16 results on '"Shinsuke, Shibata"'
Search Results
2. A non-invasive system to monitor in vivo neural graft activity after spinal cord injury
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Kentaro Ago, Narihito Nagoshi, Kent Imaizumi, Takahiro Kitagawa, Momotaro Kawai, Keita Kajikawa, Reo Shibata, Yasuhiro Kamata, Kota Kojima, Munehisa Shinozaki, Takahiro Kondo, Satoshi Iwano, Atsushi Miyawaki, Masanari Ohtsuka, Haruhiko Bito, Kenta Kobayashi, Shinsuke Shibata, Tomoko Shindo, Jun Kohyama, Morio Matsumoto, Masaya Nakamura, and Hideyuki Okano
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Mice ,Neural Stem Cells ,Animals ,Medicine (miscellaneous) ,Cell Differentiation ,Recovery of Function ,General Agricultural and Biological Sciences ,Spinal Cord Injuries ,General Biochemistry, Genetics and Molecular Biology ,Stem Cell Transplantation - Abstract
Expectations for neural stem/progenitor cell (NS/PC) transplantation as a treatment for spinal cord injury (SCI) are increasing. However, whether and how grafted cells are incorporated into the host neural circuit and contribute to motor function recovery remain unknown. The aim of this project was to establish a novel non-invasive in vivo imaging system to visualize the activity of neural grafts by which we can simultaneously demonstrate the circuit-level integration between the graft and host and the contribution of graft neuronal activity to host behaviour. We introduced Akaluc, a newly engineered luciferase, under the control of enhanced synaptic activity-responsive element (E-SARE), a potent neuronal activity-dependent synthetic promoter, into NS/PCs and engrafted the cells into SCI model mice. Through the use of this system, we found that the activity of grafted cells was integrated with host behaviour and driven by host neural circuit inputs. This non-invasive system is expected to help elucidate the therapeutic mechanism of cell transplantation treatment for SCI.
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- 2022
3. Novel bile acid biosynthetic pathways are enriched in the microbiome of centenarians
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Ramnik J. Xavier, Shoki Okamoto, Hera Vlamakis, Satoshi Sasajima, Junichiro Irie, Shinsuke Shibata, Koji Atarashi, Yasumichi Arai, Wataru Suda, Seiko Narushima, Ashwin N. Skelly, Yuko Sato, Masahira Hattori, Makoto Suematsu, Damian R. Plichta, Takahiro Sasaki, Yuki Okamura, Yuki Sugiura, Michael A. Fischbach, Dan R. Littman, Hiroshi Nittono, Nobuko Moritoki, Takeshi Tanoue, Tsuyoshi Murai, Nobuyoshi Hirose, Kenya Honda, Kozue Takeshita, Akira Honda, Yoshifumi Uwamino, Takashi Inoue, Hajime Takei, Youxian Li, Hiroshi Itoh, Kyoji Moriya, and Sean M. Kearney
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chemistry.chemical_classification ,Multidisciplinary ,Lithocholic acid ,biology ,Bile acid ,medicine.drug_class ,Metabolism ,Antimicrobial ,biology.organism_classification ,In vitro ,Microbiology ,chemistry.chemical_compound ,Enzyme ,chemistry ,medicine ,Microbiome ,Enterococcus faecium - Abstract
Centenarians have a decreased susceptibility to ageing-associated illnesses, chronic inflammation and infectious diseases1–3. Here we show that centenarians have a distinct gut microbiome that is enriched in microorganisms that are capable of generating unique secondary bile acids, including various isoforms of lithocholic acid (LCA): iso-, 3-oxo-, allo-, 3-oxoallo- and isoallolithocholic acid. Among these bile acids, the biosynthetic pathway for isoalloLCA had not been described previously. By screening 68 bacterial isolates from the faecal microbiota of a centenarian, we identified Odoribacteraceae strains as effective producers of isoalloLCA both in vitro and in vivo. Furthermore, we found that the enzymes 5α-reductase (5AR) and 3β-hydroxysteroid dehydrogenase (3β-HSDH) were responsible for the production of isoalloLCA. IsoalloLCA exerted potent antimicrobial effects against Gram-positive (but not Gram-negative) multidrug-resistant pathogens, including Clostridioides difficile and Enterococcus faecium. These findings suggest that the metabolism of specific bile acids may be involved in reducing the risk of infection with pathobionts, thereby potentially contributing to the maintenance of intestinal homeostasis. The microbiota of centenarians (aged 100 years and older) comprise gut microorganisms that are capable of generating unique secondary bile acids, including isoallolithocholic acid, a bile acid with potent antimicrobial effects against Gram-positive—but not Gram-negative—multidrug-resistant pathogens.
