2023/09/12 更新

写真a

ミヤタ タカシ
宮田 崇
MIYATA Takashi
所属
大学院医学系研究科 附属医学教育研究支援センター 特任研究部門 特任助教
職名
特任助教

学位 1

  1. 博士(医学) ( 2021年1月   名古屋大学 ) 

 

論文 21

  1. Generation and purification of ACTH-secreting hPSC-derived pituitary cells for effective transplantation.

    Taga S, Suga H, Nakano T, Kuwahara A, Inoshita N, Kodani Y, Nagasaki H, Sato Y, Tsumura Y, Sakakibara M, Soen M, Miwata T, Ozaki H, Kano M, Watari K, Ikeda A, Yamanaka M, Takahashi Y, Kitamoto S, Kawaguchi Y, Miyata T, Kobayashi T, Sugiyama M, Onoue T, Yasuda Y, Hagiwara D, Iwama S, Tomigahara Y, Kimura T, Arima H

    Stem cell reports   18 巻 ( 8 ) 頁: 1657 - 1671   2023年8月

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    記述言語:英語   出版者・発行元:Stem Cell Reports  

    Pituitary organoids are promising graft sources for transplantation in treatment of hypopituitarism. Building on development of self-organizing culture to generate pituitary-hypothalamic organoids (PHOs) using human pluripotent stem cells (hPSCs), we established techniques to generate PHOs using feeder-free hPSCs and to purify pituitary cells. The PHOs were uniformly and reliably generated through preconditioning of undifferentiated hPSCs and modulation of Wnt and TGF-β signaling after differentiation. Cell sorting using EpCAM, a pituitary cell-surface marker, successfully purified pituitary cells, reducing off-target cell numbers. EpCAM-expressing purified pituitary cells reaggregated to form three-dimensional pituitary spheres (3D-pituitaries). These exhibited high adrenocorticotropic hormone (ACTH) secretory capacity and responded to both positive and negative regulators. When transplanted into hypopituitary mice, the 3D-pituitaries engrafted, improved ACTH levels, and responded to in vivo stimuli. This method of generating purified pituitary tissue opens new avenues of research for pituitary regenerative medicine.

    DOI: 10.1016/j.stemcr.2023.05.002

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  2. Response to endoplasmic reticulum stress in arginine vasopressin neurons

    Hagiwara Daisuke, Azuma Yoshinori, Kawaguchi Yohei, Miyata Takashi, Arima Hiroshi

    ENDOCRINE JOURNAL   70 巻 ( 6 ) 頁: 567 - 572   2023年5月

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    記述言語:英語   出版者・発行元:Endocrine Journal  

    Arginine vasopressin (AVP) is an antidiuretic hormone synthesized principally in the hypothalamic supraoptic and paraventricular nuclei. The immunoglobulin heavy chain binding protein (BiP), one of the most abundant endoplasmic reticulum (ER) chaperones, is highly expressed in AVP neurons, even under basal conditions. Moreover, its expression is upregulated in proportion to the increase in AVP expression under dehydration. These data suggest that AVP neurons are constantly exposed to ER stress. BiP knockdown in AVP neurons induces ER stress and autophagy, resulting in AVP neuronal loss, indicating that BiP is pivotal in maintaining the AVP neuron system. Furthermore, inhibition of autophagy after BiP knockdown exacerbates AVP neuronal loss, suggesting that autophagy induced under ER stress is a protective cellular mechanism by which AVP neurons cope with ER stress. Familial neurohypophysial diabetes insipidus (FNDI) is an autosomal dominant disorder caused by mutations in the AVP gene. It is characterized by delayed-onset progressive polyuria and eventual AVP neuronal loss. In AVP neurons of FNDI model mice, mutant protein aggregates are confined to a specific compartment of the ER, called the ER-associated compartment (ERAC). The formation of ERACs contributes to maintaining the function of the remaining intact ER, and mutant protein aggregates in ERACs undergo autophagic-lysosomal degradation without isolation or translocation from the ER, representing a novel protein degradation system in the ER.

    DOI: 10.1507/endocrj.EJ23-0193

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  3. Anti-tumor effects of anti-programmed cell death-1 antibody treatment are attenuated in streptozotocin-induced diabetic mice

    Ito Masaaki, Iwama Shintaro, Sugiyama Daisuke, Yasuda Yoshinori, Okuji Takayuki, Kobayashi Tomoko, Zhou Xin, Yamagami Ayana, Onoue Takeshi, Miyata Takashi, Sugiyama Mariko, Hagiwara Daisuke, Suga Hidetaka, Banno Ryoichi, Nishikawa Hiroyoshi, Arima Hiroshi

    SCIENTIFIC REPORTS   13 巻 ( 1 ) 頁: 5939   2023年4月

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    記述言語:英語   出版者・発行元:Scientific Reports  

