability to breed in small spaces. Ten years ago, we established color-imaging transgenic rats and methods for the direct visualization of their tissues. Since then, our transgenic rats have been used throughout the various fields that are concerned with cell transplantation therapy. In this minireview, we summarize results from some of the groups that have used our transgenic rats at the bench level and in cell transplantation research.
  • Naoya Kasahara, Takumi Teratani, Junshi Doi, Yuki Iijima, Masashi Maeda, Shinji Uemoto, Yasuhiro Fujimoto, Naohiro Sata, Yoshikazu Yasuda, Eiji Kobayashi
    Cell medicine 5 (2-3) 75 - 81 2013/11 [Refereed]
    Pancreatic islet transplantation has received widespread attention as a promising treatment for type 1 diabetes. However, islets for transplantation are subject to damage from a number of sources, including ischemic injury during removal and delivery of the donor pancreas, enzymatic digestion during islet isolation, and reperfusion injury after transplantation in the recipient. Here we found that protein fractions secreted by mesenchymal stem cells (MSCs) were capable of activating preserved islets. A conditioned medium from the supernatant obtained by culturing adipose tissue MSCs (derived from wild-type Lewis rats) was prepared for 2 days in serum-free medium. Luc-Tg rat islets to which an organ preservation solution was added were then incubated at 4°C with fractions of various molecular weights prepared from the conditioned medium. Under the treatment with some of the fractions, by 4 days the relative luminescence intensities (representative of the ATP levels of the cold-preserved islets) had increased to over 150% of their initial values. Our novel system may be able to restore isolated islets to the condition they were in before transport, culture, and transplantation.
  • Yuki Iijima, Takashi Ajiki, Takumi Teratani, Yuichi Hoshino, Eiji Kobayashi
    Plastic and reconstructive surgery. Global open 1 (8) e70  2013/11 [Refereed]
    BACKGROUND: Ischemia exceeding 6 hours makes clinical limb replantation difficult and places the patient at risk of functional deficit or limb loss. We investigated the preservation of muscle function and morphology with solutions in rat hindlimb in vivo and in vitro. METHODS: Quadriceps femoris muscles from luciferase transgenic rats were preserved for 24 hours at 4°C in extracellular-type trehalose containing Kyoto (ETK), University of Wisconsin (UW), or lactated Ringer's (LR) solution (control). Muscle luminescence was measured with a bioimaging system. Amputated limbs of Lewis rats preserved with ETK, UW, or LR for 6 or 24 hours at 4°C were transplanted orthotopically. At week 8, terminal latency and amplitude were measured in the tibialis anterior muscle. The muscles were also analyzed histologically. RESULTS: Isolated muscles preserved in ETK or UW had significantly higher luminescence than did muscles immersed in LR (P < 0.05). In the 6-hour-preserved limb transplantation model, although the 3 groups had almost the same terminal latency, electrical amplitude was significantly lower in the LR group. Histologically, muscles preserved with LR showed the most atrophic changes. In the 24-hour-preserved model, the survival rate of the LR group was 37.5% in contrast to 80% in the ETK and UW groups. Electrical signals were not detected in the LR group owing to severe muscle atrophy and fibrosis. The ETK and UW groups showed good muscle function electrophysiologically. CONCLUSIONS: Preservation solutions can protect muscle function and morphology in ischemia-reperfusion limbs and improve recipient survival rates after transplantation of long-term-preserved limbs.
  • Junji Iwasaki, Toshiyuki Hata, Shinji Uemoto, Yasuhiro Fujimoto, Hiroyuki Kanazawa, Takumi Teratani, Shuji Hishikawa, Eiji Kobayashi
    Organogenesis 9 (4) 273 - 9 1547-6278 2013/10 [Refereed]
    In developing therapeutic alternatives to liver transplantation, we have used the strategy of applying a small intestinal segment as a scaffold for hepatocyte transplantation and also as a portocaval shunt (PCS) system to address both liver dysfunction and portal hypertension. The aim of this study was to investigate the feasibility of such an intestinal segment in animal models. Hepatocytes isolated from luciferase-transgenic Lewis rats were transplanted into jejunal segments of wild-type Lewis rats with mucosa removal without PCS application. Luciferase-derived luminescence from transplanted hepatocytes was stably detected for 30 days. Then, we performed autologous hepatocyte transplantation into the submucosal layer of an isolated and vascularized small intestinal segment in pigs. Transplanted hepatocytes were isolated from the resected left-lateral lobe of the liver. On day 7, hepatocyte clusters and bile duct-like structures were observed histologically. To create an intestinal PCS system in pigs, an auto-graft of the segmental ileum and interposing vessel graft were anastomosed to the portal vein trunk and inferior vena cava. However, thrombi were observed in vessels of the intestinal PCSs. We measured the correlation between infusion pressure and flow volume in whole intestines ex vivo in both species and found that the high pressure corresponding to portal hypertension was still insufficient to maintain the patency of the intestinal grafts. In conclusion, we demonstrated the feasibility of the small intestine as a scaffold for hepatocyte transplantation in rat and pig models, but PCS using an intestinal graft failed to maintain patency in a pig model.