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- 2021
4. The liver–brain–gut neural arc maintains the Treg cell niche in the gut
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Po Sung Chu, Masayuki Inoue, Yuya Hagihara, Takaharu Okada, Akihiko Yoshimura, Mamoru Tanida, Yosuke Harada, Harumichi Ishigame, Minoru Matsui, Toshihiko Yada, Yusaku Iwasaki, Kentaro Miyamoto, Hideyuki Okano, Takanori Kanai, Wataru Suda, Nobuhito Taniki, Shinsuke Shibata, Nobuhiro Nakamoto, Yuko Kitagawa, Yohei Mikami, Masahira Hattori, Toshiaki Teratani, Tomohisa Sujino, Keita Kohno, Takahiro Suzuki, Koji Okabayashi, and Makoto Tsuda
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0301 basic medicine ,Multidisciplinary ,Liver cytology ,Reflex arc ,digestive, oral, and skin physiology ,Central nervous system ,Biology ,Gut flora ,biology.organism_classification ,Cell biology ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Muscarinic acetylcholine receptor ,medicine ,Brainstem ,Receptor ,030217 neurology & neurosurgery ,Homeostasis - Abstract
Recent clinical and experimental evidence has evoked the concept of the gut–brain axis to explain mutual interactions between the central nervous system and gut microbiota that are closely associated with the bidirectional effects of inflammatory bowel disease and central nervous system disorders1–4. Despite recent advances in our understanding of neuroimmune interactions, it remains unclear how the gut and brain communicate to maintain gut immune homeostasis, including in the induction and maintenance of peripheral regulatory T cells (pTreg cells), and what environmental cues prompt the host to protect itself from development of inflammatory bowel diseases. Here we report a liver–brain–gut neural arc that ensures the proper differentiation and maintenance of pTreg cells in the gut. The hepatic vagal sensory afferent nerves are responsible for indirectly sensing the gut microenvironment and relaying the sensory inputs to the nucleus tractus solitarius of the brainstem, and ultimately to the vagal parasympathetic nerves and enteric neurons. Surgical and chemical perturbation of the vagal sensory afferents at the hepatic afferent level reduced the abundance of colonic pTreg cells; this was attributed to decreased aldehyde dehydrogenase (ALDH) expression and retinoic acid synthesis by intestinal antigen-presenting cells. Activation of muscarinic acetylcholine receptors directly induced ALDH gene expression in both human and mouse colonic antigen-presenting cells, whereas genetic ablation of these receptors abolished the stimulation of antigen-presenting cells in vitro. Disruption of left vagal sensory afferents from the liver to the brainstem in mouse models of colitis reduced the colonic pTreg cell pool, resulting in increased susceptibility to colitis. These results demonstrate that the novel vago-vagal liver–brain–gut reflex arc controls the number of pTreg cells and maintains gut homeostasis. Intervention in this autonomic feedback feedforward system could help in the development of therapeutic strategies to treat or prevent immunological disorders of the gut. A liver–brain–gut neural circuit responds to the gut microenvironment and regulates the activity of peripheral regulatory T cells in the colon by controlling intestinal antigen-presenting cells in a muscarinic signalling-dependent manner.
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- 2020
5. Renin–angiotensin system impairs macrophage lipid metabolism to promote age-related macular degeneration in mouse models
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Kazuo Tsubota, Hideyuki Okano, Hirohiko Kawashima, Kohei Homma, Eriko Toda, Hideto Osada, Norihiro Nagai, Yoko Ozawa, Yasuo Uchiyama, Shinsuke Shibata, and Naymel A. Guzman
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0301 basic medicine ,genetic structures ,Medicine (miscellaneous) ,Renin-Angiotensin System ,Mice ,0302 clinical medicine ,Biology (General) ,biology ,Photoreceptor outer segment ,Lipoproteins, LDL ,Mechanisms of disease ,medicine.anatomical_structure ,lipids (amino acids, peptides, and proteins) ,Disease Susceptibility ,General Agricultural and Biological Sciences ,ATP Binding Cassette Transporter 1 ,Signal Transduction ,medicine.medical_specialty ,QH301-705.5 ,Diet, High-Fat ,Models, Biological ,Receptor, Angiotensin, Type 1 ,Retina ,Article ,General Biochemistry, Genetics and Molecular Biology ,Proinflammatory cytokine ,03 medical and health sciences ,Internal medicine ,Renin–angiotensin system ,medicine ,Animals ,Retinal pigment epithelium ,business.industry ,Macrophages ,Macular degeneration ,Lipid metabolism ,Lipid Metabolism ,medicine.disease ,Angiotensin II ,eye diseases ,PPAR gamma ,Disease Models, Animal ,030104 developmental biology ,Endocrinology ,ABCA1 ,biology.protein ,sense organs ,business ,Angiotensin II Type 1 Receptor Blockers ,Biomarkers ,030217 neurology & neurosurgery - Abstract
Metabolic syndrome, a condition involving obesity and hypertension, increases the risk of aging-associated diseases such as age-related macular degeneration (AMD). Here, we demonstrated that high-fat diet (HFD)-fed mice accumulated oxidized low-density lipoprotein (ox-LDL) in macrophages through the renin–angiotensin system (RAS). The ox-LDL-loaded macrophages were responsible for visual impairment in HFD mice along with a disorder of the retinal pigment epithelium (RPE), which is required for photoreceptor outer segment renewal. RAS repressed ELAVL1, which reduced PPARγ, impeding ABCA1 induction to levels that are sufficient to excrete overloaded cholesterol within the macrophages. The ox-LDL-loaded macrophages expressed inflammatory cytokines and attacked the RPE. An antihypertensive drug, angiotensin II type 1 receptor (AT1R) blocker, resolved the decompensation of lipid metabolism in the macrophages and reversed the RPE condition and visual function in HFD mice. AT1R signaling could be a future therapeutic target for macrophage-associated aging diseases, such as AMD., Nagai et al. show that mice fed high-fat diet (HFD) accumulate oxidized low-density lipoprotein in macrophages through the renin–angiotensin system, which impairs visual function. They find that angiotensin II type 1 receptor (AT1R) improves the visual function of HFD mice, suggesting AT1R signaling as a potential therapeutic target for age-related macular degeneration.
