研究者詳細 - 岡野　栄之

論文 - 岡野　栄之

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MIF: functions in brain and glioblastoma

Ohta Shigeki, Kawakami Yutaka, Okano Hideyuki

Oncotarget 8 （ 29 ） 46706 - 46707 2017年06月

ISSN 1949-2553

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Hypoxia Epigenetically Confers Astrocytic Differentiation Potential on Human Pluripotent Cell-Derived Neural Precursor Cells

Yasui Tetsuro, Uezono Naohiro, Nakashima Hideyuki, Noguchi Hirofumi, Matsuda Taito, Noda-Andoh Tomoko, Okano Hideyuki, Nakashima Kinichi

Stem Cell Reports 8 （ 6 ） 1743 - 1756 2017年06月

ISSN 2213-6711

Human neural precursor cells (hNPCs) derived from pluripotent stem cells display a high propensity for neuronal differentiation, but they require long-term culturing to differentiate efficiently into astrocytes. The mechanisms underlying this biased fate specification of hNPCs remain elusive. Here, we show that hypoxia confers astrocytic differentiation potential on hNPCs through epigenetic gene regulation, and that this was achieved by cooperation between hypoxia-inducible factor 1α and Notch signaling, accompanied by a reduction of DNA methylation level in the promoter region of a typical astrocyte-specific gene, Glial fibrillary acidic protein. Furthermore, we found that this hypoxic culture condition could be applied to rapid generation of astrocytes from Rett syndrome patient-derived hNPCs, and that these astrocytes impaired neuronal development. Thus, our findings shed further light on the molecular mechanisms regulating hNPC differentiation and provide attractive tools for the development of therapeutic strategies for treating astrocyte-mediated neurological disorders.

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A noncoding RNA containing a SINE-B1 motif associates with meiotic metaphase chromatin and has an indispensable function during spermatogenesis

Nakajima Ryusuke, Sato Takuya, Ogawa Takehiko, Okano Hideyuki, Noce Toshiaki

PLoS ONE 12 （ 6 ） 2017年06月

ISSN 1932-6203

A search for early response genes that are activated following germ cell induction from mouse embryonic stem cells in vitro led us to the isolation of a long noncoding RNA that contains a SINE (short interspersed element)-B1F motif that was named R53. In situ hybridization and northern blot analyses revealed that the R53 subfragment RNA bears a B1F motif, is processed from the primary transcript, is expressed in adult testis and is predominantly localized in meiotic metaphase chromatin during spermatogenesis. Recent studies of chromosome- associated RNAs have explored novel functions of noncoding RNAs. Specifically, chromosome-bound noncoding RNAs function not only as structural components of chromosome but also as scaffolds that recruit epigenetic modulators for transcriptional regulation, and they are dynamically rearranged during the cell cycle. However, few studies have explored meiotic chromatin; thus, R53 RNA appears to be the first long noncoding RNA to be tightly associated with the metaphase chromatin during spermatogenesis. Furthermore, R53 knockdown using a lentivirus-mediated RNAi injected into mouse testis and organ culture of the fragments revealed a remarkable reduction in postmeiotic cells and irregular upregulation of several postmeiotic genes, which suggests the possibility that the SINE-B1- derived noncoding RNA R53 plays an indispensable role in the transcriptional regulation of key spermatogenesis genes.

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Developmental trajectory of the corpus callosum from infancy to the juvenile stage

Sakai Tomoko, Mikami Akichika, Suzuki Juri, Miyabe-Nishiwaki Takako, Matsui Mie, Tomonaga Masaki, Hamada Yuzuru, Matsuzawa Tetsuro, Okano Hideyuki, Oishi Kenichi