  • N. Kasahara, T. Kikuchi, J. Doi, T. Teratani, Y. Fujimoto, S. Uemoto, Y. Yasuda, E. Kobayashi
    Transplantation Proceedings 45 (6) 2486 - 2490 0041-1345 2013/07 [Refereed]
  • Masashi Maeda, Naoya Kasahara, Junshi Doi, Yuki Iijima, Takeshi Kikuchi, Takumi Teratani, Eiji Kobayashi
    Heart Asia 5 (1) 7 - 14 1759-1104 2013 [Refereed]
    OBJECTIVE: We developed a novel luciferase-based viability assay for assessing the viability of hearts preserved in different solutions. We examined whether this in vitro system could predict heart damage and survival after transplantation in rats. DESIGN: By our novel system, preserved heart viability evaluation and transplanted heart-graft functional research study. SETTING: University basic science laboratory. INTERVENTIONS: Isolated Luciferase-transgenic Lewis (LEW) rat cardiac-tissue-chips were plated on 96-well tissue-culture plates and incubated in preservation solutions at 4°C. Viability was measured as photon intensity by using a bio-imaging system. Heart-grafts preserved in University of Wisconsin (UW), extracellular-trehalose-Kyoto (ETK), Euro-Collins (EC), histidin-tryptophan-ketoglutarat solution (HTK), lactated Ringer's (LR) or normal saline solution were transplanted cervically by using a cuff-technique or into the abdomens of syngeneic wild-type LEW rats by using conventional microsurgical suture techniques. MAIN OUTCOME MEASURES: Imaging an evaluation of preservation heart-graft and functional analysis. RESULTS: Cardiac-tissue-chips preserved with UW, HTK or ETK solution gave higher luminance than those preserved with EC, LR or normal saline (p<0.03). After 24 h of preservation of hearts in each solution at 4°C, the beating of the isolated hearts was evaluated. The success rate, evaluation of beating, of cervical heart transplants using UW and ETK solution exceeded 70%, but those using other preservation solutions were lower (UW: 100%, ETK: 75%, EC: 42.86%, HTK: 14.29%, normal saline: 0%). Histological analysis of cervical heart-grafts after 3 h preservation by myeloperoxidase (MPO), zona occludens-1(ZO-1), and caspase-3 immunostaining revealed different degrees of preservation damage in all grafts. CONCLUSIONS: Our novel assay system is simple and can test multiple solutions. It should therefore be a powerful tool for developing and improving new heart-graft preservation solutions.
  • Jun-Ya Kaimori, Satomi Iwai, Masaki Hatanaka, Takumi Teratani, Yoshitsugu Obi, Hidetoshi Tsuda, Yoshitaka Isaka, Takashi Yokawa, Kagayaki Kuroda, Naotsugu Ichimaru, Masayoshi Okumi, Koji Yazawa, Hiromi Rakugi, Norio Nonomura, Shiro Takahara, Eiji Kobayashi
    PloS one 8 (5) e63573  2013 [Refereed]
    The main objective of this study was to assess cardiac death (CD) kidney grafts before transplantation to determine whether blood oxygen level-dependent (BOLD) and diffusion MRI techniques can predict damage to these grafts after transplantation. We assessed CD kidney tissue by BOLD and diffusion MRI. We also examined pathological and gene expression changes in CD kidney grafts before and after transplantation. Although there was significantly more red cell congestion (RCC) in the inner stripe of the outer medulla (IS) in both 1 h after cardiac death (CD1h) and CD2h kidneys destined for grafts before transplantation compared with CD0h (p<0.05), CD2h, but not CD1h, kidney grafts had significantly different RCC in the IS 2 days after transplantation (p<0.05). Consistent with these pathological findings, tissue plasminogen activator (tPA) gene expression was increased only in the cortex and medulla of CD2h kidney grafts after transplantation. BOLD MRI successfully and non-invasively imaged and quantified RCC in the IS in both CD1h and CD2h kidney grafts (p<0.05). Diffusion MRI also non-invasively assessed increased the apparent diffusion coefficient in the IS and decreased it in the outer stripe (OS) of CD2h grafts, in concordance with interstitial edema in the IS and tubule cellular edema in the OS. These two types of edema in the outer medulla could explain the prolonged RCC in the IS only of CD2h kidney grafts, creating part of a vicious cycle inhibiting red cells coming out of capillary vessels in the IS. Perfusion with University of Wisconsin solution before MRI measurements did not diminish the difference in tissue damage between CD1h and CD2h kidney grafts. BOLD and diffusion MRI, which are readily available non-invasive tools for evaluating CD kidney grafts tissue damage, can predict prolonged organ damage, and therefore the outcome, of transplanted CD kidney grafts.
  • Takumi Teratani, Hitomi Matsunari, Naoya Kasahara, Hiroshi Nagashima, Tatsuo Kawarasaki, Eiji Kobayashi
    Current diabetes reviews 8 (5) 382 - 9 2012/09 [Refereed]
    Translational research is necessary for the development of efficient experimental animal models that can be used to develop innovative medical treatments, such as improvements in organ or tissue transplantation. We have developed animal models that produce photogenic proteins in their islet cells: rats models expressing the gene for luciferase or green fluorescent protein (GFP), and pig models expressing the gene for GFP or Kusabira-Orange. We also developed methods for preserving isolated islets in culture and showed that the fluorescence of the islets remains at usable levels for at least seven days. These models will enable transplanted islets to be visualized without the need for chemical reactions, and will be useful for research on the biology of islets as well as for the development of new transplantation methods.
  • Eiji Kobayashi, Shuji Hishikawa, Takumi Teratani, Alan T Lefor
    Transplantation research 1 (1) 8 - 8 2012/08 [Refereed]
    To improve the welfare of experimental animals, investigators seek to respect the 3R principle (Replacement, Reduction, and Refinement). Even when large animal studies are essential before moving to clinical trials, it is important to look for ways to reduce the number of experimental animals used. At the Center for the Development of Advanced Medical Technology, we consider 'medical' pigs to be ideal preclinical model systems.We have been using both wild-type and genetically modified pigs. We began using this approach about 10 years ago with a 'total pig system' to model human health and disease for the purposes of both medical skill education and the development of new devices and therapeutic strategies.At our Center, medical students and residents use pigs to gain experience with surgical skills and train for emergency procedures after appropriate simulation training. Senior clinicians have also used these models to advance the development of innovative tools for endo- and laparoscopic procedures. The Center focuses on translational research for organ transplantation and stem cell therapy. Several pig models have been established for liver, intestine, kidney, pancreas, and lung transplantation. Mesenchymal stromal cells have been established in green fluorescent protein- and red fluorescent protein-transgenic pigs and tested to trans-differentiate organogenesis. A program to establish induced pluripotent stem cells in the pig is ongoing at our Center.Here, we review our 10 years of activity in this field. Based on our experience in surgical education and research, experimental pigs are valuable models in translational research.