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- 2020
6. Cell therapy for spinal cord injury by using human iPSC-derived region-specific neural progenitor cells
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Tomoko Shindo, Kent Imaizumi, Yasuhiro Kamata, Morio Matsumoto, Hideyuki Okano, Takahiro Kitagawa, Shinsuke Shibata, Keita Kajikawa, Kota Kojima, Munehisa Shinozaki, Masaya Nakamura, Narihito Nagoshi, and Reo Shibata
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0301 basic medicine ,medicine.medical_treatment ,Induced Pluripotent Stem Cells ,Cell- and Tissue-Based Therapy ,Mice, SCID ,Spinal cord injury ,Motor Activity ,Biology ,lcsh:RC346-429 ,Cell Line ,Cell therapy ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Neural Stem Cells ,Mice, Inbred NOD ,otorhinolaryngologic diseases ,medicine ,Animals ,Humans ,Induced pluripotent stem cell ,Region-specific neural progenitors ,Molecular Biology ,lcsh:Neurology. Diseases of the nervous system ,Spinal Cord Injuries ,Stem cell therapy ,Behavior, Animal ,Research ,Cell Differentiation ,Recovery of Function ,Stem-cell therapy ,Spinal cord ,medicine.disease ,Neural stem cell ,Transplantation ,stomatognathic diseases ,030104 developmental biology ,medicine.anatomical_structure ,Spinal Cord ,Organ Specificity ,Forebrain ,Neuroscience ,030217 neurology & neurosurgery - Abstract
The transplantation of neural progenitor cells (NPCs) derived from human induced pluripotent stem cells (iPSCs) has beneficial effects on spinal cord injury (SCI). However, while there are many subtypes of NPCs with different regional identities, the subtype of iPSC-derived NPCs that is most appropriate for cell therapy for SCI has not been identified. Here, we generated forebrain- and spinal cord-type NPCs from human iPSCs and grafted them onto the injured spinal cord in mice. These two types of NPCs retained their regional identities after transplantation and exhibited different graft-host interconnection properties. NPCs with spinal cord regional identity but not those with forebrain identity resulted in functional improvement in SCI mice, especially in those with mild-to-moderate lesions. This study highlights the importance of the regional identity of human iPSC-derived NPCs used in cell therapy for SCI.
