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3. SETBP1 is dispensable for normal and malignant hematopoiesis

Author

Tanaka, Atsushi, Nishimura, Koutarou, Saika, Wataru, Kon, Ayana, Koike, Yui, Tatsumi, Hiromi, Takeda, June, Nomura, Masaki, Zang, Weijia, Nakayama, Manabu, Matsuda, Masashi, Yamazaki, Hiromi, Fukumoto, Miki, Ito, Hiromi, Hayashi, Yasutaka, Kitamura, Toshio, Kawamoto, Hiroshi, Takaori-Kondo, Akifumi, Koseki, Haruhiko, Ogawa, Seishi, and Inoue, Daichi

Published
2023
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4. H1FOO-DD promotes efficiency and uniformity in reprogramming to naive pluripotency

Author

Kunitomi, Akira, Hirohata, Ryoko, Osawa, Mitsujiro, Washizu, Kaho, Arreola, Vanessa, Saiki, Norikazu, Kato, Tomoaki M., Nomura, Masaki, Kunitomi, Haruko, Ohkame, Tokiko, Ohkame, Yusuke, Kawaguchi, Jitsutaro, Hara, Hiroto, Kusano, Kohji, Yamamoto, Takuya, Takashima, Yasuhiro, Tohyama, Shugo, Yuasa, Shinsuke, Fukuda, Keiichi, Takasu, Naoko, and Yamanaka, Shinya

Published
2024
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5. BRD9 determines the cell fate of hematopoietic stem cells by regulating chromatin state

Author

Xiao, Muran, Kondo, Shinji, Nomura, Masaki, Kato, Shinichiro, Nishimura, Koutarou, Zang, Weijia, Zhang, Yifan, Akashi, Tomohiro, Viny, Aaron, Shigehiro, Tsukasa, Ikawa, Tomokatsu, Yamazaki, Hiromi, Fukumoto, Miki, Tanaka, Atsushi, Hayashi, Yasutaka, Koike, Yui, Aoyama, Yumi, Ito, Hiromi, Nishikawa, Hiroyoshi, Kitamura, Toshio, Kanai, Akinori, Yokoyama, Akihiko, Fujiwara, Tohru, Goyama, Susumu, Noguchi, Hideki, Lee, Stanley C., Toyoda, Atsushi, Hinohara, Kunihiko, Abdel-Wahab, Omar, and Inoue, Daichi

Published
2023
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8. Aberrant EVI1 splicing contributes to EVI1-rearranged leukemia

Author

Tanaka, Atsushi, Nakano, Taizo A., Nomura, Masaki, Yamazaki, Hiromi, Bewersdorf, Jan P., Mulet-Lazaro, Roger, Hogg, Simon, Liu, Bo, Penson, Alex, Yokoyama, Akihiko, Zang, Weijia, Havermans, Marije, Koizumi, Miho, Hayashi, Yasutaka, Cho, Hana, Kanai, Akinori, Lee, Stanley C., Xiao, Muran, Koike, Yui, Zhang, Yifan, Fukumoto, Miki, Aoyama, Yumi, Konuma, Tsuyoshi, Kunimoto, Hiroyoshi, Inaba, Toshiya, Nakajima, Hideaki, Honda, Hiroaki, Kawamoto, Hiroshi, Delwel, Ruud, Abdel-Wahab, Omar, and Inoue, Daichi

Published
2022
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9. MYC Releases Early Reprogrammed Human Cells from Proliferation Pause via Retinoblastoma Protein Inhibition

Author

Rand, Tim A, Sutou, Kenta, Tanabe, Koji, Jeong, Daeun, Nomura, Masaki, Kitaoka, Fumiyo, Tomoda, Emi, Narita, Megumi, Nakamura, Michiko, Nakamura, Masahiro, Watanabe, Akira, Rulifson, Eric, Yamanaka, Shinya, and Takahashi, Kazutoshi