  • Kei Matsumoto, Takashi Yokoo, Hitomi Matsunari, Satomi Iwai, Shinya Yokote, Takumi Teratani, Yousof Gheisari, Osahiko Tsuji, Hideyuki Okano, Yasunori Utsunomiya, Tatsuo Hosoya, Hirotaka James Okano, Hiroshi Nagashima, Eiji Kobayashi
    Stem cells (Dayton, Ohio) 30 (6) 1228 - 35 2012/06 [Refereed]
    Recent findings have demonstrated that stem cells can differentiate into mature tissue when supplied with a niche containing factors identical to those in the normal developmental program. A niche for the development of an organ can be provided by xenotransplantation of a similar developing organ. However, this process has many technical, safety, and ethical concerns. Here, we established xenotransplantation models that control endogenous mesenchymal stem cell (MSC) differentiation into mature erythropoietin (EPO)-producing tissue in a niche provided by a developing xenometanephros. Transplantation of rat metanephroi into mouse omentum, and similarly pig metanephroi into cat omentum, led to the recruitment of host cells and EPO production. EPO-expressing cells were not differentiated from integrating vessels because they did not coexpress endothelial markers (Tie-2 and VE-cadherin). Instead, EPO-expressing cells were shown to be derived from circulating host cells, as shown by enhanced green fluorescent protein (EGFP) expression in the grown transplants of chimeric mice bearing bone marrow from a transgenic mouse expressing EGFP under the control of the EPO promoter. These results suggest that donor cell recruitment and differentiation in a xenotransplanted developing organ may be consistent between species. The cells responsible for EPO expression were identified as MSCs by injecting human bone marrow-derived MSCs and endothelial progenitor cells into NOD/SCID mice. Furthermore, using metanephroi from transgenic ER-E2F1 suicide-inducible mice, the xenotissue component could be eliminated, leaving autologous EPO-producing tissue. Our findings may alleviate adverse effects due to long-lasting immunosuppression and help mitigate ethical concerns.
  • Satomi Iwai, Takeshi Kikuchi, Naoya Kasahara, Takumi Teratani, Takashi Yokoo, Iwao Sakonju, Shouzou Okano, Eiji Kobayashi
    PloS one 7 (3) e33157  2012 [Refereed]
    BACKGROUND: The aim of this study was to investigate factors that may improve the condition of a marginal kidney preserved with a normothermic solution following cardiac death (CD) in a model of rat kidney transplantation (RTx). METHODS: Post-euthanasia, Lewis (LEW) donor rats were left for 1 h in a 23°C room. These critical kidney grafts were preserved in University of Wisconsin (UW), lactate Ringer's (LR), or extracellular-trehalose-Kyoto (ETK) solution, followed by intracellular-trehalose-Kyoto (ITK) solution at 4, 23, or 37°C for another 1 h, and finally transplanted into bilaterally nephrectomized LEW recipient rats (n = 4-6). Grafts of rats surviving to day 14 after RTx were evaluated by histopathological examination. The energy activity of these marginal rat kidneys was measured by high-performance liquid chromatography (HPLC; n = 4 per group) and fluorescence intensity assay (n = 6 per group) after preservation with UW or ETK solutions at each temperature. Finally, the transplanted kidney was assessed by an in vivo luciferase imaging system (n = 2). RESULTS: Using the 1-h normothermic preservation of post-CD kidneys, five out of six recipients in the ETK group survived until 14 days, in contrast to zero out of six in the UW group (p<0.01). Preservation with ITK rather than ETK at 23°C tended to have an inferior effect on recipient survival (p = 0.12). Energy activities of the fresh donor kidneys decreased in a temperature-dependent manner, while those of post-CD kidneys remained at the lower level. ETK was superior to UW in protecting against edema of the post-CD kidneys at the higher temperature. Luminescence intensity of successful grafts recovered within 1 h, while the intensity of grafts of deceased recipients did not change at 1 h post-reperfusion. CONCLUSIONS: Normothermic storage with extracellular-type solution containing trehalose might prevent reperfusion injury due to temperature-dependent tissue edema.
  • Takumi Teratani, Eiji Kobayashi
    Cell medicine 3 (1-3) 3 - 11 2012/01 [Refereed]
    The rat is an excellent cell transplantation model. In accordance with the innovative development of in vivo bioimaging technology, over the last decade we have been developing an engineered rat system based on transgenic technology and have been demonstrating the usefulness of the system with genetically encoded imaging probes such as fluorescent and luminescent proteins. In cooperation with the Japan Society for Organ Preservation and Medical Biology (President: Professor T. Asano), we have also been using luciferase-Tg rats for research into organ preservation and cell transplantation. In this minireview, we introduce the results obtained recently by using these powerful experimental tools during international collaboration in cell transplantation research.
  • Tetsuya Ishikawa, Agnieszka Banas, Takumi Teratani, Hideki Iwaguro, Takahiro Ochiya
    Cell transplantation 21 (2-3) 387 - 99 2012 [Refereed]
    Human embryonic stem (ES) cells and induced pluripotent stem (iPS) cells have an enormous potential; however, their potential clinical application is being arrested due to various limitations such as teratoma formation followed by tumorigenesis, emergent usage, and the quality control of cells, as well as safety issues regarding long-term culture are also delaying their clinical application. In addition, human ES cells have two crucial issues: immunogenicity and ethical issues associated with their clinical application. The efficient generation of human iPS cells requires gene transfer, yet the mechanism underlying pluripotent stem cell induction has not yet been fully elucidated. Otherwise, although human adult regenerative cells including mesenchymal stem cells have a limited capacity for differentiation, they are nevertheless promising candidates for tissue regeneration in a clinical setting. This review highlights the use of regenerative cells for transplantation in hepatic failure.
