Published Papers - Noguchi Hirofumi

Synergistic induction of astrocytic differentiation by factors secreted from meninges in the mouse developing brain

Yoichiro Kawamura, Sayako Katada, Hirofumi Noguchi, Hiroyuki Yamamoto, Tsukasa Sanosaka, Koji Iihara, Kinichi Nakashima

FEBS Letters ( Wiley Blackwell )  591 ( 22 ) 3709 - 3720   2017.11 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Astrocytes, which support diverse neuronal functions, are generated from multipotent neural stem/precursor cells (NS/PCs) during brain development. Although many astrocyte-inducing factors have been identified and studied in vitro, the regions and/or cells that produce these factors in the developing brain remain elusive. Here, we show that meninges-produced factors induce astrocytic differentiation of NS/PCs. Consistent with the timing when astrocytic differentiation of NS/PCs increases, expression of astrocyte-inducing factors is upregulated. Meningeal secretion-mimicking combinatorial treatment of NS/PCs with bone morphogenetic protein 4, retinoic acid and leukemia inhibitory factor synergistically activate the promoter of a typical astrocytic marker, glial fibrillary acidic protein. Taken together, our data suggest that meninges play an important role in astrocytic differentiation of NS/PCs in the developing brain.

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Exogenous DKK-3/REIC inhibits Wnt/β-catenin signaling and cell proliferation in human kidney cancer KPK1.

Xu J, Sadahira T, Kinoshita R, Li SA, Huang P, Wada K, Araki M, Ochiai K, Noguchi H, Sakaguchi M, Nasu Y, Watanabe M

Oncology letters ( Oncology Letters )  14 ( 5 ) 5638 - 5642   2017.11 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Isolation and characterization of lymphoid enhancer factor-1-positive deciduous dental pulp stem-like cells after transfection with a piggyBac vector containing LEF1 promoter-driven selection markers

Tomoya Murakami, Issei Saitoh, Masahiro Sato, Emi Inada, Miki Soda, Masataka Oda, Hisanori Domon, Yoko Iwase, Tadashi Sawami, Kazunari Matsueda, Yutaka Terao, Hayato Ohshima, Hirofumi Noguchi, Haruaki Hayasaki

ARCHIVES OF ORAL BIOLOGY ( PERGAMON-ELSEVIER SCIENCE LTD )  81   110 - 120   2017.09 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Objective: Lymphoid enhancer-binding factor-1 (LEF1) is a 48-kD nuclear protein that is expressed in pre-B and T cells. LEF1 is also an important member of the Wnt/beta-catenin signaling pathway that plays important roles in the self-renewal and differentiation of embryonic stem cells. We speculated that LEF1 might function in the stem cells from human exfoliated deciduous teeth (SHED). In this study, we attempted to isolate such LEF1-positive cells from human deciduous dental pulp cells (HDDPCs) by genetic engineering technology, using the human LEF1 promoter. Design: A piggyBac transposon plasmid (pTA-LEN) was introduced into HDDPCs, using the Neon (R) transfection system. After G418 selection, the emerging colonies were assessed for EGFP-derived fluorescence by fluorescence microscopy. Reverse transcription polymerase chain reaction (RT-PCR) analysis was performed using RNA isolated from these colonies to examine stem cell-specific transcript expression. Osteoblastic or neuronal differentiation was induced by cultivating the LEF1-positive cells with differentiation-inducing medium. Results: RT-PCR analysis confirmed the expression of several stem cell markers, including OCT3/4, SOX2, REX1, and NANOG, in LEF1-positive HDDPCs, which could be differentiated into osteoblasts and neuronal cells. Conclusions: The isolated LEF1-positive HDDPCs exhibited the properties of stem cells, suggesting that LEF1 might serve as a marker for SHED.