Subjects
Biochemistry and Cell Biology, Biological Sciences, Rare Diseases, 1.1 Normal biological development and functioning, Underpinning research, Antigens, Surface, Cell Line, Cell Proliferation, Cellular Reprogramming, Cyclin-Dependent Kinase Inhibitor p16, Humans, Induced Pluripotent Stem Cells, Kruppel-Like Factor 4, Phosphorylation, Proteoglycans, Proto-Oncogene Proteins c-myc, RNA Interference, RNA, Small Interfering, Retinoblastoma Protein, Transcription Factors, Tripartite Motif Proteins, Ubiquitin-Protein Ligases, LIN41, MYC, immortalization, induced pluripotent stem cell, pluripotency, post-transcriptional regulation, proliferation, reprogramming, senescence, Medical Physiology, Biological sciences
Abstract

Here, we report that MYC rescues early human cells undergoing reprogramming from a proliferation pause induced by OCT3/4, SOX2, and KLF4 (OSK). We identified ESRG as a marker of early reprogramming cells that is expressed as early as day 3 after OSK induction. On day 4, ESRG positive (+) cells converted to a TRA-1-60 (+) intermediate state. These early ESRG (+) or TRA-1-60 (+) cells showed a proliferation pause due to increased p16INK4A and p21 and decreased endogenous MYC caused by OSK. Exogenous MYC did not enhance the appearance of initial reprogramming cells but instead reactivated their proliferation and improved reprogramming efficiency. MYC increased expression of LIN41, which potently suppressed p21 post-transcriptionally. MYC suppressed p16 INK4A. These changes inactivated retinoblastoma protein (RB) and reactivated proliferation. The RB-regulated proliferation pause does not occur in immortalized fibroblasts, leading to high reprogramming efficiency even without exogenous MYC.

Published
2018

11. A Weighted Spike-Triggered Average of a Fluctuating Stimulus Yielding the Phase Response Curve

Author

Ota, Kaiichiro, Nomura, Masaki, and Aoyagi, Toshio

Subjects
Nonlinear Sciences - Adaptation and Self-Organizing Systems
Abstract

We demonstrate that the phase response curve (PRC) can be reconstructed using a weighted spike-triggered average of an injected fluctuating input. The key idea is to choose the weight to be proportional to the magnitude of the fluctuation of the oscillatory period. Particularly, when a neuron exhibits random switching behavior between two bursting modes, two corresponding PRCs can be simultaneously reconstructed, even from the data of a single trial. This method offers an efficient alternative to the experimental investigation of oscillatory systems, without the need for detailed modeling., Comment: 5 pages, 5 figures

Published
2008

14. Analysis of Oscillator Neural Networks for Sparsely Coded Phase Patterns

Author

Nomura, Masaki and Aoyagi, Toshio

Subjects
Condensed Matter - Disordered Systems and Neural Networks, Quantitative Biology
Abstract

We study a simple extended model of oscillator neural networks capable of storing sparsely coded phase patterns, in which information is encoded both in the mean firing rate and in the timing of spikes. Applying the methods of statistical neurodynamics to our model, we theoretically investigate the model's associative memory capability by evaluating its maximum storage capacities and deriving its basins of attraction. It is shown that, as in the Hopfield model, the storage capacity diverges as the activity level decreases. We consider various practically and theoretically important cases. For example, it is revealed that a dynamically adjusted threshold mechanism enhances the retrieval ability of the associative memory. It is also found that, under suitable conditions, the network can recall patterns even in the case that patterns with different activity levels are stored at the same time. In addition, we examine the robustness with respect to damage of the synaptic connections. The validity of these theoretical results is confirmed by reasonable agreement with numerical simulations., Comment: 23 pages, 11 figures

Published
2000
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15. An Oscillator Neural Network Retrieving Sparsely Coded Phase Patterns

Author

Aoyagi, Toshio and Nomura, Masaki

Subjects
Condensed Matter - Disordered Systems and Neural Networks, Quantitative Biology
Abstract

Little is known theoretically about the associative memory capabilities of neural networks in which information is encoded not only in the mean firing rate but also in the timing of firings. Particularly, in the case that the fraction of active neurons involved in memorizing patterns becomes small, it is biologically important to consider the timings of firings and to study how such consideration influences storage capacities and quality of recalled patterns. For this purpose, we propose a simple extended model of oscillator neural networks to allow for expression of non-firing state. %which is able to memorize sparsely coded phase patterns including non-firing states. Analyzing both equilibrium states and dynamical properties in recalling processes, we find that the system possesses good associative memory., Comment: 9 pages, 3 Postscript figures, uses epsbox.sty