  • Naohisa Takaoka, Tatsuya Takayama, Takumi Teratani, Takayuki Sugiyama, Soichi Mugiya, Seiichiro Ozono
    BMC molecular biology 12 31 - 31 2011/07 [Refereed]
    BACKGROUND: Improving the treatment of renal cell carcinoma (RCC) will depend on the development of better biomarkers for predicting disease progression and aiding the design of appropriate therapies. One such marker may be fatty acid binding protein 7 (FABP7), also known as B-FABP and BLBP, which is expressed normally in radial glial cells of the developing central nervous system and cells of the mammary gland. Melanomas, glioblastomas, and several types of carcinomas, including RCC, overexpress FABP7. The abundant expression of FABP7 in primary RCCs compared to certain RCC-derived cell lines may allow the definition of the molecular components of FABP7's regulatory system. RESULTS: We determined FABP7 mRNA levels in six RCC cell lines. Two were highly expressed, whereas the other and the embryonic kidney cell line (HEK293) were weakly expressed FABP7 transcripts. Western blot analysis of the cell lines detected strong FABP7 expression only in one RCC cell line. Promoter activity in the RCC cell lines was 3- to 21-fold higher than that of HEK293. Deletion analysis demonstrated that three FABP7 promoter regions contributed to upregulated expression in RCC cell lines, but not in the HEK293 cell. Competition analysis of gel shifts indicated that OCT1, OCT6, and nuclear factor I (NFI) bound to the FABP7 promoter region. Supershift experiments indicated that BRN2 (POU3F2) and NFI bound to the FABP7 promoter region as well. There was an inverse correlation between FABP7 promoter activity and BRN2 mRNA expression. The FABP7-positive cell line's NFI-DNA complex migrated faster than in other cell lines. Levels of NFIA mRNA were higher in the HEK293 cell line than in any of the six RCC cell lines. In contrast, NFIC mRNA expression was lower in the HEK293 cell line than in the six RCC cell lines. CONCLUSIONS: Three putative FABP7 promoter regions drive reporter gene expression in RCC cell lines, but not in the HEK293 cell line. BRN2 and NFI may be key factors regulating the expression of FABP7 in certain RCC-derived cell lines.
  • Hiroyuki Kanazawa, Yasuhiro Fujimoto, Takumi Teratani, Junji Iwasaki, Naoya Kasahara, Kouji Negishi, Tatsuaki Tsuruyama, Shinji Uemoto, Eiji Kobayashi
    PloS one 6 (4) e19195  2011/04 [Refereed]
    BACKGROUND: Ischemia-reperfusion (I/R) injury associated with living donor liver transplantation impairs liver graft regeneration. Mesenchymal stem cells (MSCs) are potential cell therapeutic targets for liver disease. In this study, we demonstrate the impact of MSCs against hepatic I/R injury and hepatectomy. METHODOLOGY/PRINCIPAL FINDINGS: We used a new rat model in which major hepatectomy with I/R injury was performed. Male Lewis rats were separated into two groups: an MSC group given MSCs after reperfusion as treatment, and a Control group given phosphate-buffered saline after reperfusion as placebo. The results of liver function tests, pathologic changes in the liver, and the remnant liver regeneration rate were assessed. The fate of transplanted MSCs in the luciferase-expressing rats was examined by in vivo luminescent imaging. The MSC group showed peak luciferase activity of transplanted MSCs in the remnant liver 24 h after reperfusion, after which luciferase activity gradually declined. The elevation of serum alanine transaminase levels was significantly reduced by MSC injection. Histopathological findings showed that vacuolar change was lower in the MSC group compared to the Control group. In addition, a significantly lower percentage of TUNEL-positive cells was observed in the MSC group compared with the controls. Remnant liver regeneration rate was accelerated in the MSC group. CONCLUSIONS/SIGNIFICANCE: These data suggest that MSC transplantation provides trophic support to the I/R-injured liver by inhibiting hepatocellular apoptosis and by stimulating regeneration.
  • Takeshi Katsuda, Takumi Teratani, Takahiro Ochiya, Yasuyuki Sakai
    Journal of biochemistry 148 (3) 281 - 8 2010/09 [Refereed]
    An auxiliary liver represents a promising alternative for liver transplantation. The use of a large amount of mature hepatocytes, however, despite their high function, is limited in a clinical setting. Here, we propose a novel transplantation system that dramatically improved a diseased animal by incorporating fetal liver cells (FLCs) as a cell source, the mesentery as a transplantation site and a hyaluronic acid (HA) sponge as a cell scaffold. We transplanted wild-type Long Evans Agouti rat FLCs embedded in HA sponges onto the mesentery of Long Evans Cinnamon (LEC) rats, an animal model for Wilson's disease. The FLC-loaded HA sponges successfully grafted and consequently prevented jaundice. Accordingly, the treated animals showed a significant reduction in blood copper concentration, which consequently led to significant decreases in serum total bilirubin and direct bilirubin, and to a significant increase in albumin productivity. Furthermore, haematoxylin and eosin staining of the host livers demonstrated that fibrosis at the periportal area was moderated in the treated animals. In conclusion, we transplanted FLC-loaded HA sponges onto the mesenteric blood vessels, leading to thick, liver-like tissue possessing blood vessels, and the liver tissue engineered thus exhibited a remarkable therapeutic effect on the copper metabolism deficiency of LEC rats.