    Hyperglycemia impairs immune response; however, it remains unknown whether the anti-tumor effects of anti-programmed cell death-1 antibody (PD-1-Ab) treatment are changed in hyperglycemic conditions. We analyzed the effect of PD-1-Ab on tumor growth in streptozotocin-induced diabetic mice (STZ-mice) subcutaneously inoculated with MC38 (a colon carcinoma cell line). Furthermore, we assessed the expression of chemokines by polymerase chain reaction (PCR) array in tumor-draining lymph nodes (dLNs) of these mice and MC38 cells cultured in different glucose concentrations. The suppressive effect of PD-1-Ab on tumor growth was attenuated. This was accompanied by fewer tumor-infiltrating CD8+ T cells, and STZ-mice had fewer tumor-infiltrating CD11c+ dendritic cells (DCs) than normoglycemic mice. mRNA expression levels of CXCL9, a chemokine recruiting CD8+ T cells, were lower in dLNs of STZ-mice than in normoglycemic mice after PD-1-Ab treatment, and its protein was expressed in DCs. In MC38 cells cultured with 25 mM glucose, mRNA expression of CCL7, a chemokine recruiting DCs, was decreased compared to cells cultured with 5 mM glucose. These results suggest that the STZ-induced hyperglycemia impairs the effect of PD-1-Ab treatment on MC38 tumor growth, and is accompanied by reduced infiltration of DCs and CD8+ T cells and decreased expression of CCL7 and CXCL9.

    DOI: 10.1038/s41598-023-33049-7

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  4. Generation of hypothalamic neural stem cell-like cells in vitro from human pluripotent stem cells

    Miwata Tsutomu, Suga Hidetaka, Kawaguchi Yohei, Sakakibara Mayu, Kano Mayuko, Taga Shiori, Soen Mika, Ozaki Hajime, Asano Tomoyoshi, Sasaki Hiroo, Miyata Takashi, Yasuda Yoshinori, Kobayashi Tomoko, Sugiyama Mariko, Onoue Takeshi, Takagi Hiroshi, Hagiwara Daisuke, Iwama Shintaro, Arima Hiroshi

    STEM CELL REPORTS   18 巻 ( 4 ) 頁: 869 - 883   2023年4月

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    記述言語:英語   出版者・発行元:Stem Cell Reports  

    When damaged, restoring the function of the hypothalamus is currently impossible. It is unclear whether neural stem cells exist in the hypothalamus. Studies have reported that adult rodent tanycytes around the third ventricle function as hypothalamic neural stem cell-like cells. However, it is currently impossible to collect periventricular cells from humans. We attempted to generate hypothalamic neural stem cell-like cells from human embryonic stem cells (ESCs). We focused on retina and anterior neural fold homeobox (RAX) because its expression is gradually restricted to tanycytes during the late embryonic stage. We differentiated RAX::VENUS knockin human ESCs (hESCs) into hypothalamic organoids and sorted RAX+ cells from mature organoids. The isolated RAX+ cells formed neurospheres and exhibited self-renewal and multipotency. Neurogenesis was observed when neurospheres were transplanted into the mouse hypothalamus. We isolated RAX+ hypothalamic neural stem cell-like cells from wild-type human ES organoids. This is the first study to differentiate human hypothalamic neural stem cell-like cells from pluripotent stem cells.

    DOI: 10.1016/j.stemcr.2023.02.006

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  5. Knockdown of endoplasmic reticulum chaperone BiP leads to the death of parvocellular AVP/CRH neurons in mice

    Kawaguchi Yohei, Hagiwara Daisuke, Tsumura Tetsuro, Miyata Takashi, Kobayashi Tomoko, Sugiyama Mariko, Onoue Takeshi, Yasuda Yoshinori, Iwama Shintaro, Suga Hidetaka, Banno Ryoichi, Grinevich Valery, Arima Hiroshi

    JOURNAL OF NEUROENDOCRINOLOGY   35 巻 ( 1 ) 頁: e13223   2023年1月

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    記述言語:英語   出版者・発行元:Journal of Neuroendocrinology  

    Arginine vasopressin (AVP) is expressed in both magnocellular (magnAVP) and parvocellular AVP (parvAVP) neurons of the paraventricular nucleus, and AVP colocalizes with corticotropin-releasing hormone (CRH) only in the parvocellular neurons. The immunoglobulin heavy chain binding protein (BiP) is a major endoplasmic reticulum (ER) chaperone which regulates the unfolded protein response under ER stress. We previously demonstrated that knockdown of BiP in magnAVP neurons exacerbated ER stress, which resulted in the autophagy-associated cell death of magnAVP neurons. Using the same approach, in the present study we examined the role of BiP in mouse parvAVP/CRH neurons. Our data demonstrate that BiP is expressed in mouse parvAVP/CRH neurons under nonstress conditions and is upregulated in proportion to the increase in CRH expression after adrenalectomy. For BiP knockdown in parvAVP/CRH neurons, we utilized a viral approach in combination with shRNA interference. Knockdown of BiP expression induced ER stress in parvAVP/CRH neurons, as reflected by the expression of C/EBP homologous protein. Furthermore, BiP knockdown led to the loss of parvAVP/CRH neurons after 4 weeks. In summary, our results demonstrate that BiP plays a pivotal role in parvAVP/CRH neurons, which function as neuroendocrine cells producing a large number of secretory proteins.