Published
1998
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21. Improved Sendai viral system for reprogramming to naive pluripotency

Author

Kunitomi, Akira, primary, Hirohata, Ryoko, additional, Arreola, Vanessa, additional, Osawa, Mitsujiro, additional, Kato, Tomoaki M., additional, Nomura, Masaki, additional, Kawaguchi, Jitsutaro, additional, Hara, Hiroto, additional, Kusano, Kohji, additional, Takashima, Yasuhiro, additional, Takahashi, Kazutoshi, additional, Fukuda, Keiichi, additional, Takasu, Naoko, additional, and Yamanaka, Shinya, additional

Published
2022
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22. Zen Philosophy of Mindfulness: Nen 念 according to Dōgen’s Shōbōgenzō

Author

Nomura, Masaki

Subjects
Zen, mindfulness, Dōgen, Shōbōgenzō, threefold wisdom
Abstract

The purpose of this paper is to holistically comprehend the concept of nen 念 in the Zen philosophy of Dōgen (道元 1200–1253), which is one of the origins of Mindfulness-Based Stress Reduction, in relation to his principal concepts. This article specifically investigates its usages in his masterpiece, Treasury of the True Dharma Eye (Shōbōgenzō 正法眼蔵), according to each step of the threefold wisdom (san-e 三慧); for mindfulness is a common thread among them and he presents the concept of “monshishū-shō 聞思修證”, of which shō 證 stands for “awakening”. It is revealed that Dōgen considers “study” (mon 聞) and “reflection” (shi 思) to be essential on the Buddhist path, as well as “practice” (shū 修), and that nen 念 in Dōgen’s philosophy is the self beyond the sense of body-mind or time, which can be attained after long cultivation. Also, the connections among nen 念 and his critical concepts such as “just sitting” (shikan taza 祇管打坐), “dropping off body-mind” (shinjin datsuraku 身心脱落), and “oneness of practice and awakening” (shūshō ittō 修證一等) are elucidated.

Published
2022
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25. Generation of hypoimmunogenic induced pluripotent stem cells by CRISPR-Cas9 system and detailed evaluation for clinical application

Author

50578002, Kitano, Yuko, Nishimura, Sayaka, Kato, Tomoaki M., Ueda, Anna, Takigawa, Kaho, Umekage, Masafumi, Nomura, Masaki, Kawakami, Ayane, Ogawa, Haruna, Xu, Huaigeng, Hotta, Akitsu, Takasu, Naoko, Tsukahara, Masayoshi, 50578002, Kitano, Yuko, Nishimura, Sayaka, Kato, Tomoaki M., Ueda, Anna, Takigawa, Kaho, Umekage, Masafumi, Nomura, Masaki, Kawakami, Ayane, Ogawa, Haruna, Xu, Huaigeng, Hotta, Akitsu, Takasu, Naoko, and Tsukahara, Masayoshi

Abstract

In order to expand the promise of regenerative medicine using allogeneic induced pluripotent stem cells (iPSCs), precise and efficient genome editing of human leukocyte antigen (HLA) genes would be advantageous to minimize the immune rejection caused by mismatches of HLA type. However, clinical-grade genome editing of multiple HLA genes in human iPSC lines remains unexplored. Here, we optimized the protocol for good manufacturing practice (GMP)-compatible CRISPR-Cas9 genome editing to deplete the three gene locus (HLA-A, HLA-B, and CIITA genes) simultaneously in HLA homozygous iPSCs. The use of HLA homozygous iPSCs has one main advantage over heterozygous iPSCs for inducing biallelic knockout by a single gRNA. RNA-seq and flow cytometry analyses confirmed the successful depletion of HLAs, and lineage-specific differentiation into cardiomyocytes was verified. We also confirmed that the pluripotency of genome-edited iPSCs was successfully maintained by the three germ layers of differentiation. Moreover, whole-genome sequencing, karyotyping, and optical genome mapping analyses revealed no evident genomic abnormalities detected in some clones, whereas unexpected copy number losses, chromosomal translocations, and complex genomic rearrangements were observed in other clones. Our results indicate the importance of multidimensional analyses to ensure the safety and quality of the genome-edited cells. The manufacturing and assessment pipelines presented here will be the basis for clinical-grade genome editing of iPSCs.