PLoS ONE 12 （ 6 ） 2017年06月

ISSN 1932-6203

How brains develop during early life is one of the most important topics in neuroscience because it underpins the neuronal functions that mature during this period. A comparison of the neurodevelopmental patterns among humans and nonhuman primates is essential to infer evolutional changes in neuroanatomy that account for higher-order brain functions, especially those specific to humans. The corpus callosum (CC) is the major white matter bundle that connects the cerebral hemispheres, and therefore, relates to a wide variety of neuronal functions. In humans, the CC area rapidly expands during infancy, followed by relatively slow changes. In chimpanzees, based on a cross-sectional study, slow changes in the CC area during the juvenile stage and later have also been reported. However, little is known about the developmental changes during infancy. A longitudinal study is also required to validate the previous cross-sectional observations about the chimpanzee CC. The present longitudinal study of magnetic resonance imaging scans demonstrates that the CC development in chimpanzees and humans is characterized by a rapid increase during infancy, followed by gradual increase during the juvenile stage. Several differences between the two species were also identified. First, there was a tendency toward a greater increase in the CC areas during infancy in humans. Second, there was a tendency toward a greater increase in the rostrum during the juvenile stage in chimpanzees. The rostral body is known to carry fibers between the bilateral prefrontal and premotor cortices, and is involved in behavior planning and control, verbal working memory, and number conception. The rostrum is known to carry fibers between the prefrontal cortices, and is involved in attention control. The interspecies differences in the developmental trajectories of the rostral body and the rostrum might be related to evolutional changes in the brain systems.

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Muscle architectural properties in the common marmoset (Callithrix jacchus)

Ogihara Naomichi, Oishi Motoharu, Kanai Ryogo, Shimada Hikaru, Kondo Takahiro, Yoshino-Saito Kimika, Ushiba Junichi, Okano Hideyuki

Primates 1 - 12 2017年05月

ISSN 0032-8332

The common marmoset, Callithrix jacchus, is a small New World monkey that has recently gained attention as an important experimental animal model in the field of neuroscience as well in rehabilitative and regenerative medicine. This attention reflects the closer phylogenetic relationship between humans and common marmosets compared to that between humans and other experimental animals. When studying the neuronal mechanism behind various types of neurological motor disorders using the common marmoset, possible differences in muscle parameters (e.g., the force-generating capacity of each of the muscles) between the common marmoset and other animals must be taken into account to permit accurate interpretation of observed motor behavior. Differences in the muscle architectural properties are expected to affect biomechanics, and hence to affect neuronal control of body movements. Therefore, we dissected the forelimbs and hind limbs of two common marmosets, including systematic analysis of the muscle mass, fascicle length, and physiological cross-sectional area (PCSA). Comparisons of the mass fractions and PCSA fractions of the forelimb and hind limb musculature among the common marmoset, human, Japanese macaque, and domestic cat demonstrated that the overall muscle architectural properties of the forelimbs and hind limbs in the common marmoset are very similar to those of the Japanese macaque, a typical quadrupedal primate. However, muscle architectural properties of the common marmoset differ from those of the domestic cat, which has relatively larger hamstrings and pedal digital flexor muscles. Compared to humans, the common marmoset exhibits relatively smaller shoulder protractor, retractor, and abductor muscles and larger elbow extensor and rotator-cuff muscles in the forelimb, and smaller plantarflexor muscles in the hind limb. These differences in the muscle architectural properties must be taken into account when interpreting motor behaviors such as locomotion and arm-reaching movements in the common marmoset.

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Fail-Safe System against Potential Tumorigenicity after Transplantation of iPSC Derivatives

Itakura Go, Kawabata Soya, Ando Miki, Nishiyama Yuichiro, Sugai Keiko, Ozaki Masahiro, Iida Tsuyoshi, Ookubo Toshiki, Kojima Kota, Kashiwagi Rei, Yasutake Kaori, Nakauchi Hiromitsu, Miyoshi Hiroyuki, Nagoshi Narihito, Kohyama Jun, Iwanami Akio, Matsumoto Morio, Nakamura Masaya, Okano Hideyuki

Stem Cell Reports 8 （ 3 ） 673 - 684 2017年03月

ISSN 2213-6711

Human induced pluripotent stem cells (iPSCs) are promising in regenerative medicine. However, the risks of teratoma formation and the overgrowth of the transplanted cells continue to be major hurdles that must be overcome. Here, we examined the efficacy of the inducible caspase-9 (iCaspase9) gene as a fail-safe against undesired tumorigenic transformation of iPSC-derived somatic cells. We used a lentiviral vector to transduce iCaspase9 into two iPSC lines and assessed its efficacy in vitro and in vivo. In vitro, the iCaspase9 system induced apoptosis in approximately 95% of both iPSCs and iPSC-derived neural stem/progenitor cells (iPSC-NS/PCs). To determine in vivo function, we transplanted iPSC-NS/PCs into the injured spinal cord of NOD/SCID mice. All transplanted cells whose mass effect was hindering motor function recovery were ablated upon transduction of iCaspase9. Our results suggest that the iCaspase9 system may serve as an important countermeasure against post-transplantation adverse events in stem cell transplant therapies.