    DOI: 10.1111/jne.13223

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  6. Resting energy expenditure depends on energy intake during weight loss in people with obesity: a retrospective cohort study

    Handa Tomoko, Onoue Takeshi, Kobayashi Tomoko, Wada Eri, Hayase Ayaka, Kinoshita Tamaki, Yamagami Ayana, Yasuda Yoshinori, Iwama Shintaro, Kawaguchi Yohei, Miyata Takashi, Sugiyama Mariko, Takagi Hiroshi, Hagiwara Daisuke, Suga Hidetaka, Banno Ryoichi, Goto Motomitsu, Arima Hiroshi

    ARCHIVES OF ENDOCRINOLOGY METABOLISM   67 巻 ( 2 ) 頁: 233 - 241   2023年

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  7. Response to endoplasmic reticulum stress in arginine vasopressin neurons

    Hagiwara Daisuke, Azuma Yoshinori, Kawaguchi Yohei, Miyata Takashi, Arima Hiroshi

    ENDOCRINE JOURNAL   70 巻 ( 6 ) 頁: 567 - 572   2023年

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  8. Mineralocorticoids induce polyuria by reducing apical aquaporin-2 expression of the kidney in partial vasopressin deficiency

    Kurimoto Junki, Takagi Hiroshi, Miyata Takashi, Kawaguchi Yohei, Hodai Yuichi, Tsumura Tetsuro, Hagiwara Daisuke, Kobayashi Tomoko, Yasuda Yoshinori, Sugiyama Mariko, Onoue Takeshi, Iwama Shintaro, Suga Hidetaka, Banno Ryoichi, Katsuki Takeshi, Ando Fumiaki, Uchida Shinichi, Arima Hiroshi

    ENDOCRINE JOURNAL   70 巻 ( 3 ) 頁: 295 - 304   2023年

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  9. Mineralocorticoids induce polyuria by reducing apical aquaporin-2 expression of the kidney in partial vasopressin deficiency

    Kurimoto Junki, Takagi Hiroshi, Miyata Takashi, Kawaguchi Yohei, Hodai Yuichi, Tsumura Tetsuro, Hagiwara Daisuke, Kobayashi Tomoko, Yasuda Yoshinori, Sugiyama Mariko, Onoue Takeshi, Iwama Shintaro, Suga Hidetaka, Banno Ryoichi, Katsuki Takeshi, Ando Fumiaki, Uchida Shinichi, Arima Hiroshi

    ENDOCRINE JOURNAL   70 巻 ( 3 ) 頁: 295 - 304   2022年11月

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    記述言語:英語   出版者・発行元:Endocrine Journal  

    The symptoms of diabetes insipidus may be masked by the concurrence of adrenal insufficiency and emerge after the administration of hydrocortisone, occasionally at high doses. To elucidate the mechanism underlying polyuria induced by the administration of high-dose corticosteroids in the deficiency of arginine vasopressin (AVP), we first examined the secretion of AVP in three patients in whom polyuria was observed only after the administration of high-dose corticosteroids. Next, we examined the effects of dexamethasone or aldosterone on water balance in wild-type and familial neurohypophyseal diabetes insipidus (FNDI) model mice. A hypertonic saline test showed that AVP secretion was partially impaired in all patients. In one patient, there were no apparent changes in AVP secretion before and after the administration of high-dose corticosteroids. In FNDI mice, unlike dexamethasone, the administration of aldosterone increased urine volumes and decreased urine osmolality. Immunohistochemical analyses showed that, after the administration of aldosterone in FNDI mice, aquaporin-2 expression was decreased in the apical membrane and increased in the basolateral membrane in the collecting duct. These changes were not observed in wild-type mice. The present data suggest that treatment with mineralocorticoids induces polyuria by reducing aquaporin-2 expression in the apical membrane of the kidney in partial AVP deficiency.

    DOI: 10.1507/endocrj.EJ22-0339

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  10. Differentiation of human induced pluripotent stem cells into hypothalamic vasopressin neurons with minimal exogenous signals and partial conversion to the naive state

    Ozaki Hajime, Suga Hidetaka, Sakakibara Mayu, Soen Mika, Miyake Natsuki, Miwata Tsutomu, Taga Shiori, Nagai Takashi, Kano Mayuko, Mitsumoto Kazuki, Miyata Takashi, Kobayashi Tomoko, Sugiyama Mariko, Onoue Takeshi, Takagi Hiroshi, Hagiwara Daisuke, Iwama Shintaro, Banno Ryoichi, Iguchi Genzo, Takahashi Yutaka, Muguruma Keiko, Inoue Haruhisa, Arima Hiroshi