Published
2022

26. Improved Sendai viral system for reprogramming to naive pluripotency

Author

70469930, 10295694, Kunitomi, Akira, Hirohata, Ryoko, Arreola, Vanessa, Osawa, Mitsujiro, Kato, Tomoaki M., Nomura, Masaki, Kawaguchi, Jitsutaro, Hara, Hiroto, Kusano, Kohji, Takashima, Yasuhiro, Takahashi, Kazutoshi, Fukuda, Keiichi, Takasu, Naoko, Yamanaka, Shinya, 70469930, 10295694, Kunitomi, Akira, Hirohata, Ryoko, Arreola, Vanessa, Osawa, Mitsujiro, Kato, Tomoaki M., Nomura, Masaki, Kawaguchi, Jitsutaro, Hara, Hiroto, Kusano, Kohji, Takashima, Yasuhiro, Takahashi, Kazutoshi, Fukuda, Keiichi, Takasu, Naoko, and Yamanaka, Shinya

Abstract

Naive human induced pluripotent stem cells (iPSCs) can be generated by reprogramming somatic cells with Sendai virus (SeV) vectors. However, only dermal fibroblasts have been successfully reprogrammed this way, and the process requires culture on feeder cells. Moreover, SeV vectors are highly persistent and inhibit subsequent differentiation of iPSCs. Here, we report a modified SeV vector system to generate transgene-free naive human iPSCs with superior differentiation potential. The modified method can be applied not only to fibroblasts but also to other somatic cell types. SeV vectors disappear quickly at early passages, and this approach enables the generation of naive iPSCs in a feeder-free culture. The naive iPSCs generated by this method show better differentiation to trilineage and extra-embryonic trophectoderm than those derived by conventional methods. This method can expand the application of iPSCs to research on early human development and regenerative medicine.

Published
2022

27. Correlation Between Genetic Abnormalities in Induced Pluripotent Stem Cell-Derivatives and Abnormal Tissue Formation in Tumorigenicity Tests

Author

Yamamoto, Takako, primary, Sato, Yoji, additional, Yasuda, Satoshi, additional, Shikamura, Masayuki, additional, Tamura, Takashi, additional, Takenaka, Chiemi, additional, Takasu, Naoko, additional, Nomura, Masaki, additional, Dohi, Hiromi, additional, Takahashi, Masayo, additional, Mandai, Michiko, additional, Kanemura, Yonehiro, additional, Nakamura, Masaya, additional, Okano, Hideyuki, additional, and Kawamata, Shin, additional

Published
2022
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31. Transplantation of Human Autologous Synovial Mesenchymal Stem Cells with Trisomy 7 into the Knee Joint and 5 Years of Follow-up

Author

Mizuno, Mitsuru, primary, Endo, Kentaro, additional, Katano, Hisako, additional, Amano, Naoki, additional, Nomura, Masaki, additional, Hasegawa, Yoshinori, additional, Ozeki, Nobutake, additional, Koga, Hideyuki, additional, Takasu, Naoko, additional, Ohara, Osamu, additional, Morio, Tomohiro, additional, and Sekiya, Ichiro, additional

Published
2021
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32. Evaluation of the Efficacy and Safety of a Clinical Grade Human Induced Pluripotent Stem Cell-Derived Cardiomyocyte Patch: A Pre-Clinical Study

Author

Miyagawa, Shigeru, primary, Kawamura, Takuji, additional, Ito, Emiko, additional, Takeda, Maki, additional, Iseoka, Hiroko, additional, Yokoyama, Junya, additional, Harada, Akima, additional, Mochizuki-Oda, Noriko, additional, Imanishi-Ochi, Yukiko, additional, Li, Junjun, additional, Sasai, Masao, additional, Kitaoka, Fumiyo, additional, Nomura, Masaki, additional, Amano, Naoki, additional, Takahashi, Tomoko, additional, Dohi, Hiromi, additional, Morii, Eiichi, additional, and Sawa, Yoshiki, additional