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Skin-derived precursors as a source of progenitors for corneal endothelial regeneration

Inagaki Emi, Hatou Shin, Higa Kazunari, Yoshida Satoru, Shibata Shinsuke, Okano Hideyuki, Tsubota Kazuo, Shimmura Shigeto

Stem Cells Translational Medicine 6 （ 3 ） 788 - 798 2017年03月

ISSN 2157-6564

Corneal blindness is the fourth leading cause of blindness in the world. Current treatment is allogenic corneal transplantation, which is limited by shortage of donors and immunological rejection. Skin-derived precursors (SKPs) are postnatal stem cells, which are self-renewing, multipotent precursors that can be isolated and expanded from the dermis. Facial skin may therefore be an accessible autologous source of neural crest derived cells. SKPs were isolated from facial skin of Wnt1- Cre/Floxed EGFP mouse. After inducing differentiation with medium containing retinoic acid and GSK 3-β inhibitor, SKPs formed polygonal corneal endothelial-like cells (sTECE). Expression of major corneal endothelial markers were confirmed by Reverse transcription polymerase chain reaction (RT-PCR) and quantitative Real time polymerase chain reaction (qRT-PCR).Western blots confirmed the expression of Na, K-ATPase protein, the major functional marker of corneal endothelial cells. Immunohistochemistry revealed the expression of zonular occludens-1 and Na, K-ATPase in cellcell junctions. In vitro functional analysis of Na, K-ATPase pump activity revealed that sTECE had significantly high pump function compared to SKPs or control 3T3 cells. Moreover, sTECE transplanted into a rabbit model of bullous keratopathy successfully maintained corneal thickness and transparency. Furthermore, we successfully induced corneal endothelial-like cells from human SKPs, and showed that transplanted corneas also maintained corneal transparency and thickness. Our findings suggest that SKPs may be used as a source of autologous cells for the treatment of corneal endothelial disease.

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Evaluation of the immunogenicity of human iPS cell-derived neural stem/progenitor cells in vitro

Ozaki Masahiro, Iwanami Akio, Nagoshi Narihito, Kohyama Jun, Itakura Go, Iwai Hiroki, Nishimura Soraya, Nishiyama Yuichiro, Kawabata Soya, Sugai Keiko, Iida Tsuyoshi, Matsubayashi Kohei, Isoda Miho, Kashiwagi Rei, Toyama Yoshiaki, Matsumoto Morio, Okano Hideyuki, Nakamura Masaya

Stem Cell Research 19 128 - 138 2017年03月

ISSN 1873-5061

To achieve the goal of a first-in-human trial for human induced pluripotent stem cell (hiPSC)-based transplantation for the treatment of various diseases, allogeneic human leukocyte antigen (HLA)-matched hiPSC cell banks represent a realistic tool from the perspective of quality control and cost performance. Furthermore, considering the limited therapeutic time-window for acute injuries, including neurotraumatic injuries, an iPS cell bank is of potential interest. However, due to the relatively immunoprivileged environment of the central nervous system, it is unclear whether HLA matching is required in hiPSC-derived neural stem/progenitor cell (hiPSC-NS/PC) transplantation for the treatment of neurodegenerative diseases and neurotraumatic injuries. In this study, we evaluated the significance of HLA matching in hiPSC-NS/PC transplantation by performing modified mixed lymphocyte reaction (MLR) assays with hiPSC-NS/PCs. Compared to fetus-derived NS/PCs, the expression levels of human leukocyte antigen-antigen D related (HLA-DR) and co-stimulatory molecules on hiPSC-NS/PCs were significantly low, even with the addition of tumor necrosis factor-α (TNFα) and/or interferon-γ (IFNγ) to mimic the inflammatory environment surrounding transplanted hiPSC-NS/PCs in injured tissues. Interestingly, both the allogeneic HLA-matched and the HLA-mismatched responses were similarly low in the modified MLR assay. Furthermore, the autologous response was also similar to the allogeneic response. hiPSC-NS/PCs suppressed the proliferative responses of allogeneic HLA-mismatched peripheral blood mononuclear cells (PBMCs) in a dose-dependent manner. Thus, the low antigen-presenting function and immunosuppressive effects of hiPSC-NS/PCs result in a depressed immune response, even in an allogeneic HLA-mismatched setting. It is crucial to verify whether these in vitro results are reproducible in a clinical setting.