    SCIENTIFIC REPORTS   12 巻 ( 1 ) 頁: 17381   2022年10月

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    記述言語:英語   出版者・発行元:Scientific Reports  

    Familial neurohypophyseal diabetes insipidus (FNDI) is a degenerative disease of vasopressin (AVP) neurons. Studies in mouse in vivo models indicate that accumulation of mutant AVP prehormone is associated with FNDI pathology. However, studying human FNDI pathology in vivo is technically challenging. Therefore, an in vitro human model needs to be developed. When exogenous signals are minimized in the early phase of differentiation in vitro, mouse embryonic stem cells (ESCs)/induced pluripotent stem cells (iPSCs) differentiate into AVP neurons, whereas human ESCs/iPSCs die. Human ESCs/iPSCs are generally more similar to mouse epiblast stem cells (mEpiSCs) compared to mouse ESCs. In this study, we converted human FNDI-specific iPSCs by the naive conversion kit. Although the conversion was partial, we found improved cell survival under minimal exogenous signals and differentiation into rostral hypothalamic organoids. Overall, this method provides a simple and straightforward differentiation direction, which may improve the efficiency of hypothalamic differentiation.

    DOI: 10.1038/s41598-022-22405-8

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  11. Elevated TSH Level, TgAb, and Prior Use of Ramucirumab or TKIs as Risk Factors for Thyroid Dysfunction in PD-L1 Blockade

    Kobayashi Tomoko, Iwama Shintaro, Yamagami Ayana, Yasuda Yoshinori, Okuji Takayuki, Ito Masaaki, Zhou Xin, Ando Masahiko, Onoue Takeshi, Miyata Takashi, Sugiyama Mariko, Hagiwara Daisuke, Suga Hidetaka, Banno Ryoichi, Hase Tetsunari, Morise Masahiro, Ito Takanori, Kikumori Toyone, Inoue Megumi, Ando Yuichi, Masuda Norikazu, Kawashima Hiroki, Hashimoto Naozumi, Arima Hiroshi

    JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM   107 巻 ( 10 ) 頁: E4115 - E4123   2022年9月

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    記述言語:英語   出版者・発行元:Journal of Clinical Endocrinology and Metabolism  

    Background: Thyroid dysfunction is frequently caused by treatment with antiprogrammed cell death-1 ligand 1 antibodies (PD-L1-Abs) and anticancer drugs, including ramucirumab (RAM) and multitargeted tyrosine kinase inhibitors (multi-TKIs), which are often used prior to PD-L1-Ab treatment in cancer patients. Methods: A total of 148 patients treated with PD-L1-Abs were evaluated for antithyroid antibodies at baseline and for thyroid function every 6 weeks for 24 weeks after treatment initiation and then were observed until the visits stopped. Results: Of the 148 patients, 15 (10.1%) developed thyroid dysfunction after PD-L1-Ab treatment (destructive thyroiditis in 8 and hypothyroidism without preceding thyrotoxicosis in 7). The prevalence of an elevated thyroid-stimulating hormone (TSH) level at baseline (3/15 [20.0%] vs 4/133 [3.0%], P < .05), positive antithyroglobulin antibodies (TgAbs) at baseline (4/15 [26.7%] vs 5/133 [3.8%], P < .05) and prior treatment with RAM or multi-TKIs (3/15 [20.0%] vs 5/133 [3.8%], P < .05) were significantly higher in patients with vs without thyroid dysfunction. In a multivariate analysis, elevated TSH level at baseline, TgAb positivity at baseline, and prior treatment with RAM or multi-TKIs were significantly associated with the development of thyroid dysfunction, with ORs of 7.098 (95% CI 1.154-43.638), 11.927 (95% CI 2.526-56.316), and 8.476 (95% CI 1.592-45.115), respectively. Conclusion: The results of this real-world study suggest that the risk of thyroid dysfunction induced by PD-L1-Abs can be predicted by the TSH level at baseline, TgAb positivity at baseline, and prior treatment with RAM or multi-TKIs.

    DOI: 10.1210/clinem/dgac467

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  12. Inflammation in VTA Caused by HFD Induces Activation of Dopaminergic Neurons Accompanied by Binge-like Eating

    Sun Runan, Sugiyama Mariko, Wang Sixian, Kuno Mitsuhiro, Sasaki Tomoyuki, Hirose Tomonori, Miyata Takashi, Kobayashi Tomoko, Tsunekawa Taku, Onoue Takeshi, Yasuda Yoshinori, Takagi Hiroshi, Hagiwara Daisuke, Iwama Shintaro, Suga Hidetaka, Arima Hiroshi

    NUTRIENTS   14 巻 ( 18 )   2022年9月

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    記述言語:日本語   出版者・発行元:Nutrients  