Published
2021
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33. Pre-clinical study of induced pluripotent stem cell-derived dopaminergic progenitor cells for Parkinson’s disease

Author

10587851, 40619821, 10270779, Doi, Daisuke, Magotani, Hiroaki, Kikuchi, Tetsuhiro, Ikeda, Megumi, Hiramatsu, Satoe, Yoshida, Kenji, Amano, Naoki, Nomura, Masaki, Umekage, Masafumi, Morizane, Asuka, Takahashi, Jun, 10587851, 40619821, 10270779, Doi, Daisuke, Magotani, Hiroaki, Kikuchi, Tetsuhiro, Ikeda, Megumi, Hiramatsu, Satoe, Yoshida, Kenji, Amano, Naoki, Nomura, Masaki, Umekage, Masafumi, Morizane, Asuka, and Takahashi, Jun

Abstract

Induced pluripotent stem cell (iPSC)-derived dopaminergic (DA) neurons are an expected source for cell-based therapies for Parkinson’s disease (PD). The regulatory criteria for the clinical application of these therapies, however, have not been established. Here we show the results of our pre-clinical study, in which we evaluate the safety and efficacy of dopaminergic progenitors (DAPs) derived from a clinical-grade human iPSC line. We confirm the characteristics of DAPs by in vitro analyses. We also verify that the DAP population include no residual undifferentiated iPSCs or early neural stem cells and have no genetic aberration in cancer-related genes. Furthermore, in vivo studies using immunodeficient mice reveal no tumorigenicity or toxicity of the cells. When the DAPs are transplanted into the striatum of 6-OHDA-lesioned rats, the animals show behavioral improvement. Based on these results, we started a clinical trial to treat PD patients in 2018.

Published
2020

39. HLA-Matched Allogeneic iPS Cells-Derived RPE Transplantation for Macular Degeneration

Author

Sugita, Sunao, primary, Mandai, Michiko, additional, Hirami, Yasuhiko, additional, Takagi, Seiji, additional, Maeda, Tadao, additional, Fujihara, Masashi, additional, Matsuzaki, Mitsuhiro, additional, Yamamoto, Midori, additional, Iseki, Kyoko, additional, Hayashi, Naoko, additional, Hono, Ayumi, additional, Fujino, Shoko, additional, Koide, Naoshi, additional, Sakai, Noriko, additional, Shibata, Yumiko, additional, Terada, Motoki, additional, Nishida, Mitsuhiro, additional, Dohi, Hiromi, additional, Nomura, Masaki, additional, Amano, Naoki, additional, Sakaguchi, Hirokazu, additional, Hara, Chikako, additional, Maruyama, Kazuichi, additional, Daimon, Takashi, additional, Igeta, Masataka, additional, Oda, Toshihiko, additional, Shirono, Utako, additional, Tozaki, Misato, additional, Totani, Kota, additional, Sugiyama, Satoshi, additional, Nishida, Kohji, additional, Kurimoto, Yasuo, additional, and Takahashi, Masayo, additional

Published
2020
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40. Application of laser micro incisions in the fire-retardant treatment.

Author

Fukuta, Satoshi, Nomura, Masaki, Kurisaki, Hiroshi, and Okamura, Hiroyuki

Abstract

In the fire-retardant treatment of wood by the vacuum-pressure impregnation method, the effect of laser micro incisions (LMI) was verified. Even with the fine incisions with a diameter of about 75 µm, uniform penetration of the fire-retardant was observed by fluorescent X-ray analysis and X-ray CT, even at a hole density of 5 holes/cm2. In the evaluation of fire resistance using cone calorimeter, the "Quasi-non-combustible" performance, which is the standard of the Building Standard Law of Japan, was obtained under the LMI conditions of 6 mm depth. [ABSTRACT FROM AUTHOR]

Published
2022
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44. MYC Releases Early Reprogrammed Human Cells from Proliferation Pause via Retinoblastoma Protein Inhibition

