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7. Human iPSC–liver organoid transplantation reduces fibrosis through immunomodulation.

Author

Tadokoro, Tomomi, Murata, Soichiro, Kato, Mimoko, Ueno, Yasuharu, Tsuchida, Tomonori, Okumura, Ayumu, Kuse, Yoshiki, Konno, Takahiro, Uchida, Yutaro, Yamakawa, Yuriko, Zushi, Marina, Yajima, Megumi, Kobayashi, Tatsuya, Hasegawa, Shunsuke, Kawakatsu-Hatada, Yumi, Hayashi, Yoshihito, Osakabe, Shun, Maeda, Takuji, Kimura, Kodai, and Mori, Akihiro

Subjects
INDUCED pluripotent stem cells, HEPATIC fibrosis, BILE ducts, CELL communication, FETAL tissues
Abstract

Donor organ shortages for transplantation remain a serious global concern, and alternative treatment is in high demand. Fetal cells and tissues have considerable therapeutic potential as, for example, organoid technology that uses human induced pluripotent stem cells (hiPSCs) to generate unlimited human fetal-like cells and tissues. We previously reported the in vivo vascularization of early fetal liver–like hiPSC-derived liver buds (LBs) and subsquent improved survival of recipient mice with subacute liver failure. Here, we show hiPSC–liver organoids (LOs) that recapitulate midgestational fetal liver promote de novo liver generation when grafted onto the surface of host livers in chemical fibrosis models, thereby recovering liver function. We found that fetal liver, a hematopoietic tissue, highly expressed macrophage-recruiting factors and antifibrotic M2 macrophage polarization factors compared with the adult liver, resulting in fibrosis reduction because of CD163+ M2-macrophage polarization. Next, we created midgestational fetal liver–like hiPSC-LOs by fusion of hiPSC-LBs to induce static cell-cell interactions and found that these contained complex structures such as hepatocytes, vasculature, and bile ducts after transplantation. This fusion allowed the generation of a large human tissue suitable for transplantation into immunodeficient rodent models of liver fibrosis. hiPSC-LOs showed superior liver function compared with hiPSC-LBs and improved survival and liver function upon transplantation. In addition, hiPSC-LO transplantation ameliorated chemically induced liver fibrosis, a symptom of liver cirrhosis that leads to organ dysfunction, through immunomodulatory effects, particularly on CD163+ phagocytic M2-macrophage polarization. Together, our results suggest hiPSC-LO transplantation as a promising therapeutic option for liver fibrosis. Editor's summary: Human induced pluripotent stem cells (hiPSCs) show clear potential for regenerative medicine, but their clinical development can be challenging. Tadokoro et al. show that fusion of hundreds of hiPSC-derived fetal liver–like buds produces larger organoids that are suitable for transplantation. Engraftment of these fused organoids onto the livers of immunocompromised mice resulted in the formation of bile duct and other liver structures, as well as connections between the human organoid and mouse liver vasculatures. These grafts partially reverted chemically induced liver fibrosis in the mice through phagocytic macrophage polarization, indicating a promising therapeutic approach that should be further tested in preclinical models of metabolic liver disease. —Catherine Charneski [ABSTRACT FROM AUTHOR]

Published
2024
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22. Efficacy and safety of 3 day versus 7 day cefditoren pivoxil regimens for acute uncomplicated cystitis: multicentre, randomized, open-label trial