    Binge eating is a characteristic symptom observed in obese individuals that is related to dysfunction of dopaminergic neurons (DNs). Intermittent administration of a high-fat diet (HFD) is reported to induce binge-like eating, but the underlying mechanisms remain unclear. We generated dopaminergic neuron specific IKKβ deficient mice (KO) to examine the effects of inflammation in DNs on binge-like eating under inflammatory conditions associated with HFD. After administration of HFD for 4 weeks, mice were fasted for 24 h, and then the consumption of HFD was measured for 2 h. We also evaluated that the mRNA expressions of inflammatory cytokines, glial markers, and dopamine signaling-related genes in the ventral tegmental area (VTA) and striatum. Moreover, insulin was administered intraventricularly to assess downstream signaling. The consumption of HFD was significantly reduced, and the phosphorylation of AKT in the VTA was significantly increased in female KO compared to wild-type (WT) mice. Analyses of mRNA expressions revealed that DNs activity and inflammation in the VTA were significantly decreased in female KO mice. Thus, our data suggest that HFD-induced inflammation with glial cell activation in the VTA affects DNs function and causes abnormal eating behaviors accompanied by insulin resistance in the VTA of female mice.

    DOI: 10.3390/nu14183835

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  13. Increased Risk of Thyroid Dysfunction by PD-1 and CTLA-4 Blockade in Patients Without Thyroid Autoantibodies at Baseline

    Iwama Shintaro, Kobayashi Tomoko, Yasuda Yoshinori, Okuji Takayuki, Ito Masaaki, Ando Masahiko, Zhou Xin, Yamagami Ayana, Onoue Takeshi, Kawaguchi Yohei, Miyata Takashi, Sugiyama Mariko, Takagi Hiroshi, Hagiwara Daisuke, Suga Hidetaka, Banno Ryoichi, Hase Tetsunari, Morise Masahiro, Wakahara Keiko, Yokota Kenji, Kato Masashi, Nishio Naoki, Tanaka Chie, Miyata Kazushi, Ogura Atsushi, Ito Takanori, Sawada Tsunaki, Shimokata Tomoya, Niimi Kaoru, Ohka Fumiharu, Ishigami Masatoshi, Gotoh Momokazu, Hashimoto Naozumi, Saito Ryuta, Kiyoi Hitoshi, Kajiyama Hiroaki, Ando Yuichi, Hibi Hideharu, Sone Michihiko, Akiyama Masashi, Kodera Yasuhiro, Arima Hiroshi

    JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM   107 巻 ( 4 ) 頁: E1620 - E1630   2022年3月

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    記述言語:日本語   出版者・発行元:Journal of Clinical Endocrinology and Metabolism  

    Background: Previous studies showed that although the risk of thyroid dysfunction [thyroid immune-related adverse events (irAEs)] induced by anti-programmed cell death-1 antibodies (PD-1-Ab) was as low as 2% to 7% in patients negative for anti-thyroid antibodies (ATAs) at baseline, it was much higher (30%-50%) in patients positive for ATAs. However, whether a similar increase occurs with combination therapy using PD-1-Ab plus anti-cytotoxic T-lymphocyte antigen-4 antibody (CTLA-4-Ab) is unknown. Methods: A total of 451 patients with malignancies treated with PD-1-Ab, CTLA-4-Ab, or a combination of PD-1-Ab and CTLA-4-Ab (PD-1/CTLA-4-Abs) were evaluated for ATAs at baseline and for thyroid function every 6 weeks for 24 weeks after treatment initiation and then observed until the last clinical visit. Results: Of the 451 patients, 51 developed thyroid irAEs after immunotherapy [41 of 416 (9.9%) treated with PD-1-Ab, 0 of 8 (0%) treated with CTLA-4-Ab, and 10 of 27 (37.0%) treated with PD-1/CTLA-4-Abs]. The cumulative incidence of thyroid irAEs was significantly higher in patients who were positive vs negative for ATAs at baseline after both PD-1-Ab [28/87 (32.2%) vs 13/329 (4.0%), P < 0.001] and PD-1/CTLA-4-Abs [6/10 (60.0%) vs 4/17 (23.5%), P < 0.05] treatments. The risk of thyroid irAEs induced by PD-1/CTLA-4Abs, which was significantly higher than that induced by PD-1-Ab, in patients negative for ATAs at baseline was not statistically different from that induced by PD-1-Ab in patients positive for ATAs at baseline. Conclusions: This study showed that the incidence of thyroid irAEs was high and not negligible after PD-1/CTLA-4-Abs treatment even in patients negative for ATAs at baseline.