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

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

STEM CELL REPORTS ( CELL PRESS )  8 ( 6 ) 1743 - 1756   2017.06 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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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 1 alpha 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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RCAN-11R peptide provides immunosuppression for fully mismatched islet allografts in mice

Hirofumi Noguchi, Koji Sugimoto, Chika Miyagi-Shiohira, Yoshiki Nakashima, Naoya Kobayashi, Issei Saitoh, Masami Watanabe, Yasufumi Noguchi

SCIENTIFIC REPORTS ( NATURE PUBLISHING GROUP )  7 ( 1 ) 3043   2017.06 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Calcineurin inhibitors have been used for transplant therapy. However, the inhibition of calcineurin outside the immune system has a number of side effects. We previously developed a cell-permeable inhibitor of NFAT (nuclear factor of activated T cells) using the polyarginine peptide delivery system. This peptide (11R-VIVIT) selectively interferes with calcineurin-NFAT interaction without affecting the activity of calcineurin phosphatase and provides immunosuppression for fully mismatched islet allografts in mice. However, our recent study showed that 11R-VIVIT affected cell viability in vitro when it was used at higher concentration because of the VIVIT sequence. The aim of this study is to develop a safer NFAT inhibitor (RCAN-11R) that does not affect cell viability, and which is less toxic than calcineurin inhibitors. The minimal sequence of the protein family of regulators of calcineurin (RCAN) that is responsible for the inhibition of calcineurin-NFAT signaling was recently characterized. The peptide could selectively interfere with the calcineurin-NFAT interaction without affecting the activity of calcineurin phosphatase, similar to 11R-VIVIT. RCAN-11R did not affect cell viability when it was used at a higher concentration than the toxic concentration of 11R-VIVIT. RCAN-11R could therefore be useful as a therapeutic agent that is less toxic than current drugs or 11R-VIVIT.

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Facilitating Transplantation.

Noguchi H

Cell medicine   9 ( 1-2 ) 1 - 2   2017.01 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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The Evaluation of Islet Purification Methods That Use Large Bottles to Create a Continuous Density Gradient.

Miyagi-Shiohira C, Kobayashi N, Saitoh I, Watanabe M, Noguchi Y, Matsushita M, Noguchi H

Cell medicine   9 ( 1-2 ) 45 - 51   2017.01 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Comparison of Purification Solutions With Different Osmolality for Porcine Islet Purification.

Miyagi-Shiohira C, Kobayashi N, Saitoh I, Watanabe M, Noguchi Y, Matsushita M, Noguchi H

Cell medicine   9 ( 1-2 ) 53 - 59   2017.01 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Evaluation of Serum-Free, Xeno-Free Cryopreservation Solutions for Human Adipose-Derived Mesenchymal Stem Cells.

Miyagi-Shiohira C, Kobayashi N, Saitoh I, Watanabe M, Noguchi Y, Matsushita M, Noguchi H

Cell medicine   9 ( 1-2 ) 15 - 20   2017.01 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Enhanced Adipogenic Differentiation of Human Adipose-Derived Stem Cells in an In Vitro Microenvironment: The Preparation of Adipose-Like Microtissues Using a Three-Dimensional Culture.

Miyamoto Y, Ikeuchi M, Noguchi H, Yagi T, Hayashi S

Cell medicine   9 ( 1-2 ) 35 - 44   2017.01 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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心停止下膵島移植に向けた持続冷却灌流保存法による膵臓保存