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- 2020
7. The Japan Monkey Centre Primates Brain Imaging Repository for comparative neuroscience: an archive of digital records including records for endangered species
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Yuta Shintaku, Kenichi Oishi, Yuki Ogawa, Yuzuru Hamada, Naoto Kimura, Hideyuki Okano, Shinsuke Shibata, Tomoko Sakai, Kazumi Sogabe, Hiroki Ohta, Hirotaka James Okano, Junichi Hata, and Susumu Mori
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Primates ,0301 basic medicine ,Databases, Factual ,Pygmy marmoset ,Neuroimaging ,Macaque ,03 medical and health sciences ,0302 clinical medicine ,Japan ,biology.animal ,Animals ,Primate ,Bonnet macaque ,biology ,Endangered Species ,Neurosciences ,Brain ,Records ,Marmoset ,Callithrix ,biology.organism_classification ,Biological Evolution ,Macaca mulatta ,Magnetic Resonance Imaging ,Guenon ,Japanese macaque ,030104 developmental biology ,Animal ecology ,Animal Science and Zoology ,Cartography ,030217 neurology & neurosurgery - Abstract
Advances in magnetic resonance imaging (MRI) and computational analysis technology have enabled comparisons among various primate brains in a three-dimensional electronic format. Results from comparative studies provide information about common features across primates and species-specific features of neuroanatomy. Investigation of various species of non-human primates is important for understanding such features, but the majority of comparative MRI studies have been based on experimental primates, such as common marmoset, macaques, and chimpanzee. A major obstacle has been the lack of a database that includes non-experimental primates' brain MRIs. To facilitate scientific discoveries in the field of comparative neuroanatomy and brain evolution, we launched a collaborative project to develop an open-resource repository of non-human primate brain images obtained using ex vivo MRI. As an initial open resource, here we release a collection of structural MRI and diffusion tensor images obtained from 12 species: pygmy marmoset, owl monkey, white-fronted capuchin, crab-eating macaque, Japanese macaque, bonnet macaque, toque macaque, Sykes' monkey, red-tailed monkey, Schmidt's guenon, de Brazza's guenon, and lar gibbon. Sixteen postmortem brain samples from the 12 species, stored in the Japan Monkey Centre (JMC), were scanned using a 9.4-T MRI scanner and made available through the JMC collaborative research program ( http://www.j-monkey.jp/BIR/index_e.html ). The expected significant contributions of the JMC Primates Brain Imaging Repository include (1) resources for comparative neuroscience research, (2) preservation of various primate brains, including those of endangered species, in a permanent digital form, (3) resources with higher resolution for identifying neuroanatomical features, compared to previous MRI atlases, (4) resources for optimizing methods of scanning large fixed brains, and (5) references for veterinary neuroradiology. User-initiated research projects beyond these contributions are also anticipated.
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- 2018
8. Enteric Glial Dysfunction Evoked by Apolipoprotein E Deficiency Contributes to Delayed Gastric Emptying
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Hitoshi Tsugawa, Hideki Mori, Seiichiro Fukuhara, Hidekazu Suzuki, Masaya Nakamura, Soraya Nishimura, Satoshi Kawase, Hideyuki Okano, Sawako Miyoshi, Takanori Kanai, Tatsuhiro Masaoka, Shinsuke Shibata, and Juntaro Matsuzaki
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0301 basic medicine ,Apolipoprotein E ,medicine.medical_specialty ,Physiology ,Gastric motility ,Myenteric Plexus ,Enteric Nervous System ,Diabetes Mellitus, Experimental ,03 medical and health sciences ,Apolipoproteins E ,Neural Stem Cells ,Internal medicine ,Glial Fibrillary Acidic Protein ,Animals ,Medicine ,Gastroparesis ,Mice, Knockout ,Glial fibrillary acidic protein ,biology ,Gastric emptying ,business.industry ,Stomach ,digestive, oral, and skin physiology ,Gastroenterology ,medicine.disease ,Transplantation ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,Gastric Emptying ,nervous system ,biology.protein ,Enteric nervous system ,business ,Ubiquitin Thiolesterase - Abstract
Diabetes is the main cause of gastroparesis accompanying decreased neuronal nitric oxide synthase (nNOS) in myenteric ganglia of the stomach. Decreased nNOS expression in the stomach also results from defects in apolipoprotein E (ApoE), which is secreted by astrocytes and has neuroprotective effects on the central nervous system. However, the roles of ApoE and enteric glial cells on gastric motility are uncertain. In this study, ApoE and enteric glial cell alterations in gastroparesis were investigated. Type 2 diabetic (db/db) mice and ApoE-knockout mice were analyzed. Gastric emptying was measured using the 13C acetic acid breath test. Expression levels of the pan-neuronal marker, protein gene product 9.5 (PGP 9.5), and glial marker, glial fibrillary acidic protein (GFAP) were examined by immunohistochemistry. Neural stem cells (NSCs) were injected into the gastric antral wall of ApoE-knockout mice. Delayed gastric emptying was observed in 27% of db/db mice with significant decreases in serum ApoE levels and GFAP expression in the gastric antrum. Gastric emptying was also delayed in ApoE-knockout mice, with a significant decrease in GFAP expression, but no change in PGP 9.5 expression. Transplantation of NSCs improved gastric emptying in ApoE-knockout mice through supplementation of GFAP-positive cells. Our results suggest that decreased enteric glial cells in ApoE-knockout mice are crucial for development of delayed gastric emptying, and NSC transplantation is effective in restoring myenteric ganglia and gastric motility.