  • Agnieszka Banas, Takumi Teratani, Yusuke Yamamoto, Makoto Tokuhara, Fumitaka Takeshita, Mitsuhiko Osaki, Takashi Kato, Hitoshi Okochi, Takahiro Ochiya
    Journal of gastroenterology and hepatology 24 (1) 70 - 7 2009/01 [Refereed]
    BACKGROUND AND AIM: Multipotential mesenchymal stem cells (MSC), present in many organs and tissues, represent an attractive tool for the establishment of a successful stem cell-based therapy in the field of regeneration medicine. Adipose tissue mesenchymal stem cells (AT-MSC), known as adipose-derived stem cells (ASC) are especially attractive in the context of future clinical applications because of their high accessibility and minimal invasiveness during the procedure to obtain them. The goal of the present study was to induce human ASC into functional hepatocytes in vitro within a very short period of time and to check their therapeutic potential in vivo. METHODS: In vitro generated ASC-derived hepatocytes were checked for hepatocyte-specific markers and functions. Afterwards, they were transplanted into nude mice with liver injury. Twenty-four hours after transplantation, biochemical parameters were evaluated in blood serum. RESULTS: We have shown here that ASC can be differentiated into hepatocytes within 13 days and can reach the functional properties of primary human hepatocytes. After transplantation into mice with acute liver failure, ASC-derived hepatocytes can restore such liver functions as ammonia and purine metabolism. Markers of liver injury, alanine aminotransferase, aspartate aminotransferase, as well as ammonia, were decreased after ASC-derived hepatocyte transplantation. CONCLUSIONS: Our data highlight the properties of ASC as having a special affinity for hepatocyte differentiation in vitro and liver regeneration in vivo. Thus, ASC may be a superior choice for the establishment of a therapy for injured liver.
  • Agnieszka Banas, Takumi Teratani, Yusuke Yamamoto, Makoto Tokuhara, Fumitaka Takeshita, Mitsuhiko Osaki, Masaki Kawamata, Takashi Kato, Hitoshi Okochi, Takahiro Ochiya
    Stem cells (Dayton, Ohio) 26 (10) 2705 - 12 2008/10 [Refereed]
    Mesenchymal stem cells (MSCs), largely present in the adult human body, represent an attractive tool for the establishment of a stem cell-based therapy for liver diseases. Recently, the therapeutic potential and immunomodulatory activity of MSCs have been revealed. Adipose tissue-derived mesenchymal stem cells (AT-MSCs), so-called adipose-derived stem cells or adipose stromal cells, because of their high accessibility with minimal invasiveness, are especially attractive in the context of future clinical applications. The goal of the present study was to evaluate the therapeutic potential of AT-MSCs by their transplantation into nude mice with CCl(4)-caused liver injury. We observed that after transplantation, AT-MSCs can improve liver functions, which we verified by changes in the levels of biochemical parameters. Ammonia, uric acid, glutamic-pyruvic transaminase, and glutamic-oxaloacetic transaminase concentrations returned to a nearly normal level after AT-MSC transplantation. These results raised the question of how AT-MSCs can achieve this. To discover the possible mechanisms involved in this therapeutic ability of AT-MSCs, in vitro production of cytokines and growth factors was analyzed and compared with MSCs from bone marrow (BM-MSCs) and normal human dermal fibroblasts (NHDFs). As a result we observed that AT-MSCs secrete interleukin 1 receptor alpha (IL-1Ralpha), IL-6, IL-8, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), monocyte chemotactic protein 1, nerve growth factor, and hepatocyte growth factor in a volume higher than both BM-MSCs and NHDFs. Thus, our findings suggest that AT-MSCs may account for their broad therapeutic efficacy in animal models of liver diseases and in the clinical settings for liver disease treatment. Disclosure of potential conflicts of interest is found at the end of this article.
  • Shinobu Ueda, Masaki Kawamata, Takumi Teratani, Taku Shimizu, Yoshitaka Tamai, Hiromasa Ogawa, Katsuyuki Hayashi, Hiroyuki Tsuda, Takahiro Ochiya
    PloS one 3 (7) e2800  2008/07 [Refereed]
    The rat is a reference animal model for physiological studies and for the analysis of multigenic human diseases such as hypertension, diabetes, neurological disorders, and cancer. The rats have long been used in extensive chemical carcinogenesis studies. Thus, the rat embryonic stem (rES) cell is an important resource for the study of disease models. Attempts to derive ES cells from various mammals, including the rat, have not succeeded. Here we have established two independent rES cells from Wister rat blastocysts that have undifferentiated characters such as Nanog and Oct3/4 genes expression and they have stage-specific embryonic antigen (SSEA) -1, -3, -4, and TRA-1-81 expression. The cells were successfully cultured in an undifferentiated state and can be possible over 18 passages with maintaining more than 40% of normal karyotype. Their pluripotent potential was confirmed by the differentiation into derivatives of the endoderm, mesoderm, and ectoderm. Most importantly, the rES cells are capable of producing chimera rats. Therefore, we established pluripotent rES cell lines that are widely used to produce genetically modified experimental rats for study of human diseases.
  • Kazumori Arai, Sachiko Takano, Takumi Teratani, Yasuhiro Ito, Toshihiro Yamada, Ryushi Nozawa
    Current cancer drug targets 8 (4) 243 - 52 2008/06 [Refereed]
    S100 protein A8 and A9 naturally form a stable heterocomplex. Recently, we have proved that S100A9 overexpression in various adenocarcinomas is associated with poor tumor differentiation. In this study, we examined the relationship between the expression of each protein and the pathological parameters that reflect the aggressiveness of carcinoma, in invasive ductal carcinoma (IDC) of the breast. Serial paraffin-embedded tissue sections from 101 IDC cases were immunostained with respective monoclonal antibodies, and the results were as follows: 1) A positive correlation of immunoreactivity between S100A8 and S100A9 was noticed (r=0.873 and P<0.0001); 2) The percentage of S100A9-positive tumor cells was higher than that of S100A8-positive tumor cells (P<0.001), and S100A8 alone was not detected in any case; 3) Overlap between S100A8 and S100A9 staining patterns was found in the corresponding tissue areas, but S100A9 positivity was also observed in S100A8-negative tumor cells; 4) The immunopositivity for each protein also correlated with the mitotic activity, MIB-1 index, HER2 overexpression, node metastasis, and poor pT categories and pStage (P<0.05); 5) Co-expression of both proteins was associated with poor tumor differentiation, vessel invasion, node metastasis, and poor pStage (P<0.05). Furthermore, co-expression of the proteins was also observed in MCF-7 cells, and it was suggested that the immunolocalization is related with cell cycle. Our conclusions are as follows: 1) It is suggested that S100A8 is S100A9-dependently expressed and acquires the protein stability by S100A8/A9 heterocomplex formation; 2) S100A8 and S100A9 overexpression should be considered marker of poor prognosis in IDC.