圷 尚武, 野口 洋文, 丸山 通広, 大月 和宣, 石田 健倫, 齋藤 友永, 西郷 健一, 長谷川 正行, 青山 博道, 剣持 敬

Organ Biology ( 一般社団法人　日本臓器保存生物医学会 )  24 ( 2 ) 175 - 179   2017 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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1型糖尿病に対する膵島移植が国内で始まったものの，依然として大きな問題はドナー不足である．その解決手段のひとつとして，心停止下ドナーのような，条件の悪いいわゆるマージナルドナーより採取された膵臓の有効な利用である．LifePort^TM（LP）はOrgan Recovery Systems社により開発された臓器搬送用の持続冷却灌流装置であり，現在欧米において障害を伴った腎臓の搬送に臨床応用され，その有効性が確認されている．本装置はマージナルドナーから採取された臓器移植，特に虚血再潅流障害を受けやすい膵臓の保存に有用で，膵島移植の安全性や成績の向上に有効であると考えられる．本研究では，ビーグル犬を使用し，障害膵モデルより膵臓を摘出し，LPにより持続冷却灌流保存することにより，膵臓の障害が最小限に抑えられ，従来法であるUW液や2層法による浸漬保存に比べて分離膵島の収量や機能が改善でき，臨床膵島移植に応用し，成績向上に寄与することを目的とした．［方法］ビーグル犬から30分の温阻血時間をおいて全膵を摘出し，LPにて24時間持続冷却灌流保存（LP群），UW液にて24時間冷却浸漬保存（UW群），2層法にて24時間冷却浸漬保存（2層法群）し，膵島分離を行い，その形態・機能を比較検討した．［結果］形態的には，LP群でより大きく，形の良い膵島が分離できた．また，膵島収量については，純化前後でLP群においてUW群や2層法群に比べて良好であった．また，分離膵島のインスリン分泌能を評価するStatic Incubationの結果でも，LP群でUW群や2層法群に比べて良好な結果であった．［結論］心停止下ドナーよりの膵島移植を想定したモデルにおいて，LPによる障害膵の持続冷却灌流保存は，UW液や2層法による冷却浸漬保存に比べて，分離膵島の収量や機能保持に優れていることが示唆された．しかし，臨床応用のためには，さらなる保存条件や膵島分離法の改善が必要であると考えられた．

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A proteome analysis of pig pancreatic islets and exocrine tissue by liquid chromatography with tandem mass spectrometry

Yoshiki Nakashima, Chika Miyagi-Shiohira, Naoya Kobayashi, Issei Saitoh, Masami Watanabe, Hirofumi Noguchi

ISLETS ( TAYLOR & FRANCIS INC )  9 ( 6 ) 159 - 176   2017 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Liquid chromatography with tandem mass spectrometry (LC-MS/MS) is a proteome analysis method, and the shotgun analysis by LC-MS/MS comprehensively identifies proteins from tissues and cells with high resolving power. In this study, we analyzed the protein expression in pancreatic tissue by LC-MS/MS. Islets isolated from porcine pancreata (purity 95%) and exocrine tissue (purity 99%) were used in this study. LC-MS/MS showed that 13 proteins were expressed in pancreatic islets only (Group I), 43 proteins were expressed in both islets and exocrine tissue (Group I&E), and 102 proteins were expressed in exocrine tissue only (Group E). Proteins involved in islet differentiation and cell proliferation were identified in Group I (e.g. CLUS, CMGA, MIF). In addition, various functional proteins (e.g. SCG2, TBA1A) were identified in islet by using the new method of principal component analysis (PCA)'. However, the function of such proteins on islets remains unclear. EPCAM was identified in Group E. Group E was found to include proteins involved in clinical inflammatory diseases such as pancreatitis (e.g. CBPA1, CGL, CYTB, ISK1 and PA21B). Many of these identified proteins were reported less frequently in previous studies, and HS71B, NEC2, PRAF3 and SCG1 were newly detected in Group I while CPNS1, DPEP1, GANAB, GDIB, GGT1, HSPB1, ICTL, VILI, MUTA, NDKB, PTGR1, UCHL3, VAPB and VINC were newly detected in Group E. These results show that comprehensive expression analysis of proteins by LC-MS/MS is useful as a method to investigate new factors constructing cellular component, biological process, and molecular function.

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Targeted DNA demethylation in vivo using dCas9-peptide repeat and scFv-TET1 catalytic domain fusions.