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- 2017
9. The adeno-associated virus rh10 vector is an effective gene transfer system for chronic spinal cord injury
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Osahiko Tsuji, Jun Kohyama, Hideyuki Okano, Morio Matsumoto, Yutaka Hoshino, Masaya Nakamura, Kenji Nishide, Kota Kojima, Nobuko Moritoki, Shinsuke Shibata, and Narihito Nagoshi
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Recombinant Fusion Proteins ,Science ,Genetic enhancement ,Genetic Vectors ,Spinal cord injury ,Biology ,Gene delivery ,medicine.disease_cause ,Article ,Mice ,Bacterial Proteins ,Luciferases, Firefly ,medicine ,Animals ,Humans ,Bioluminescence imaging ,Adeno-associated virus ,Spinal Cord Injuries ,Tropism ,Neurons ,Multidisciplinary ,Gene Transfer Techniques ,Genetic Therapy ,Dependovirus ,medicine.disease ,Fusion protein ,Disease Models, Animal ,Luminescent Proteins ,Oligodendroglia ,Viral Tropism ,Astrocytes ,Cancer research ,Tissue tropism ,Medicine - Abstract
Treatment options for chronic spinal cord injury (SCI) remain limited due to unfavourable changes in the microenvironment. Gene therapy can overcome these barriers through continuous delivery of therapeutic gene products to the target tissue. In particular, adeno-associated virus (AAV) vectors are potential candidates for use in chronic SCI, considering their safety and stable gene expression in vivo. Given that different AAV serotypes display different cellular tropisms, it is extremely important to select an optimal serotype for establishing a gene transfer system during the chronic phase of SCI. Therefore, we generated multiple AAV serotypes expressing ffLuc-cp156, a fusion protein of firefly luciferase and Venus, a variant of yellow fluorescent protein with fast and efficient maturation, as a reporter, and we performed intraparenchymal injection in a chronic SCI mouse model. Among the various serotypes tested, AAVrh10 displayed the highest photon count on bioluminescence imaging. Immunohistological analysis revealed that AAVrh10 showed favourable tropism for neurons, astrocytes, and oligodendrocytes. Additionally, with AAVrh10, the area expressing Venus was larger in the injury epicentre and extended to the surrounding tissue. Furthermore, the fluorescence intensity was significantly higher with AAVrh10 than with the other vectors. These results indicate that AAVrh10 may be an appropriate serotype for gene delivery to the chronically injured spinal cord. This promising tool may be applied for research and development related to the treatment of chronic SCI.
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- 2019
10. SAMD9 mutations cause a novel multisystem disorder, MIRAGE syndrome, and are associated with loss of chromosome 7
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Satoshi Narumi, Hirosuke Inoue, Masanori Adachi, Masakazu Miyawaki, Asumi Higa, Toshiro Hara, Maki Fukami, Tomonobu Hasegawa, Naomichi Matsumoto, Tadamune Kinjo, Yukichi Tanaka, Hiroyuki Hamada, Hironaka Urano, Naoko Amano, Kenji Ihara, Jun Kudoh, Ryuji Fukuzawa, Kenichi Miyako, Tomohiro Ishii, Saori Kinjo, Shinsuke Shibata, Takahiro Okutani, Atsushi Shimizu, Noriko Miyake, Tetsuya Yamaguchi, Minako Kihara, Shiro Yamada, Koji Muroya, Noriyuki Katsumata, Hiroyuki Kitajima, Katsuaki Toyoshima, Zenro Kizaki, Miyuki Kohno, Koji Tsugawa, Manabu Kenmochi, Yosuke Kitagawa, Shouichi Ohga, Kentaro Shiga, and Hideyuki Okano
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Male ,0301 basic medicine ,medicine.medical_specialty ,Adolescent ,Genotype ,Endosomes ,Biology ,medicine.disease_cause ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Genetics ,medicine ,Humans ,Enteropathy ,Child ,Growth Disorders ,Exome sequencing ,Late endosome ,Chromosome 7 (human) ,Mutation ,Adrenal hypoplasia ,Infant, Newborn ,Intracellular Signaling Peptides and Proteins ,Infant ,Proteins ,Middle Aged ,medicine.disease ,Molecular biology ,Pedigree ,ErbB Receptors ,Phenotype ,030104 developmental biology ,Endocrinology ,Hypoadrenocorticism, Familial ,Myelodysplastic Syndromes ,030220 oncology & carcinogenesis ,Female ,DAX1 ,Chromosomes, Human, Pair 7 ,Adrenal Insufficiency ,Congenital disorder - Abstract
Adrenal hypoplasia is a rare, life-threatening congenital disorder. Here we define a new form of syndromic adrenal hypoplasia, which we propose to term MIRAGE (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy) syndrome. By exome sequencing and follow-up studies, we identified 11 patients with adrenal hypoplasia and common extra-adrenal features harboring mutations in SAMD9. Expression of the wild-type SAMD9 protein, a facilitator of endosome fusion, caused mild growth restriction in cultured cells, whereas expression of mutants caused profound growth inhibition. Patient-derived fibroblasts had restricted growth, decreased plasma membrane EGFR expression, increased size of early endosomes, and intracellular accumulation of giant vesicles carrying a late endosome marker. Of interest, two patients developed myelodysplasitc syndrome (MDS) that was accompanied by loss of the chromosome 7 carrying the SAMD9 mutation. Considering the potent growth-restricting activity of the SAMD9 mutants, the loss of chromosome 7 presumably occurred as an adaptation to the growth-restricting condition.