Author

Sadahira, Takuya, Wada, Koichiro, Araki, Motoo, Ishii, Ayano, Takamoto, Atsushi, Kobayashi, Yasuyuki, Watanabe, Masami, Watanabe, Toyohiko, Nasu, Yasutomo, Kumon, Hiromi, Nasu, Yasutomo, Akaeda, Teruaki, Akazawa, Nobuyuki, Akebi, Naoki, Araki, Daiji, Araki, Tohru, Araki, Motoo, Arata, Ryoji, Ariyoshi, Yuichi, Ando, Eiichi, Ando, Nobuyoshi, Ishii, Ayano, Ishii, Kazushi, Ishikawa, Tsutomu, Ishito, Noritaka, Ichikawa, Takaharu, Inoue, Takaaki, Inoue, Miyabi, Inoue, Yosuke, Irie, Shin, Iwata, Takehiro, Uesugi, Tatsuya, Uehara, Shinya, Uematsu, Katsutoshi, Uno, Satoshi, Edamura, Kohei, Ebara, Shin, Oiwa, Yuko, Oeda, Tadashi, Ohashi, Teruhisa, Ohashi, Yozo, Ozawa, Hideo, Ochi, Junzo, Ono, Noriaki, Kai, Seiji, Kaku, Haruki, Katayama, Satoshi, Katayama, Yasuhiro, Kaneshige, Tetuzo, Kawauchi, Keiichiro, Kawaguchi, Masashi, Kawada, Tatsushi, Kanbara, Taiki, Kishi, Mikio, Kishimoto, Ryo, Kusaka, Nobuyuki, Kusumi, Norihiro, Kunitomi, Kimito, Kubota, Risa, Kumon, Hiromi, Kurahashi, Hiroaki, Kojima, Hironori, Kobayashi, Tomoko, Kobayashi, Yasuyuki, Kobuke, Makoto, Kondo, Katsuyoshi, Saika, Takashi, Sakaeda, Kazuma, Sakuramoto, Koji, Sako, Shinichi, Sako, Tomoko, Sasaoka, Taketo, Sasaki, Katsumi, Sadahira, Takuya, Jo, Yoshimasa, Sugimoto, Morito, Seno, Yuko, Takao, Akira, Takamura, Kosuke, Takamura, Kousuke, Takamoto, Atsushi, Takamoto, Hitoshi, Takeda, Katsuji, Takenaka, Tadasu, Tanaka, Daisuke, Tanimoto, Ryuta, Tsugawa, Masaya, Tsushima, Tomoyasu, Tsuboi, Hiromu, Tojo, Syunji, Tokinaga, Kenji, Tominaga, Yusuke, Doi, Keisuke, Nagai, Atsushi, Nakajima, Hirochika, Nakada, Tetsuya, Nakatsuka, Hirokazu, Nakamura, Aya, Nakayama, Yasuki, Nasu, Yoshitsugu, Nishikawa, Daisuke, Nishiguchi, Jun, Nishitani, Yoshio, Nishimura, Shingo, Nishimura, Motoichi, Nishiyama, Yasuhiro, Nibuno, Hajime, Nozaki, Kunihiro, Nose, Hiroyuki, Noda, Gaku, Hashimoto, Hideaki, Hata, Kazuhiro, Hayashi, Toshihide, Hayashi, Nobuki, Hayata, Syunji, Hara, Ryoei, Hirata, Takeshi, Fujii, Tomohiro, Fujio, Kei, Fujita, Ryuji, Bekku, Kensuke, Maehara, Takanori, Maki, Yoshio, Matsumoto, Yuko, Manabe, Daisuke, Mayumi, Yusuke, Maruyama, Yuki, Mitsui, Yosuke, Miyaji, Sadayuki, Munemasa, Syuhei, Murao, Wataru, Murakami, Takanori, Murata, Tadashi, Mori, Akihiro, Morita, Akira, Monden, Koichi, Yamasaki, Tomoya, Yamashita, Masahiro, Yamada, Daiduke, Yamato, Toyoko, Yamane, Toru, Yamanoi, Tomoaki, Yamamoto, Yasuo, Yukari, Kazuaki, Yokoyama, Teruhiko, Yoshioka, Takashi, Watanabe, Toyohiko, Watanabe, Masami, Watanabe, Yuichi, and Wada, Koichiro

Published
2017
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32. Impact of Hemodialysis on Clinical Outcomes in Patients Undergoing Lower Extremity Bypass Surgery for Peripheral Artery Disease—10-year Follow-Up Study.

Author

Kumada, Yoshitaka, Kawai, Norikazu, Ishida, Narihiro, Mori, Akihiro, Ishii, Hideki, Ohshima, Satoru, Ito, Ryuta, Umemoto, Norio, Takahashi, Hiroshi, and Murohara, Toyoaki

Subjects
LEG surgery, ISCHEMIA, CONFIDENCE intervals, PERIPHERAL vascular diseases, SURGERY, PATIENTS, VASCULAR surgery, TREATMENT effectiveness, DESCRIPTIVE statistics, HEMODIALYSIS, AMPUTATION, LONGITUDINAL method, PROPORTIONAL hazards models
Abstract

We investigated the clinical impact of hemodialysis on long-term outcomes of bypass surgery in patients with peripheral artery disease. We evaluated 660 consecutive patients who underwent successful bypass surgery (392 hemodialysis and 268 non-hemodialysis). The endpoint was amputation-free survival (AFS). To minimize differences in clinical characteristics between the 2 groups, propensity score matching was performed. The AFS rates for 10-year follow-up were 39.3% and 67.7% in hemodialysis and non-hemodialysis patients [hazard ratio (HR) 2.21, 95% confidence interval (CI) 1.65–3.01, P <.0001]. Cumulative incidence of amputation was higher in the hemodialysis group than in the non-hemodialysis group [(19.4 vs 8.4%, HR 2.15, 95% CI 1.29–3.74, P =.0027). In a matched cohort (n = 210 each), AFS was still lower in the hemodialysis patients (53.1 vs 66.3%, HR 1.94, 95% CI 1.36–2.82, P =.0003). However, there was no significant difference in amputation rate between the groups (10.5 vs 10.6%, HR.97, 95% CI 0.49–1.87, P =.93). In a sub-analysis of patients with critical limb ischemia, similar results were obtained. The 10-year AFS was consistently lower in the hemodialysis group than in the non-hemodialysis group. However, the amputation rate was comparable between the groups when matched for the differences in clinical characteristics. [ABSTRACT FROM AUTHOR]

Published
2022
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41. Utility of a corticotropin‐releasing hormone test to differentiate pituitary‐dependent hyperadrenocorticism from cortisol‐producing adrenal tumors in dogs.