  • Yusuke Yamamoto, Agnieszka Banas, Shigenori Murata, Madoka Ishikawa, Chun R Lim, Takumi Teratani, Izuho Hatada, Kenichi Matsubara, Takashi Kato, Takahiro Ochiya
    The FEBS journal 275 (6) 1260 - 73 2008/03 [Refereed]
    The specific features of the plasticity of adult stem cells are largely unknown. Recently, we demonstrated the hepatic differentiation of human adipose tissue-derived mesenchymal stem cells (AT-MSCs). To identify the genes responsible for hepatic differentiation, we examined the gene expression profiles of AT-MSC-derived hepatocytes (AT-MSC-Hepa) using several microarray methods. The resulting sets of differentially expressed genes (1639 clones) were comprehensively analyzed to identify the pathways expressed in AT-MSC-Hepa. Clustering analysis revealed a striking similarity of gene clusters between AT-MSC-Hepa and the whole liver, indicating that AT-MSC-Hepa were similar to liver with regard to gene expression. Further analysis showed that enriched categories of genes and signaling pathways such as complementary activation and the blood clotting cascade in the AT-MSC-Hepa were relevant to liver-specific functions. Notably, decreases in Twist and Snail expression indicated that mesenchymal-to-epithelial transition occurred in the differentiation of AT-MSCs into hepatocytes. Our data show a similarity between AT-MSC-Hepa and the liver, suggesting that AT-MSCs are modulated by their environmental conditions, and that AT-MSC-Hepa may be useful in basic studies of liver function as well as in the development of stem cell-based therapy.
  • 高橋 亨, 寺谷 工, 西川 昌輝, 藤井 輝夫, 落谷 孝広, 酒井 康行
    化学工学会 研究発表講演要旨集 公益社団法人 化学工学会 2008 298 - 298 2008
  • Agnieszka Banas, Yusuke Yamamoto, Takumi Teratani, Takahiro Ochiya
    Developmental dynamics : an official publication of the American Association of Anatomists 236 (12) 3228 - 41 1058-8388 2007/12 [Refereed]
    Many studies on stem cell plasticity are challenging the concept that stem cells contain an intrinsically predefined, unidirectional differentiation program. This means that the developmental fate of a stem cell is dependent on the general potential of the cell (pre-determined stem cell fate) as well as on microenvironmental cues, such as stimuli from growth factors (stem cell niche). Here, we reviewed reports that examined the hepatocyte differentiation ability of stem cells from two different sources: embryonic stem cells and adult stem cells. All of those stem cells revealed the ability to give rise to hepatocyte-like cells using different induction strategies. However, it is still not clear which of those stem cells would be the best source for hepatocyte replacement or which would be the best protocol. We herein present the current knowledge regarding available protocols and factors used in order to obtain functional hepatocytes from stem cells.
  • Agnieszka Banas, Takumi Teratani, Yusuke Yamamoto, Makoto Tokuhara, Fumitaka Takeshita, Gary Quinn, Hitoshi Okochi, Takahiro Ochiya
    Hepatology (Baltimore, Md.) 46 (1) 219 - 28 0270-9139 2007/07 [Refereed]
    UNLABELLED: Recent observations indicate that several stem cells can differentiate into hepatocytes; thus, cell-based therapy is a potential alternative to liver transplantation. The goal of the present study was to examine the in vitro hepatic differentiation potential of adipose tissue-derived mesenchymal stem cells (AT-MSCs). We used AT-MSCs from different age patients and found that, after incubation with specific growth factors (hepatocyte growth factor [HGF], fibroblast growth factor [FGF1], FGF4) the CD105(+) fraction of AT-MSCs exhibited high hepatic differentiation ability in an adherent monoculture condition. CD105(+) AT-MSC-derived hepatocyte-like cells revealed several liver-specific markers and functions, such as albumin production, low-density lipoprotein uptake, and ammonia detoxification. More importantly, CD105(+) AT-MSC-derived hepatocyte-like cells, after transplantation into mice incorporated into the parenchyma of the liver. CONCLUSION: Adipose tissue is a source of multipotent stem cells that can be easily isolated, selected, and induced into mature, transplantable hepatocytes. The fact that they are easy to procure ex vivo in large numbers makes them an attractive tool for clinical studies in the context of establishing an alternative therapy for liver dysfunction.
  • Takumi Teratani, Tomohiro Domoto, Ken Kuriki, Teruyo Kageyama, Tatsuya Takayama, Akira Ishikawa, Seiichiro Ozono, Ryushi Nozawa
    Urology 69 (2) 236 - 40 2007/02 
    OBJECTIVES: To clarify the gene expression patterns of fatty acid-binding protein (FABP) and evaluate it as a potential marker for the diagnosis of renal cell carcinoma (RCC). RCC is the most common renal neoplasm. METHODS: The expression of eight FABP genes in normal human tissues, tumor cell lines, and surgically resected RCC tissues (n = 54) was evaluated by reverse transcriptase-polymerase chain reaction. Additionally, the gene expression of FABPs in the urine of healthy volunteers (n = 12) and patients with RCC (n = 5) was investigated. RESULTS: In these results, the carcinoma tissues but not the noncancerous (normal) parts of the kidney samples resected from patients with RCC expressed the transcript for brain-type FABP (B-FABP), indicating that expression of the B-FABP gene is a novel marker for RCC. Furthermore, the B-FABP cDNA fragment was not amplified by reverse transcriptase-polymerase chain reaction in the urine samples of healthy donors or patients with RCC after surgical operation. However, B-FABP cDNA was amplified in the patients' urine samples collected before surgery. CONCLUSIONS: This novel method can be used as a powerful ancillary in the diagnosis of RCC.