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Differential gene expression profiles in neurons generated from lymphoblastoid B-cell line-derived iPS cells from monozygotic twin cases with treatment-resistant schizophrenia and discordant responses to clozapine

Nakazawa Takanobu, Kikuchi Masataka, Ishikawa Mitsuru, Yamamori Hidenaga, Nagayasu Kazuki, Matsumoto Takuya, Fujimoto Michiko, Yasuda Yuka, Fujiwara Mikiya, Okada Shota, Matsumura Kensuke, Kasai Atsushi, Hayata-Takano Atsuko, Shintani Norihito, Numata Shusuke, Takuma Kazuhiro, Akamatsu Wado, Okano Hideyuki, Nakaya Akihiro, Hashimoto Hitoshi, Hashimoto Ryota

Schizophrenia Research 181 75 - 82 2017年03月

ISSN 0920-9964

Schizophrenia is a chronic psychiatric disorder with complex genetic and environmental origins. While many antipsychotics have been demonstrated as effective in the treatment of schizophrenia, a substantial number of schizophrenia patients are partially or fully unresponsive to the treatment. Clozapine is the most effective antipsychotic drug for treatment-resistant schizophrenia; however, clozapine has rare but serious side-effects. Furthermore, there is inter-individual variability in the drug response to clozapine treatment. Therefore, the identification of the molecular mechanisms underlying the action of clozapine and drug response predictors is imperative. In the present study, we focused on a pair of monozygotic twin cases with treatment-resistant schizophrenia, in which one twin responded well to clozapine treatment and the other twin did not. Using induced pluripotent stem (iPS) cell-based technology, we generated neurons from iPS cells derived from these patients and subsequently performed RNA-sequencing to compare the transcriptome profiles of the mock or clozapine-treated neurons. Although, these iPS cells similarly differentiated into neurons, several genes encoding homophilic cell adhesion molecules, such as protocadherin genes, showed differential expression patterns between these two patients. These results, which contribute to the current understanding of the molecular mechanisms of clozapine action, establish a new strategy for the use of monozygotic twin studies in schizophrenia research.

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Correlation of insulin resistance and motor function in spinal and bulbar muscular atrophy

Nakatsuji Hideaki, Araki Amane, Hashizume Atsushi, Hijikata Yasuhiro, Yamada Shinichiro, Inagaki Tomonori, Suzuki Keisuke, Banno Haruhiko, Suga Noriaki, Okada Yohei, Ohyama Manabu, Nakagawa Tohru, Kishida Ken, Funahashi Tohru, Shimomura Iichiro, Okano Hideyuki, Katsuno Masahisa, Sobue Gen