    DOI: 10.1210/clinem/dgab829

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  14. Functional Lactotrophs in Induced Adenohypophysis Differentiated From Human iPS Cells

    Miyake Natsuki, Nagai Takashi, Suga Hidetaka, Osuka Satoko, Kasai Takatoshi, Sakakibara Mayu, Soen Mika, Ozaki Hajime, Miwata Tsutomu, Asano Tomoyoshi, Kano Mayuko, Muraoka Ayako, Nakanishi Natsuki, Nakamura Tomoko, Goto Maki, Yasuda Yoshinori, Kawaguchi Yohei, Miyata Takashi, Kobayashi Tomoko, Sugiyama Mariko, Onoue Takeshi, Hagiwara Daisuke, Iwama Shintaro, Iwase Akira, Inoshita Naoko, Arima Hiroshi, Kajiyama Hiroaki

    ENDOCRINOLOGY   163 巻 ( 3 )   2022年3月

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    記述言語:日本語   出版者・発行元:Endocrinology (United States)  

    Prolactin (PRL), a hormone involved in lactation, is mainly produced and secreted by the lactotrophs of the anterior pituitary (AP) gland. We previously reported a method to generate functional adrenocorticotropic hormone-producing cells by differentiating the AP and hypothalamus simultaneously from human induced pluripotent stem cells (iPSCs). However, PRL-producing cells in the induced AP have not been investigated. Here, we confirmed the presence of PRL-producing cells and evaluated their endocrine functions. We differentiated pituitary cells from human iPSCs using serum-free floating culture of embryoid-like aggregates with quick reaggregation (SFEB-q) method and evaluated the appearance and function of PRL-producing cells. Secretion of PRL from the differentiated aggregates was confirmed, which increased with further culture. Fluorescence immunostaining and immunoelectron microscopy revealed PRL-producing cells and PRL-positive secretory granules, respectively. PRL secretion was promoted by various prolactin secretagogues such as thyrotropin-releasing hormone, vasoactive intestinal peptide, and prolactin-releasing peptide, and inhibited by bromocriptine. Moreover, the presence of tyrosine hydroxylase-positive dopaminergic nerves in the hypothalamic tissue area around the center of the aggregates connecting to PRL-producing cells indicated the possibility of recapitulating PRL regulatory mechanisms through the hypothalamus. In conclusion, we generated pituitary lactotrophs from human iPSCs; these displayed similar secretory responsiveness as human pituitary cells in vivo. In the future, this is expected to be used as a model of human PRL-producing cells for various studies, such as drug discovery, prediction of side effects, and elucidation of tumorigenic mechanisms using disease-specific iPSCs. Furthermore, it may help to develop regenerative medicine for the pituitary gland.

    DOI: 10.1210/endocr/bqac004

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  15. GABA(B) receptor signaling in the caudate putamen is involved in binge-like consumption during a high fat diet in mice

    Sun Runan, Tsunekawa Taku, Hirose Tomonori, Yaginuma Hiroshi, Taki Keigo, Mizoguchi Akira, Miyata Takashi, Kobayashi Tomoko, Sugiyama Mariko, Onoue Takeshi, Takagi Hiroshi, Hagiwara Daisuke, Ito Yoshihiro, Iwama Shintaro, Suga Hidetaka, Banno Ryoichi, Bettler Bernhard, Arima Hiroshi

    SCIENTIFIC REPORTS   11 巻 ( 1 ) 頁: 19296   2021年9月

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    記述言語:日本語   出版者・発行元:Scientific Reports  

    Previous studies suggest that signaling by the gamma-aminobutyric acid (GABA) type B receptor (GABABR) is involved in the regulation of binge eating, a disorder which might contribute to the development of obesity. Here, we show that intermittent access to a high fat diet (HFD) induced binge-like eating behavior with activation of dopamine receptor d1 (drd1)-expressing neurons in the caudate putamen (CPu) and nucleus accumbens (NAc) in wild-type (WT) mice. The activation of drd1-expressing neurons during binge-like eating was substantially increased in the CPu, but not in the NAc, in corticostriatal neuron-specific GABABR-deficient knockout (KO) mice compared to WT mice. Treatment with the GABABR agonist, baclofen, suppressed binge-like eating behavior in WT mice, but not in KO mice, as reported previously. Baclofen also suppressed the activation of drd1-expressing neurons in the CPu, but not in the NAc, during binge-like eating in WT mice. Thus, our data suggest that GABABR signaling in CPu neurons expressing drd1 suppresses binge-like consumption during a HFD in mice.

    DOI: 10.1038/s41598-021-98590-9

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  16. Deficiency of WFS1 leads to the impairment of AVP secretion under dehydration in male mice

    Kurimoto Junki, Takagi Hiroshi, Miyata Takashi, Hodai Yuichi, Kawaguchi Yohei, Hagiwara Daisuke, Suga Hidetaka, Kobayashi Tomoko, Sugiyama Mariko, Onoue Takeshi, Ito Yoshihiro, Iwama Shintaro, Banno Ryoichi, Tanabe Katsuya, Tanizawa Yukio, Arima Hiroshi

    PITUITARY   24 巻 ( 4 ) 頁: 582 - 588   2021年8月

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    記述言語:日本語   出版者・発行元:Pituitary  