  • Tomohiro Domoto, Youko Miyama, Hiroko Suzuki, Takumi Teratani, Kazumori Arai, Takayuki Sugiyama, Tatsuya Takayama, Soichi Mugiya, Seiichiro Ozono, Ryushi Nozawa
    Cancer science 98 (1) 77 - 82 1347-9032 2007/01 [Refereed]
    This study aimed to analyze expression of S100A10, annexin II and B-FABP genes in renal cell carcinoma (RCC) and their potential value as tumor markers. Furthermore, any correlation between the gene expression and prognostic indicators of RCC was analyzed. Expression of each gene was estimated by RT-PCR in the non-neoplastic (normal) and tumorous parts of resected kidney samples. Also, each antigen was immunostained in RCC and normal kidney tissues. Expression of the S100A10 gene averaged 2.5-fold higher in the tumor than that in the normal tissues (n = 47), after standardization against that of beta-actin. However, expression of annexin II, a natural ligand of S100A10, was only 1.64-fold higher. In the tissue sections of RCC, S100A10 and annexin II were immunostained in membranes. In the normal renal epithelia, however, both antigens were stained in the Bowman's capsule and the tubules from Henle's loop through the collecting duct system, but not in the proximal tubules, from where most RCC are derived. In contrast, expression of the B-FABP gene was 20-fold higher in the tumor. No B-FABP was immunohistochemically detected in normal kidney sections, but it was stained in the cytoplasm of RCC tissue sections. S100A10 and B-FABP genes were overexpressed regardless of nuclear grade and stage of RCC. Immunopositivity in RCC tissues (n = 13) was 100% for S100A10 and annexin II, and 70% for B-FABP; however, no clear relationship was observed in either antigen with nuclear grade and stage. It was found that all three performed well as RCC markers. B-FABP was most specific to RCC, as it was expressed little in normal kidney tissues.
  • Agnieszka Banas, Gary Quinn, Yusuke Yamamoto, Takumi Teratani, Takahiro Ochiya
    Advances in experimental medicine and biology 585 3 - 17 0065-2598 2006 [Refereed]
  • Yusuke Yamamoto, Takumi Teratani, Hanako Yamamoto, Gary Quinn, Sigenori Murata, Rieko Ikeda, Kenji Kinoshita, Kenichi Matsubara, Takashi Kato, Takahiro Ochiya
    Hepatology (Baltimore, Md.) 42 (3) 558 - 67 0270-9139 2005/09 [Refereed]
    Hepatic differentiation at the molecular level is poorly understood, mainly because of the lack of a suitable model. Recently, using adherent monoculture conditions, we demonstrated the direct differentiation of hepatocytes from embryonic stem (ES) cells. In this study, we exploited the direct differentiation model to compare the gene expression profiles of ES cell-derived hepatocytes with adult mouse liver using DNA microarray technology. The results showed that the ES cell-derived hepatocyte gene expression pattern is very similar to adult mouse liver. Through further analysis of gene ontology categories for the 232 most radically altered genes, we found that the significant categories related to hepatic function. Furthermore, through the use of small interfering RNA technology in vitro, hepatocyte nuclear factor 3beta/FoxA2 was identified as having an essential role in hepatic differentiation. These results demonstrate that ES cell-derived hepatocytes recapitulate the gene expression profile of adult mouse liver to a significant degree and indicate that our direct induction system progresses via endoderm differentiation. In conclusion, our system closely mimics in vivo hepatic differentiation at the transcriptional level and could, therefore, be useful for studying the molecular basis of hepatocyte differentiation per se.
  • Fumitaka Takeshita, Yoshiko Minakuchi, Shunji Nagahara, Kimi Honma, Hideo Sasaki, Kotaro Hirai, Takumi Teratani, Nachi Namatame, Yusuke Yamamoto, Koji Hanai, Takashi Kato, Akihiko Sano, Takahiro Ochiya
    Proceedings of the National Academy of Sciences of the United States of America 102 (34) 12177 - 82 0027-8424 2005/08 [Refereed]
    Silencing of gene expression by small interfering RNAs (siRNAs) is rapidly becoming a powerful tool for genetic analysis and represents a potential strategy for therapeutic product development. However, there are no reports of systemic delivery for siRNAs toward treatment of bone-metastatic cancer. Accordingly, we report here that i.v. injection of GL3 luciferase siRNA complexed with atelocollagen showed effective reduction of luciferase expression from bone-metastatic prostate tumor cells developed in mouse thorax, jaws, and/or legs. We also show that the siRNA/atelocollagen complex can be efficiently delivered to tumors 24 h after injection and can exist intact at least for 3 days. Furthermore, atelocollagen-mediated systemic administration of siRNAs such as enhancer of zeste homolog 2 and phosphoinositide 3'-hydroxykinase p110-alpha-subunit, which were selected as candidate targets for inhibition of bone metastasis, resulted in an efficient inhibition of metastatic tumor growth in bone tissues. In addition, upregulation of serum IL-12 and IFN-alpha levels was not associated with the in vivo administration of the siRNA/atelocollagen complex. Thus, for treatment of bone metastasis of prostate cancer, an atelocollagen-mediated systemic delivery method could be a reliable and safe approach to the achievement of maximal function of siRNA.