Journal of Neurology 1 - 9 2017年02月

ISSN 0340-5354

This study aimed to evaluate various metabolic parameters in patients with spinal and bulbar muscular atrophy (SBMA), to investigate the association between those indices and disease severity, and to explore the underlying molecular pathogenesis. We compared the degree of obesity, metabolic parameters, and blood pressure in 55 genetically confirmed SBMA patients against those in 483 age- and sex-matched healthy control. In SBMA patients, we investigated the correlation between these factors and motor functional indices. SBMA patients had lower body mass index, blood glucose, and Hemoglobin A1c, but higher blood pressure, homeostasis model assessment of insulin resistance (HOMA-IR, a marker of insulin resistance), total cholesterol, and adiponectin levels than the control subjects. There were no differences in visceral fat areas, high-density lipoprotein-cholesterol (HDL-C), or triglyceride levels in two groups. Revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R) correlated positively with HDL-C, but negatively with HOMA-IR. Through stepwise multiple regression analysis, we identified HOMA-IR as a significant metabolic determinant of ALSFRS-R. In biochemical analysis, we found that decreased expressions of insulin receptors, insulin receptor substrate-1 and insulin receptor-β, in autopsied muscles and fibroblasts of SBMA patients. This study demonstrates that SBMA patients have insulin resistance, which is associated with the disease severity. The expressions of insulin receptors are attenuated in the skeletal muscle of SBMA, providing a possible pathomechanism of metabolic alterations. These findings suggested that insulin resistance is a metabolic index reflecting disease severity and pathogenesis as well as a potential therapeutic target for SBMA.

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Induction of hair follicle dermal papilla cell properties in human induced pluripotent stem cell-derived multipotent LNGFR(+)THY-1(+) mesenchymal cells

Veraitch Ophelia, Mabuchi Yo, Matsuzaki Yumi, Sasaki Takashi, Okuno Hironobu, Tsukashima Aki, Amagai Masayuki, Okano Hideyuki, Ohyama Manabu

Scientific Reports 7 2017年02月

ISSN 2045-2322

The dermal papilla (DP) is a specialised mesenchymal component of the hair follicle (HF) that plays key roles in HF morphogenesis and regeneration. Current technical difficulties in preparing trichogenic human DP cells could be overcome by the use of highly proliferative and plastic human induced pluripotent stem cells (hiPSCs). In this study, hiPSCs were differentiated into induced mesenchymal cells (iMCs) with a bone marrow stromal cell phenotype. A highly proliferative and plastic LNGFR(+)THY-1(+) subset of iMCs was subsequently programmed using retinoic acid and DP cell activating culture medium to acquire DP properties. The resultant cells (induced DP-substituting cells [iDPSCs]) exhibited up-regulated DP markers, interacted with human keratinocytes to up-regulate HF related genes, and when co-grafted with human keratinocytes in vivo gave rise to fibre structures with a hair cuticle-like coat resembling the hair shaft, as confirmed by scanning electron microscope analysis. Furthermore, iDPSCs responded to the clinically used hair growth reagent, minoxidil sulfate, to up-regulate DP genes, further supporting that they were capable of, at least in part, reproducing DP properties. Thus, LNGFR(+)THY-1(+) iMCs may provide material for HF bioengineering and drug screening for hair diseases.

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q-Space Myelin Map imaging for longitudinal analysis of demyelination and remyelination in multiple sclerosis patients treated with fingolimod

Tanikawa Mariko, Nakahara Jin, Hata Junichi, Suzuki Shigeaki, Fujiyoshi Kanehiro, Fujiwara Hirokazu, Momoshima Suketaka, Jinzaki Masahiro, Nakamura Masaya, Okano Hideyuki, Takahashi Shinichi, Suzuki Norihiro

Journal of the Neurological Sciences 373 352 - 357 2017年02月

ISSN 0022-510X

Background Fingolimod (FTY) is an oral sphingosine-1-phosphate receptor modulator that reduces relapse and slows brain atrophy in multiple sclerosis (MS) patients. In addition, FTY has been shown to enhance remyelination in certain animal models. Objective To analyze feasibility of a novel q-space Myelin Map imaging to monitor demyelination and remyelination under FTY treatment in MS patients. Methods Treatment outcomes of 24 consecutive MS patients treated with FTY were analyzed. A longitudinal analysis of q-space Myelin Map imaging was performed in a subset of these patients. Results During the treatment course (average of 16.1 months), 10 patients (42%) exhibited improvement on the Expanded Disability Status Scale (EDSS) or maintained disability-free state (“optimal responders”). The average baseline age and EDSS score were significantly younger and milder in optimal responders compared to the rest of patients. A pilot longitudinal q-space Myelin Map study in 8 patients (including 4 optimal responders) showed that optimal responders tended to show signs of remyelination while exhibiting no newly evolved demyelinated lesions. Conclusion FTY may improve disability in younger patients with milder MS, and absence of demyelination activity and presence of remyelination activity may in part be associated with such improvement. q-Space Myelin Map imaging is a clinically feasible modality to monitor demyelination and remyelination in MS patients.