Morita S, Noguchi H, Horii T, Nakabayashi K, Kimura M, Okamura K, Sakai A, Nakashima H, Hata K, Nakashima K, Hatada I

Nature biotechnology   34 ( 10 ) 1060 - 1065   2016.10 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Tissue-Specific Stem Cells Obtained by Reprogramming of Non-Obese Diabetic (NOD) Mouse-Derived Pancreatic Cells Confer Insulin Production in Response to Glucose

Issei Saitoh, Masahiro Sato, Miki Soda, Emi Inada, Yoko Iwase, Tomoya Murakami, Hayato Ohshima, Haruaki Hayasaki, Hirofumi Noguchi

PLOS ONE ( PUBLIC LIBRARY SCIENCE )  11 ( 9 ) e0163580   2016.09 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Type 1 diabetes occurs due to the autoimmune destruction of pancreatic beta-cells in islets. Transplantation of islets is a promising option for the treatment of patients with type 1 diabetes that experience hypoglycemic unawareness despite maximal care, but the present shortage of donor islets hampers such transplantation. Transplantation of insulin-producing cells derived from the patients themselves would be one of the most promising approaches to cure type 1 diabetes. Previously, we demonstrated that insulin-producing cells could be produced by transfecting murine pancreatic cells with Yamanaka's reprogramming factors. Non-obese diabetic (NOD) mice are naturally occurring mutant mice defective in insulin production due to autoimmune ablation of pancreatic beta-cells. In this study, we showed that glucose-sensitive insulin-producing cells are successfully generated by transfecting primary pancreatic cells from NOD mice (aged 6 months old) with a plasmid harboring the cDNAs for Oct-3/4, Sox2, Klf4, and c-Myc. Transfection was repeated 4 times in a 2 day-interval. Sixty-five days after final transfection, cobblestone-like colonies appeared. They proliferated in vitro and expressed pluripotency-related genes as well as Pdx1, a transcription factor specific to tissue-specific stem cells for the beta-cell lineage. Transplantation of these cells into nude mice failed to produce teratoma unlike induced pluripotent stem cells (iPSCs). Induction of these cells to the pancreatic beta-cell lineage demonstrated their capability to produce insulin in response to glucose. These findings suggest that functional pancreatic beta-cells can be produced from patients with type 1 diabetes. We call these resultant cells as "induced tissue-specific stem cells from the pancreas" (iTS-P) that could be valuable sources of safe and effective materials for cell-based therapy in type 1 diabetes.

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DNA Methyltransferase 1 Is Indispensable for Development of the Hippocampal Dentate Gyrus.

Noguchi H, Murao N, Kimura A, Matsuda T, Namihira M, Nakashima K

The Journal of neuroscience : the official journal of the Society for Neuroscience   36 ( 22 ) 6050 - 6068   2016.06 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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書評:Molecular Biology of the Cell（細胞の分子生物学）

野口 洋文

Organ Biology ( 一般社団法人　日本臓器保存生物医学会 )  23 ( 2 ) 196 - 197   2016 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Prenatal deletion of DNA methyltransferase 1 in neural stem cells impairs neurogenesis and causes anxiety-like behavior in adulthood.

Noguchi H, Kimura A, Murao N, Namihira M, Nakashima K

Neurogenesis (Austin, Tex.)   3 ( 1 ) e1232679   2016 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Creating a Future of Transplantation.

Noguchi H

Cell medicine   8 ( 1-2 ) 1   2015.12 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Spheroid Formation and Evaluation of Hepatic Cells in a Three-Dimensional Culture Device.

Miyamoto Y, Ikeuchi M, Noguchi H, Yagi T, Hayashi S

Cell medicine   8 ( 1-2 ) 47 - 56   2015.12 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Choice of Feeders Is Important When First Establishing iPSCs Derived From Primarily Cultured Human Deciduous Tooth Dental Pulp Cells.

Saitoh I, Inada E, Iwase Y, Noguchi H, Murakami T, Soda M, Kubota N, Hasegawa H, Akasaka E, Matsumoto Y, Oka K, Yamasaki Y, Hayasaki H, Sato M

Cell medicine   8 ( 1-2 ) 9 - 23   2015.12 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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