Author

10295694, Rand, Tim A., Sutou, Kenta, Tanabe, Koji, Jeong, Daeun, Nomura, Masaki, Kitaoka, Fumiyo, Tomoda, Emi, Narita, Megumi, Nakamura, Michiko, Nakamura, Masahiro, Watanabe, Akira, Rulifson, Eric, Yamanaka, Shinya, Takahashi, Kazutoshi, 10295694, Rand, Tim A., Sutou, Kenta, Tanabe, Koji, Jeong, Daeun, Nomura, Masaki, Kitaoka, Fumiyo, Tomoda, Emi, Narita, Megumi, Nakamura, Michiko, Nakamura, Masahiro, Watanabe, Akira, Rulifson, Eric, Yamanaka, Shinya, and Takahashi, Kazutoshi

Abstract

Here, we report that MYC rescues early human cells undergoing reprogramming from a proliferation pause induced by OCT3/4, SOX2, and KLF4 (OSK). We identified ESRG as a marker of early reprogramming cells that is expressed as early as day 3 after OSK induction. On day 4, ESRG positive (+) cells converted to a TRA-1-60 (+) intermediate state. These early ESRG (+) or TRA-1-60 (+) cells showed a proliferation pause due to increased p16INK4A and p21 and decreased endogenous MYC caused by OSK. Exogenous MYC did not enhance the appearance of initial reprogramming cells but instead reactivated their proliferation and improved reprogramming efficiency. MYC increased expression of LIN41, which potently suppressed p21 post-transcriptionally. MYC suppressed p16 INK4A. These changes inactivated retinoblastoma protein (RB) and reactivated proliferation. The RB-regulated proliferation pause does not occur in immortalized fibroblasts, leading to high reprogramming efficiency even without exogenous MYC.

Published
2018

46. Aberrant EVI1splicing contributes to EVI1-rearranged leukemia

Author

Tanaka, Atsushi, Nakano, Taizo A., Nomura, Masaki, Yamazaki, Hiromi, Bewersdorf, Jan P., Mulet-Lazaro, Roger, Hogg, Simon, Liu, Bo, Penson, Alex, Yokoyama, Akihiko, Zang, Weijia, Havermans, Marije, Koizumi, Miho, Hayashi, Yasutaka, Cho, Hana, Kanai, Akinori, Lee, Stanley C., Xiao, Muran, Koike, Yui, Zhang, Yifan, Fukumoto, Miki, Aoyama, Yumi, Konuma, Tsuyoshi, Kunimoto, Hiroyoshi, Inaba, Toshiya, Nakajima, Hideaki, Honda, Hiroaki, Kawamoto, Hiroshi, Delwel, Ruud, Abdel-Wahab, Omar, and Inoue, Daichi

Abstract

Detailed genomic and epigenomic analyses of MECOM(the MDS1 and EVI1 complex locus) have revealed that inversion or translocation of chromosome 3 drive inv(3)/t(3;3) myeloid leukemias via structural rearrangement of an enhancer which upregulates transcription of EVI1. Here we identify a novel, previously unannotated oncogenic RNA-splicing derived isoform of EVI1which is frequently present in inv(3)/t(3;3) AML and directly contributes to leukemic transformation. This EVI1 isoform is generated by oncogenic mutations in the core RNA splicing factor SF3B1, which is mutated in >30% of inv(3)/t(3;3) myeloid neoplasm patients and thereby represents the single most commonly co-occurring genomic alteration in inv(3)/t(3;3) patients. SF3B1mutations are statistically uniquely enriched in inv(3)/t(3;3) myeloid neoplasm patients and patient-derived cell lines compared with other forms of AML and promote mis-splicing of EVI1 generating an in-frame insertion of six amino acids at the 3’ end of the second Zinc finger domain of EVI1. Expression of this EVI1 splice variant enhanced the self-renewal of hematopoietic stem cells and introduction of mutant SF3B1 in mice bearing the humanized inv(3)(q21q26) allele resulted in generation of this novel EVI1 isoform in mice and hastened leukemogenesis in vivo.The mutant SF3B1 spliceosome depends upon an exonic splicing enhancer within EVI1exon 13 to promote usage of a cryptic branch point and aberrant 3’ splice site within intron 12 resulting in the generation of this isoform. These data provide a mechanistic basis for the frequent co-occurrence of SF3B1mutations as well as new insights into the pathogenesis of myeloid leukemias harboring inv(3)/t(3;3).

Published
2024
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