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Elucidation of developmental patterns of marmoset corpus callosum through a comparative MRI in marmosets, chimpanzees, and humans

Sakai Tomoko, Komaki Yuji, Hata Junichi, Okahara Junko, Okahara Norio, Inoue Takashi, Mikami Akichika, Matsui Mie, Oishi Kenichi, Sasaki Erika, Okano Hideyuki

Neuroscience Research 2017年02月

ISSN 0168-0102

The corpus callosum (CC) is present in all primate brains and is the major white matter tract connecting the cerebral hemispheres for integration of sensory, motor and higher-order cognitive information. The midsagittal area of the CC has frequently been used as a sensitive biomarker of brain development. Although the marmoset has been considered as an alternative non-human primate model for neuroscience research, the developmental patterns of the CC have not been explored. The present longitudinal study of magnetic resonance imaging demonstrated that marmosets show a rapid increase of CC during infancy, followed by a slow increase during the juvenile stage, as observed in chimpanzees and humans. Marmosets also show a tendency toward a greater increase in CC during late infancy and the juvenile stage, as observed in humans, but not in chimpanzees. However, several differences between marmosets and humans were identified. There was a tendency toward a greater maturation of the human CC during early infancy. Furthermore, there was a tendency toward a greater increase during late infancy and the juvenile stage in marmosets, compared to that observed in chimpanzees and humans. These differences in the developmental trajectories of the CC may be related to evolutional changes in social behavior.

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Dysfunction of ventrolateral striatal dopamine receptor type 2-expressing medium spiny neurons impairs instrumental motivation

Tsutsui-Kimura Iku, Takiue Hiroyuki, Yoshida Keitaro, Xu Ming, Yano Ryutaro, Ohta Hiroyuki, Nishida Hiroshi, Bouchekioua Youcef, Okano Hideyuki, Uchigashima Motokazu, Watanabe Masahiko, Takata Norio, Drew Michael R., Sano Hiromi, Mimura Masaru, Tanaka Kenji F.

Nature Communications 8 2017年02月

ISSN 2041-1723

Impaired motivation is present in a variety of neurological disorders, suggesting that decreased motivation is caused by broad dysfunction of the nervous system across a variety of circuits. Based on evidence that impaired motivation is a major symptom in the early stages of Huntington's disease, when dopamine receptor type 2-expressing striatal medium spiny neurons (D2-MSNs) are particularly affected, we hypothesize that degeneration of these neurons would be a key node regulating motivational status. Using a progressive, time-controllable, diphtheria toxin-mediated cell ablation/dysfunction technique, we find that loss-of-function of D2-MSNs within ventrolateral striatum (VLS) is sufficient to reduce goal-directed behaviours without impairing reward preference or spontaneous behaviour. Moreover, optogenetic inhibition and ablation of VLS D2-MSNs causes, respectively, transient and chronic reductions of goal-directed behaviours. Our data demonstrate that the circuitry containing VLS D2-MSNs control motivated behaviours and that VLS D2-MSN loss-of-function is a possible cause of motivation deficits in neurodegenerative diseases.

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Altered Tau Isoform Ratio Caused by Loss of FUS and SFPQ Function Leads to FTLD-like Phenotypes

Ishigaki Shinsuke, Fujioka Yusuke, Okada Yohei, Riku Yuichi, Udagawa Tsuyoshi, Honda Daiyu, Yokoi Satoshi, Endo Kuniyuki, Ikenaka Kensuke, Takagi Shinnosuke, Iguchi Yohei, Sahara Naruhiko, Takashima Akihiko, Okano Hideyuki, Yoshida Mari, Warita Hitoshi, Aoki Masashi, Watanabe Hirohisa, Okado Haruo, Katsuno Masahisa, Sobue Gen