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- 2016
11. Migration and differentiation of transplanted enteric neural crest-derived cells in murine model of Hirschsprung’s disease
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Yasuhide Morikawa, Shinsuke Shibata, Masaya Nakamura, Yumi Matsuzaki, Naoki Shimojima, Ryuhei Nishikawa, Narihito Nagoshi, Ryo Hotta, Hideyuki Okano, Hirotaka James Okano, and Tatsuo Kuroda
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Pathology ,medicine.medical_specialty ,JAACT Special Issue ,medicine.medical_treatment ,Clinical Biochemistry ,Biomedical Engineering ,Bioengineering ,Cell Biology ,Stem-cell therapy ,Biology ,Neural stem cell ,Neuroepithelial cell ,Endothelial stem cell ,Neurosphere ,Immunology ,medicine ,Progenitor cell ,Stem cell ,Biotechnology ,Adult stem cell - Abstract
Stem cell therapy offers the potential of rebuilding the enteric nervous system (ENS) in the aganglionic bowel of patients with Hirschsprung's disease. P0-Cre/Floxed-EGFP mice in which neural crest-derived cells express EGFP were used to obtain ENS stem/progenitor cells. ENS stem/progenitor cells were transplanted into the bowel of Ret(-/-) mouse, an animal model of Hirschsprung's disease. Immunohistochemical analysis was performed to determine whether grafted cells gave rise to neurons in the recipient bowel. EGFP expressing neural crest-derived cells accounted for 7.01 ± 2.52 % of total cells of gastrointestinal tract. ENS stem/progenitor cells were isolated using flow cytometry and expanded as neurosphere-like bodies (NLBs) in a serum-free culture condition. Some cells in NLBs expressed neural crest markers, p75 and Sox10 and neural stem/progenitor cells markers, Nestin and Musashi1. Multipotency of isolated ENS stem/progenitor cells was determined as they differentiated into neurons, glial cells, and myofibloblasts in culture. When co-cultured with explants of hindgut of Ret(-/-) mice, ENS stem/progenitor cells migrated into the aganglionic bowel and gave rise to neurons. ENS stem/progenitor cells used in this study appear to be clinically relevant donor cells in cell therapy to treat Hirschsprung's disease capable of colonizing the affected bowel and giving rise to neurons.
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- 2014
12. Sema3A regulates bone-mass accrual through sensory innervations
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Shinsuke Shibata, Toru Fukuda, Hiroshi Itoh, Ren Xu, Yoshinori Asou, Shu Takeda, Koji Fujita, Zirong Gu, Hideyuki Okano, Chengshan Ma, Takashi Hirai, Atsushi Okawa, Mitsuhiro Enomoto, Satoko Sunamura, Waka Bando, Hiroki Ochi, Kenichi Shinomiya, Yutaka Yoshida, Ayako Kimura, Cheng Xu, and Tsuyoshi Sato
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Male ,medicine.medical_specialty ,Sensory Receptor Cells ,Bone and Bones ,Bone remodeling ,Mice ,Semaphorin ,Internal medicine ,medicine ,Animals ,Cells, Cultured ,Osteoblasts ,Multidisciplinary ,Chemistry ,Cell Differentiation ,Semaphorin-3A ,Osteoblast ,SEMA3A ,Organ Size ,medicine.anatomical_structure ,Endocrinology ,Female ,Axon guidance ,Bone Remodeling ,Neural development ,Homeostasis ,Sensory nerve - Abstract
Semaphorin 3A (Sema3A) is a diffusible axonal chemorepellent that has an important role in axon guidance. Previous studies have demonstrated that Sema3a(-/-) mice have multiple developmental defects due to abnormal neuronal innervations. Here we show in mice that Sema3A is abundantly expressed in bone, and cell-based assays showed that Sema3A affected osteoblast differentiation in a cell-autonomous fashion. Accordingly, Sema3a(-/-) mice had a low bone mass due to decreased bone formation. However, osteoblast-specific Sema3A-deficient mice (Sema3acol1(-/-) and Sema3aosx(-/-) mice) had normal bone mass, even though the expression of Sema3A in bone was substantially decreased. In contrast, mice lacking Sema3A in neurons (Sema3asynapsin(-/-) and Sema3anestin(-/-) mice) had low bone mass, similar to Sema3a(-/-) mice, indicating that neuron-derived Sema3A is responsible for the observed bone abnormalities independent of the local effect of Sema3A in bone. Indeed, the number of sensory innervations of trabecular bone was significantly decreased in Sema3asynapsin(-/-) mice, whereas sympathetic innervations of trabecular bone were unchanged. Moreover, ablating sensory nerves decreased bone mass in wild-type mice, whereas it did not reduce the low bone mass in Sema3anestin(-/-) mice further, supporting the essential role of the sensory nervous system in normal bone homeostasis. Finally, neuronal abnormalities in Sema3a(-/-) mice, such as olfactory development, were identified in Sema3asynasin(-/-) mice, demonstrating that neuron-derived Sema3A contributes to the abnormal neural development seen in Sema3a(-/-) mice, and indicating that Sema3A produced in neurons regulates neural development in an autocrine manner. This study demonstrates that Sema3A regulates bone remodelling indirectly by modulating sensory nerve development, but not directly by acting on osteoblasts.