  • Takumi Teratani, Hanako Yamamoto, Kazuhiko Aoyagi, Hiroki Sasaki, Akira Asari, Gary Quinn, Hideo Sasaki, Masaaki Terada, Takahiro Ochiya
    Hepatology (Baltimore, Md.) 41 (4) 836 - 46 0270-9139 2005/04 [Refereed]
    The molecules responsible for hepatic differentiation from embryonic stem (ES) cells have yet to be elucidated. Here we have identified growth factors that allow direct hepatic fate-specification from ES cells by using simple adherent monolayer culture conditions. ES cell-derived hepatocytes showed liver-specific characteristics, including several metabolic activities, suggesting that ES cells can differentiate into functional hepatocytes without the requirement for embryoid body (EB) formation, in vivo transplantation, or a coculture system. Most importantly, transplantation of ES cell-derived hepatocytes in mice with cirrhosis showed significant therapeutic effects. In conclusion, this novel system for hepatic fate specification will help elucidate the precise molecular mechanisms of hepatic differentiation in vitro and could represent an attractive approach for developing stem cell therapies for treatment of hepatic disease in humans. Supplementary material for this article can be found on the HEPATOLOGY website (
  • Takumi Teratani, Gary Quinn, Yusuke Yamamoto, Tomoya Sato, Hiroko Yamanokuchi, Akira Asari, Takahiro Ochiya
    Cell transplantation 14 (9) 629 - 35 0963-6897 2005 [Refereed]
    This study investigated the three-dimensional culture of hepatocytes differentiated from mouse embryonic stem (ES) cells with a porous hyaluronan (HA) sponge support. Hepatocytes were immobilized within the pores of the support. Spheroids could be observed within the support, each containing between 20 and 50 hepatocytes. To examine the liver-specific functions of the hepatocytes in the culture, the levels of albumin secreted into the medium were analyzed. The secretion of albumin was stable over the course of 32 days, longer than that in both conventional monolayer and collagen sponge cultures. To elucidate further the liver-specific functions of hepatocytes embedded in the HA sponge, metabolic activities of the hepatocytes were examined for their ability to eliminate ammonia from culture media and the synthesis of urea nitrogen. While rates of ammonia removal and urea nitrogen synthesis were similar to those in both conventional monolayer and in collagen sponge cultures, these functions were maintained for longer duration in cells embedded in the HA sponge. These results demonstrate that the porous HA sponge is an effective support for the in vitro culture of ES-derived hepatocytes used for both basic and applied studies for cell transplantation.
  • Hanako Yamamoto, Gary Quinn, Akira Asari, Hiroko Yamanokuchi, Takumi Teratani, Masaaki Terada, Takahiro Ochiya
    Hepatology (Baltimore, Md.) 37 (5) 983 - 93 0270-9139 2003/05 [Refereed]
    Embryonic stem (ES) cells provide a unique source for tissue regeneration. We examined whether mouse ES cells can efficiently differentiate into transplantable hepatocytes. ES cells were implanted into mouse livers 24 hours after carbon tetrachloride intoxication; ES-derived cells with several hepatocyte-cell-markers were generated. They were able to grow in vitro and showed morphology consistent with typical mature hepatocytes and expressed hepatocyte-specific genes. After transplantation into the carbon tetrachloride-injured mouse liver, ES-derived green fluorescent protein-positive cells were incorporated into liver tissue and rescued mice from hepatic injury. No teratoma formation was observed in the transplant recipients. In conclusion, ES cells can provide a valuable tool for studying the molecular basis for differentiation of hepatocytes and form the basis for cell therapies.
  • Takumi Teratani, Takumi Watanabe, Kaori Yamahara, Hiromichi Kumagai, Akira Ishikawa, Kazumori Arai, Ryushi Nozawa
    Biochemical and biophysical research communications 291 (3) 623 - 7 0006-291X 2002/03 [Refereed]
    Reverse transcription--polymerase chain reaction (RT-PCR) identified the expression of calcium-binding protein S100A5 in the noncancerous parts of resected samples from renal cell carcinoma (RCC) patients (n = 7) but not in the carcinoma lesions. Rabbit anti-S100A5 antibody immunohistochemically detected the antigen in the thick ascending limb of Henle, distal convoluted tubule, and collecting duct system. No apparent immunopositivity was observed in the glomerulus, proximal tubules, interstitial cells, or RCC cells. Thus, it was suggested that S100A5 protein plays an inherent functional role to the post-thick ascending limb of Henle portion in the nephron. Further, the carcinomas tested were originated probably not in the S100A5-positive distal epithelium but in the -negative epithelium of proximal tubules. Then, total RNA was extracted by phenol/chloroform from 1 ml urine of healthy volunteers, and S100A5 was amplified by RT-PCR from all samples (n = 12), indicating that the transcript of S100A5 is detectable even in the cells released into urine.
  • Takumi Teratani, Takumi Watanabe, Fuminari Kuwahara, Hiromichi Kumagai, Shuzou Kobayashi, Utaka Aoki, Akira Ishikawa, Kazumori Arai, Ryushi Nozawa
    Cancer letters 175 (1) 71 - 7 0304-3835 2002/01 [Refereed]
    Expression of 16 S100 family calcium-binding protein genes was evaluated by PCR in ten human tissue cDNA libraries. Six to 12 S100 genes were expressed in a tissue-specific manner. Then, the expression in the surgically resected renal cell carcinoma (RCC) and a cultured RCC cell line was studied by RT-PCR. Although eight to nine S100 genes were transcribed in the normal kidney library and non-cancerous part of resected kidney tumors, S100A1 and S100A10 genes were not expressed. However, these genes were newly expressed in the RCC lesions (n=7) and the RCC cell line, indicating that expression of S100A1 and S100A10 genes is accompanied by RCC.
  • Kazumori Arai, Takumi Teratani, Ryushi Nozawa, Toshihiro Yamada
    Oncology Reports 1021-335X 2001/05 [Refereed]


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