Cell Reports 18 （ 5 ） 1118 - 1131 2017年01月

ISSN 2211-1247

Fused in sarcoma (FUS) and splicing factor, proline- and glutamine-rich (SFPQ) are RNA binding proteins that regulate RNA metabolism. We found that alternative splicing of the Mapt gene at exon 10, which generates 4-repeat tau (4R-T) and 3-repeat tau (3R-T), is regulated by interactions between FUS and SFPQ in the nuclei of neurons. Hippocampus-specific FUS- or SFPQ-knockdown mice exhibit frontotemporal lobar degeneration (FTLD)-like behaviors, reduced adult neurogenesis, accumulation of phosphorylated tau, and hippocampal atrophy with neuronal loss through an increased 4R-T/3R-T ratio. Normalization of this increased ratio by 4R-T-specific silencing results in recovery of the normal phenotype. These findings suggest a biological link among FUS/SFPQ, tau isoform alteration, and phenotypic expression, which may function in the early pathomechanism of FTLD.

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Efficient induction of dopaminergic neuron differentiation from induced pluripotent stem cells reveals impaired mitophagy in PARK2 neurons

Suzuki Sadafumi, Akamatsu Wado, Kisa Fumihiko, Sone Takefumi, Ishikawa Kei ichi, Kuzumaki Naoko, Katayama Hiroyuki, Miyawaki Atsushi, Hattori Nobutaka, Okano Hideyuki

Biochemical and Biophysical Research Communications 483 （ 1 ） 88 - 93 2017年01月

ISSN 0006-291X

Patient-specific induced pluripotent stem cells (iPSCs) show promise for use as tools for in vitro modeling of Parkinson's disease. We sought to improve the efficiency of dopaminergic (DA) neuron induction from iPSCs by the using surface markers expressed in DA progenitors to increase the significance of the phenotypic analysis. By sorting for a CD184^high/CD44^- fraction during neural differentiation, we obtained a population of cells that were enriched in DA neuron precursor cells and achieved higher differentiation efficiencies than those obtained through the same protocol without sorting. This high efficiency method of DA neuronal induction enabled reliable detection of reactive oxygen species (ROS) accumulation and vulnerable phenotypes in PARK2 iPSCs-derived DA neurons. We additionally established a quantitative system using the mt-mKeima reporter system to monitor mitophagy in which mitochondria fuse with lysosomes and, by combining this system with the method of DA neuronal induction described above, determined that mitophagy is impaired in PARK2 neurons. These findings suggest that the efficiency of DA neuron induction is important for the precise detection of cellular phenotypes in modeling Parkinson's disease.

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Sox21 deletion in mice causes postnatal growth deficiency without physiological disruption of hypothalamic-pituitary endocrine axes

Cheung Leonard Y M, Okano Hideyuki, Camper Sally A.

Molecular and Cellular Endocrinology 439 213 - 223 2017年01月

ISSN 0303-7207

The hypothalamic-pituitary axes are the coordinating centers for multiple endocrine gland functions and physiological processes. Defects in the hypothalamus or pituitary gland can cause reduced growth and severe short stature, affecting approximately 1 in 4000 children, and a large percentage of cases of pituitary hormone deficiencies do not have an identified genetic cause. SOX21 is a protein that regulates hair, neural, and trophoblast stem cell differentiation. Mice lacking Sox21 have reduced growth, but the etiology of this growth defect has not been described. We studied the expression of Sox21 in hypothalamic-pituitary development and examined multiple endocrine axes in these mice. We find no evidence of reduced intrauterine growth, food intake, or physical activity, but there is evidence for increased energy expenditure in mutants. In addition, despite changes in pituitary hormone expression, hypothalamic-pituitary axes appear to be functional. Therefore, SOX21 variants may be a cause of non-endocrine short stature in humans.