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- 2013
13. A selective Sema3A inhibitor enhances regenerative responses and functional recovery of the injured spinal cord
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Zhigang He, Hirotaka James Okano, Kazuo Kumagai, Akiyoshi Kishino, Yoshio Goshima, Chikao Nakayama, Akio Iwanami, Masaya Nakamura, Kaoru Kikuchi, Yoshiaki Toyama, Shinsuke Shibata, Shinjiro Kaneko, Ayako Moriya, Hideyuki Okano, Mamoru Ito, Takeshi Ikegami, Masahiko Taniguchi, Osamu Konishi, Toru Kimura, and Yasufumi Sato
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Angiogenesis ,Regeneration (biology) ,Central nervous system ,SEMA3A ,General Medicine ,Anatomy ,Biology ,medicine.disease ,Spinal cord ,General Biochemistry, Genetics and Molecular Biology ,Cell biology ,medicine.anatomical_structure ,nervous system ,In vivo ,Apoptosis ,medicine ,Spinal cord injury - Abstract
Axons in the adult mammalian central nervous system (CNS) exhibit little regeneration after injury. It has been suggested that several axonal growth inhibitors prevent CNS axonal regeneration. Recent research has demonstrated that semaphorin3A (Sema3A) is one of the major inhibitors of axonal regeneration. We identified a strong and selective inhibitor of Sema3A, SM-216289, from the fermentation broth of a fungal strain. To examine the effect of SM-216289 in vivo, we transected the spinal cord of adult rats and administered SM-216289 into the lesion site for 4 weeks. Rats treated with SM-216289 showed substantially enhanced regeneration and/or preservation of injured axons, robust Schwann cell-mediated myelination and axonal regeneration in the lesion site, appreciable decreases in apoptotic cell number and marked enhancement of angiogenesis, resulting in considerably better functional recovery. Thus, Sema3A is essential for the inhibition of axonal regeneration and other regenerative responses after spinal cord injury (SCI). These results support the possibility of using Sema3A inhibitors in the treatment of human SCI.
- Published
- 2006
14. Inflammatory cascades mediate synapse elimination in spinal cord compression
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Masaya Nakamura, Yuji Komaki, Yoshiaki Toyama, Keigo Hikishima, Morito Takano, Shinsuke Shibata, Hideyuki Okano, and Soya Kawabata
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Pathology ,medicine.medical_specialty ,Time Factors ,Immunology ,Inflammation ,Spinal canal stenosis ,Severity of Illness Index ,Synapse ,Mice ,Cellular and Molecular Neuroscience ,Spinal cord compression ,medicine ,Animals ,Pyrophosphatases ,Movement Disorders ,Microglia ,business.industry ,Complement C1q ,Gene Expression Profiling ,Macrophages ,Research ,General Neuroscience ,Neurodegeneration ,cervical compressive myelopathy ,Spinal cord ,medicine.disease ,Magnetic Resonance Imaging ,complement activation classical pathway ,Mice, Mutant Strains ,Pathophysiology ,Disease Models, Animal ,tip-toe walking Yoshimura mice ,medicine.anatomical_structure ,Gene Expression Regulation ,Spinal Cord ,Neurology ,Mutation ,Synapses ,synapse elimination ,medicine.symptom ,business ,Spinal Cord Compression ,Cysteine-Rich Protein 61 ,Signal Transduction - Abstract
Background Cervical compressive myelopathy (CCM) is caused by chronic spinal cord compression due to spondylosis, a degenerative disc disease, and ossification of the ligaments. Tip-toe walking Yoshimura (twy) mice are reported to be an ideal animal model for CCM-related neuronal dysfunction, because they develop spontaneous spinal cord compression without any artificial manipulation. Previous histological studies showed that neurons are lost due to apoptosis in CCM, but the mechanism underlying this neurodegeneration was not fully elucidated. The purpose of this study was to investigate the pathophysiology of CCM by evaluating the global gene expression of the compressed spinal cord and comparing the transcriptome analysis with the physical and histological findings in twy mice. Methods Twenty-week-old twy mice were divided into two groups according to the magnetic resonance imaging (MRI) findings: a severe compression (S) group and a mild compression (M) group. The transcriptome was analyzed by microarray and RT-PCR. The cellular pathophysiology was examined by immunohistological analysis and immuno-electron microscopy. Motor function was assessed by Rotarod treadmill latency and stride-length tests. Results Severe cervical calcification caused spinal canal stenosis and low functional capacity in twy mice. The microarray analysis revealed 215 genes that showed significantly different expression levels between the S and the M groups. Pathway analysis revealed that genes expressed at higher levels in the S group were enriched for terms related to the regulation of inflammation in the compressed spinal cord. M1 macrophage-dominant inflammation was present in the S group, and cysteine-rich protein 61 (Cyr61), an inducer of M1 macrophages, was markedly upregulated in these spinal cords. Furthermore, C1q, which initiates the classical complement cascade, was more upregulated in the S group than in the M group. The confocal and electron microscopy observations indicated that classically activated microglia/macrophages had migrated to the compressed spinal cord and eliminated synaptic terminals. Conclusions We revealed the detailed pathophysiology of the inflammatory response in an animal model of chronic spinal cord compression. Our findings suggest that complement-mediated synapse elimination is a central mechanism underlying the neurodegeneration in CCM.