    Wolfram syndrome (WS) is mainly caused by mutations in the WFS1 gene and characterized by diabetes mellitus, optic atrophy, hearing loss, and central diabetes insipidus (CDI). WFS1 is an endoplasmic reticulum (ER)-resident transmembrane protein, and Wfs1 knockout (Wfs1−/−) mice, which have been used as a mouse model for WS, reportedly manifested impairment of glucose tolerance due to pancreatic β-cell loss. In the present study, we examined water balance, arginine vasopressin (AVP) secretion, and ER stress in AVP neurons of the hypothalamus in Wfs1−/− mice. There were no differences in urine volumes between Wfs1−/− and wild-type mice with free access to water. Conversely, when mice were subjected to intermittent water deprivation (WD) for 20 weeks, during which water was unavailable for 2 days a week, urine volumes were larger in Wfs1−/− mice, accompanied by lower urine AVP concentrations and urine osmolality, compared to wild-type mice. The mRNA expression of immunoglobulin heavy chain binding protein, a marker of ER stress, was significantly increased in the supraoptic nucleus and paraventricular nuclei in Wfs1−/− mice compared to wild-type mice after WD. Our results thus showed that Wfs1 knockout leads to a decrease in AVP secretion during dehydration, which could explain in part the mechanisms by which Wfs1 mutations cause CDI in humans.

    DOI: 10.1007/s11102-021-01135-6

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  17. Arginine vasopressin-Venus reporter mice as a tool for studying magnocellular arginine vasopressin neurons

    Hagiwara Daisuke, Tochiya Masayoshi, Azuma Yoshinori, Tsumura Tetsuro, Hodai Yuichi, Kawaguchi Yohei, Miyata Takashi, Kobayashi Tomoko, Sugiyama Mariko, Onoue Takeshi, Takagi Hiroshi, Ito Yoshihiro, Iwama Shintaro, Suga Hidetaka, Banno Ryoichi, Arima Hiroshi

    PEPTIDES   139 巻   頁: 170517   2021年5月

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    記述言語:日本語   出版者・発行元:Peptides  

    Arginine vasopressin (AVP) synthesized in the magnocellular neurons of the hypothalamus is transported through their axons and released from the posterior pituitary into the systemic circulation to act as an antidiuretic hormone. AVP synthesis and release are precisely regulated by changes in plasma osmolality. Magnocellular AVP neurons receive innervation from osmosensory and sodium-sensing neurons, but previous studies showed that AVP neurons per se are osmosensitive as well. In the current study, we made AVP-Venus reporter mice and showed that Venus was expressed exclusively in AVP neurons and was upregulated under water deprivation. In hypothalamic organotypic cultures from the AVP-Venus mice, Venus-labeled AVP neurons in the supraoptic and paraventricular nuclei survived for 1 month, and Venus expression was upregulated by forskolin. Furthermore, in dissociated Venus-labeled magnocellular neurons, treatment with NaCl, but not with mannitol, decreased Venus fluorescence in the soma of the AVP neurons. Thus, Venus expression in AVP-Venus transgenic mice, as well as in primary cultures, faithfully showed the properties of intrinsic AVP expression. These findings indicate that AVP-Venus mice as well as the primary hypothalamic cultures could be useful for studying magnocellular AVP neurons.

    DOI: 10.1016/j.peptides.2021.170517

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  18. Endoplasmic reticulum chaperone BiP/GRP78 knockdown leads to autophagy and cell death of arginine vasopressin neurons in mice

    Kawaguchi Yohei, Hagiwara Daisuke, Miyata Takashi, Hodai Yuichi, Kurimoto Junki, Takagi Hiroshi, Suga Hidetaka, Kobayashi Tomoko, Sugiyama Mariko, Onoue Takeshi, Ito Yoshihiro, Iwama Shintaro, Banno Ryoichi, Grinevich Valery, Arima Hiroshi

    SCIENTIFIC REPORTS   10 巻 ( 1 ) 頁: 19730   2020年11月

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    記述言語:日本語   出版者・発行元:Scientific Reports  

    The immunoglobulin heavy chain binding protein (BiP), also referred to as 78-kDa glucose-regulated protein (GRP78), is a pivotal endoplasmic reticulum (ER) chaperone which modulates the unfolded protein response under ER stress. Our previous studies showed that BiP is expressed in arginine vasopressin (AVP) neurons under non-stress conditions and that BiP expression is upregulated in proportion to the increased AVP expression under dehydration. To clarify the role of BiP in AVP neurons, we used a viral approach in combination with shRNA interference for BiP knockdown in mouse AVP neurons. Injection of a recombinant adeno-associated virus equipped with a mouse AVP promoter and BiP shRNA cassette provided specific BiP knockdown in AVP neurons of the supraoptic (SON) and paraventricular nuclei (PVN) in mice. AVP neuron-specific BiP knockdown led to ER stress and AVP neuronal loss in the SON and PVN, resulting in increased urine volume due to lack of AVP secretion. Immunoelectron microscopy of AVP neurons revealed that autophagy was activated through the process of AVP neuronal loss, whereas no obvious features characteristic of apoptosis were observed. Pharmacological inhibition of autophagy by chloroquine exacerbated the AVP neuronal loss due to BiP knockdown, indicating a protective role of autophagy in AVP neurons under ER stress. In summary, our results demonstrate that BiP is essential for the AVP neuron system.