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Cochlear Cell Modeling Using Disease-Specific iPSCs Unveils a Degenerative Phenotype and Suggests Treatments for Congenital Progressive Hearing Loss

Hosoya Makoto, Fujioka Masato, Sone Takefumi, Okamoto Satoshi, Akamatsu Wado, Ukai Hideki, Ueda Hiroki R., Ogawa Kaoru, Matsunaga Tatsuo, Okano Hideyuki

Cell Reports 18 （ 1 ） 68 - 81 2017年01月

ISSN 2211-1247

Hearing impairments are the most common symptom of congenital defects, and they generally remain intractable to treatment. Pendred syndrome, the most frequent syndromic form of hereditary hearing loss, is associated with mutations in the anion exchanger pendrin. Loss of pendrin function as an anion exchanger is thought to be causative, but rodent models do not exhibit progressive deafness. Here, we report a degenerative phenotype exhibiting mutant pendrin aggregates and increased susceptibility to cellular stresses in cochlear epithelial cells induced from patient-derived induced pluripotent stem cells (iPSCs). These degenerative phenotypes were rescued by site-specific gene corrections. Moreover, low-dose rapamycin and metformin reduced aggregation and cell death. Our results provide an unexpected, comprehensive understanding of deafness due to “degenerative cochlear disease” and may contribute to rational therapeutic development. This iPSC-based disease model provides an approach to the study of pathogenesis and therapeutic development for hereditary hearing loss.

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Involvement of the septo-hippocampal cholinergic pathway in association with septal acetylcholinesterase upregulation in a mouse model of tauopathy

Hara Yuko, Motoi Yumiko, Hikishima Keigo, Mizuma Hiroshi, Onoe Hirotaka, Matsumoto Shin Ei, Elahi Montasir, Okano Hideyuki, Aoki Shigeki, Hattori Nobutaka

Current Alzheimer Research 14 （ 1 ） 94 - 103 2017年01月

ISSN 1567-2050

Background: Cholinergic cell loss in the basal forebrain, the major source of hippocampal cholinergic projections, has been implicated in Alzheimer’s disease. Objective: To examine whether the septohippocampal pathway is involved in tauopathy model mice and to elucidate the tau-associated mechanism underlying cholinergic alteration. Methods: Adult (6 to 8 months old) and old (16 to 18 months old) transgenic mice expressing wild-type human tau, Tg601, were examined using Ex vivo diffusion tensor magnetic resonance imaging (DTI) and 2-[¹⁸F]fluoro- 2-deoxy-D-glucose positron emission tomography (FDG-PET). Choline acetyltransferase (ChAT)-positive neurons in the medial septum (MS) were counted by stereological methods. Acetylcholinesterase (AChE) activity and AChE mRNA in 6 brain regions were measured. Results: Ex vivo DTI revealed that the number of fractional anisotropy (FA) streamlines in the septohippocampal tract decreased with age in Tg601 mice. The FA value in the septum was lower in old Tg601 mice than in non-tg mice. A voxel-based statistical analysis of FDG-PET revealed the presence of low glucose uptake areas, involving the MS in adults, and spread over regions including the hippocampal dentate gyrus in old mice. In the MS, the number of choline acetyltransferase (ChAT)-positive neurons decreased in old Tg601 mice. AChE activity and AChE mRNA T transcripts were exclusively higher in the septum. Conclusion: The upregulation of AChE in the septum may result in the selective degeneration of the septohippocampal cholinergic pathway in the tauopathy mouse model.

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The prospects of regenerative medicine combined with rehabilitative approaches for chronic spinal cord injury animal models

Tashiro Syoichi, Nakamura Masaya, Okano Hideyuki

Neural Regeneration Research 12 （ 1 ） 43 - 46 2017年01月

ISSN 1673-5374

Regenerative medicine has opened a window for functional recovery in acute-to-subacute phase spinal cord injury (SCI). By contrast, there are still only a few studies have focused on the treatment of the chronically injured spinal cord, in which cell-based regenerative medicine seems less effective. Since the majority of SCI patients are in the chronic phase, representing a major challenge for the clinical application of cell based regenerative medicine. Although combined therapies for the treatment of chronic SCI have attracted attention of researchers and its potential importance is also widely recognized, there had been very few studies involving rehabilitative treatments to date. In a recent study, we have demonstrated for the first time that treadmill training combined with cell transplantation significantly promotes functional recovery even in chronic SCI, not only in additive but also in synergistic manner. Even though we have succeeded to outline the profiles of recovery secondary to the combination therapy, the mechanism underlying the effects remain unsolved. In this review article, we summarize the present progress and consider the prospect of the cell-based regenerative medicine particularly combined with rehabilitative approaches for chronic SCI animal models.

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