- Published
- 2014
15. Sox10- Venus mice: a new tool for real-time labeling of neural crest lineage cells and oligodendrocytes
- Author
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Francois Renault-Mihara, Takayoshi Inoue, Momoka Sato, Akimasa Yasuda, Chihiro Akazawa, Satoshi Suyama, Masaya Nakamura, Hideyuki Okano, Yukiko U. Inoue, Shinsuke Shibata, Hiroyuki Katoh, and Narihito Nagoshi
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Genetically modified mouse ,Transgene ,SOX10 ,Mice, Transgenic ,Venus ,Biology ,Time-Lapse Imaging ,SOXE Transcription Factors ,lcsh:RC346-429 ,Mice ,Cellular and Molecular Neuroscience ,Bacterial Proteins ,Genes, Reporter ,medicine ,Animals ,Humans ,Cell Lineage ,Molecular Biology ,Spinal Cord Injuries ,lcsh:Neurology. Diseases of the nervous system ,Staining and Labeling ,Research ,Neural crest ,Embryo ,Embryo, Mammalian ,biology.organism_classification ,Oligodendrocyte ,Mice, Inbred C57BL ,Luminescent Proteins ,Oligodendroglia ,medicine.anatomical_structure ,Neural Crest ,embryonic structures ,Female ,Neuroscience - Abstract
Background While several mouse strains have recently been developed for tracing neural crest or oligodendrocyte lineages, each strain has inherent limitations. The connection between human SOX10 mutations and neural crest cell pathogenesis led us to focus on the Sox10 gene, which is critical for neural crest development. We generated Sox10- Venus BAC transgenic mice to monitor Sox10 expression in both normal development and in pathological processes. Results Tissue fluorescence distinguished neural crest progeny cells and oligodendrocytes in the Sox10- Venus mouse embryo. Immunohistochemical analysis confirmed that Venus expression was restricted to cells expressing endogenous Sox10. Time-lapse imaging of various tissues in Sox10- Venus mice demonstrated that Venus expression could be visualized at the single-cell level in vivo due to the intense, focused Venus fluorescence. In the adult Sox10- Venus mouse, several types of mature and immature oligodendrocytes along with Schwann cells were clearly labeled with Venus, both before and after spinal cord injury. Conclusions In the newly-developed Sox10- Venus transgenic mouse, Venus fluorescence faithfully mirrors endogenous Sox10 expression and allows for in vivo imaging of live cells at the single-cell level. This Sox10- Venus mouse will thus be a useful tool for studying neural crest cells or oligodendrocytes, both in development and in pathological processes.
- Published
- 2010
16. Correction: Corrigendum: Sema3A regulates bone-mass accrual through sensory innervations
- Author
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Shu Takeda, Chengshan Ma, Ayako Kimura, Hiroshi Itoh, Yoshinori Asou, Toru Fukuda, Ren Xu, Atsushi Okawa, Takashi Hirai, Koji Fujita, Cheng Xu, Mitsuhiro Enomoto, Tsuyoshi Sato, Hiroki Ochi, Zirong Gu, Shinsuke Shibata, Kenichi Shinomiya, Hideyuki Okano, Waka Bando, Satoko Sunamura, and Yutaka Yoshida
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Multidisciplinary ,Semaphorin ,SEMA3A ,Sensory system ,Femur ,Anatomy ,Biology ,Bone mass - Abstract
Nature 497, 490–493 (2013); doi:10.1038/nature12115 In this Letter the left panels of Fig. 2a show images of a femur from a semaphorin 3A-knockout (Sema3acol1−/−) mouse, rather than from a littermate Sema3af/f mouse. Figure 1 shows the correct panels. This error does not affect our conclusions and the legend of Fig.
- Published
- 2013
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