    DOI: 10.1038/s41598-020-76839-z

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  19. Degradation of Mutant Protein Aggregates within the Endoplasmic Reticulum of Vasopressin Neurons

    Miyata Takashi, Hagiwara Daisuke, Hodai Yuichi, Miwata Tsutomu, Kawaguchi Yohei, Kurimoto Junki, Ozaki Hajime, Mitsumoto Kazuki, Takagi Hiroshi, Suga Hidetaka, Kobayashi Tomoko, Sugiyama Mariko, Onoue Takeshi, Ito Yoshihiro, Iwama Shintaro, Banno Ryoichi, Matsumoto Mami, Kawakami Natsuko, Ohno Nobuhiko, Sakamoto Hirotaka, Arima Hiroshi

    ISCIENCE   23 巻 ( 10 ) 頁: 101648   2020年10月

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    記述言語:日本語   出版者・発行元:iScience  

    Misfolded or unfolded proteins in the ER are said to be degraded only after translocation or isolation from the ER. Here, we describe a mechanism by which mutant proteins are degraded within the ER. Aggregates of mutant arginine vasopressin (AVP) precursor were confined to ER-associated compartments (ERACs) connected to the ER in AVP neurons of a mouse model of familial neurohypophysial diabetes insipidus. The ERACs were enclosed by membranes, an ER chaperone and marker protein of phagophores and autophagosomes were expressed around the aggregates, and lysosomes fused with the ERACs. Moreover, lysosome-related molecules were present within the ERACs, and aggregate degradation within the ERACs was dependent on autophagic-lysosomal activity. Thus, we demonstrate that protein aggregates can be degraded by autophagic-lysosomal machinery within specialized compartments of the ER.

    DOI: 10.1016/j.isci.2020.101648

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  20. Generation of four induced pluripotent stem cell lines (FHUi003-A, FHUi003-B, FHUi004-A and FHUi004-B) from two affected individuals of a familial neurohypophyseal diabetes insipidus family

    Yoshida Satoru, Okura Hanayuki, Suga Hidetaka, Soen Mika, Kawaguchi Yohei, Kurimoto Junki, Miyata Takashi, Takagi Hiroshi, Arima Hiroshi, Fujikawa Tatsuya, Otsuka Fumio, Matsuyama Akifumi

    STEM CELL RESEARCH   48 巻   頁: 101960   2020年10月

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    記述言語:日本語   出版者・発行元:Stem Cell Research  

    Four disease-specific induced pluripotent stem cell (iPSC) lines were respectively derived from peripheral blood mononuclear cells of two affected individuals in a family affected by familial neurohypophyseal diabetes insipidus carrying the c.314G>C mutation. The expression of pluripotency markers (NANOG, OCT4, and SOX2), maintenance of a normal karyotype, absence of episomal vectors used for iPSC generation, and presence of the original pathogenic mutation were confirmed for each iPSC line. The ability to differentiate into three germ layers was confirmed by a teratoma formation assay. These iPSC lines can help in disease recapitulation in vitro using organoids and elucidation of disease mechanisms.

    DOI: 10.1016/j.scr.2020.101960

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  21. Chemical chaperone 4-phenylbutylate reduces mutant protein accumulation in the endoplasmic reticulum of arginine vasopressin neurons in a mouse model for familial neurohypophysial diabetes insipidus

    Tochiya Masayoshi, Hagiwara Daisuke, Azuma Yoshinori, Miyata Takashi, Morishita Yoshiaki, Suga Hidetaka, Onoue Takeshi, Tsunekawa Taku, Takagi Hiroshi, Ito Yoshihiro, Iwama Shintaro, Goto Motomitsu, Banno Ryoichi, Arima Hiroshi

    NEUROSCIENCE LETTERS   682 巻   頁: 50 - 55   2018年8月

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    記述言語:日本語   出版者・発行元:Neuroscience Letters  

    Familial neurohypophysial diabetes insipidus (FNDI), characterized by progressive polyuria and loss of arginine vasopressin (AVP) neurons, is an autosomal dominant disorder caused by AVP gene mutations. Our previous studies with FNDI model mice demonstrated that mutant proteins accumulated in the endoplasmic reticulum (ER) of AVP neurons. Here, we examined therapeutic effects of the chemical chaperone 4-phenylbutylate (4-PBA) in FNDI mice. Treatment with 4-PBA reduced mutant protein accumulation in the ER of FNDI mice and increased AVP release, leading to reduced urine volumes. Furthermore, AVP neuron loss under salt loading was attenuated by 4-PBA treatment. These data suggest that 4-PBA ameliorated mutant protein accumulation in the ER of AVP neurons and thereby prevented FNDI phenotype progression.

    DOI: 10.1016/j.neulet.2018.06.013

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