Author

Tanaka, Sachiyo, Suzuki, Shuji, Sato, Asaka, Teshima, Takahiro, Mori, Akihiro, Sako, Toshinori, Tanaka, Aki, and Hara, Yasushi

Subjects
CORTICOTROPIN releasing hormone, ADRENAL tumors, BEAGLE (Dog breed), DOGS, ADRENOCORTICOTROPIC hormone, ADRENAL glands
Abstract

Background: Hyperadrenocorticism (HAC) is a common endocrine disorder in dogs; however, there are no reports on the use of the corticotropin‐releasing hormone test (CRHT) to differentiate between pituitary‐dependent hyperadrenocorticism (PDH) and cortisol‐producing adrenal tumors (CPATs), both causative of HAC. Objectives: To evaluate the usefulness of CRHT as a tool to differentiate between PDH and CPAT in dogs and to determine the reference intervals for CRHT in healthy, PDH, and CPAT dogs. Animals Dogs diagnosed with PDH (n = 21), CPAT (n = 6), and healthy beagle dogs (n = 33). Methods: This prospective study included dogs with a definitive diagnosis of PDH and CPAT and healthy beagle dogs, in which CRHT was performed, were prospectively evaluated. We investigated the correlations of CRHT (endogenous adrenocorticotropic hormone [ACTH] concentration, endogenous ACTH concentration [EAC], and poststimulation ACTH concentration [PAC]) with pituitary‐to‐brain ratio (PBR) (in PDH) and with indices of adrenal ultrasonography (smaller and larger adrenal gland dorsoventral thickness in PDH and CPAT). Results: For EAC, the area under the curve (AUC) was 0.95, with a cutoff value of 26.3 pg/mL (sensitivity: 90.62%, specificity: 87.50%). The AUC for PAC was 0.96 with a cutoff value of 54.5 pg/mL (sensitivity: 100.00%, specificity: 66.67%). The 95% reference interval for CRHT in healthy (control) dogs ranged 5.00 to 79.8 pg/mL (1.10‐17.57 pmol/L) for EAC, and 1.92 to 153.42 pg/mL (0.42‐33.78 pmol/L) for PAC. There was no significant correlation between PBR and CRHT, nor adrenal size and CRHT. Conclusions and Clinical Importance: CRHT appears to be a rapid and reliable test for differentiating PDH from CPAT in dogs. [ABSTRACT FROM AUTHOR]

Published
2022
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43. Relationship between anti-insulin antibody production and severe insulin resistance in a diabetic cat.

Author

KOMIYA, Takumi, MORI, Akihiro, NISHII, Naohito, ODA, Hitomi, ONOZAWA, Eri, SEKI, Seri, and SAKO, Toshinori

Subjects
INSULIN antibodies, ANTIBODY formation, INSULIN resistance, DIABETIC acidosis, GLYCEMIC control, KETOACIDOSIS
Abstract

A 5-year-old castrated male domestic shorthair cat was diagnosed with diabetic ketoacidosis and severe insulin resistance. Although the conventional treatment for diabetic ketoacidosis was provided, the cat required frequent hospitalization because of severe dehydration and repeated diabetic ketoacidosis. We detected anti-insulin antibodies for human in this cat. Serum insulin-binding IgG levels were markedly elevated compared with those in healthy cats and other diabetic cats. We initiated prednisolone to suppress the effects of anti-insulin antibodies. After initiation of prednisolone, the cat was gradually recovered with increasing activity and appetite. Furthermore, satisfactory glycemic control was achieved with combined subcutaneous injection of insulin detemir and insulin degludec. [ABSTRACT FROM AUTHOR]

Published
2021
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48. SPECC1L regulates palate development downstream of IRF6.

Author

Hall, Everett G, Wenger, Luke W, Wilson, Nathan R, Undurty-Akella, Sraavya S, Standley, Jennifer, Augustine-Akpan, Eno-Abasi, Kousa, Youssef A, Acevedo, Diana S, Goering, Jeremy P, Pitstick, Lenore, Natsume, Nagato, Paroya, Shahnawaz M, Busch, Tamara D, Ito, Masaaki, Mori, Akihiro, Imura, Hideto, Schultz-Rogers, Laura E, Klee, Eric W, Babovic-Vuksanovic, Dusica, and Kroc, Sarah A

Published
2020
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