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Article ; Online: Identification of Senescent Cells in Peri-Implantitis and Prevention of Mini-Implant Loss Using Senolytics

Niuxin Yang / Masato Nakagawa / Aki Nishiura / Masahiro Yamada / Hidetoshi Morikuni / Yoshitomo Honda / Naoyuki Matsumoto

International Journal of Molecular Sciences, Vol 24, Iss 2507, p

2023 Volume 2507

Abstract: Peri-implantitis is a disease that causes the detachment of orthodontic mini-implants. Recently, stress-induced senescent cells have been reported to be involved in various inflammatory diseases. Senescent cell-eliminating drugs, termed “senolytics”, can ...

Abstract	Peri-implantitis is a disease that causes the detachment of orthodontic mini-implants. Recently, stress-induced senescent cells have been reported to be involved in various inflammatory diseases. Senescent cell-eliminating drugs, termed “senolytics”, can improve the symptoms of such diseases. However, the relationship between peri-implantitis and senescent cells remains unclear. In this study, we evaluated the presence of senescent cells in a rat peri-implantitis model developed with a gum ring. The effect on bone resorption and implant loss was also investigated with and without senolytics (Dasatinib and Quercetin). The number of senescence markers (p19, p21, and p16) was found to increase, and implant detachment occurred in 24 days. After the administration of senolytics, the number of senescence markers decreased and implant detachment was inhibited. This study suggests that senescent cells aggravate peri-implantitis and senolytic administration latently reduces implant loss by inhibiting senescence-related mechanisms.
Keywords	orthodontics ; mini-implant ; peri-implantitis ; senescence ; senolytics ; Dasatinib ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	610
Language	English
Publishing date	2023-01-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Extracellular laminin regulates hematopoietic potential of pluripotent stem cells through integrin β1-ILK-β-catenin-JUN axis

Akinori Yuzuriha / Sou Nakamura / Naoshi Sugimoto / Shunsuke Kihara / Masato Nakagawa / Takuya Yamamoto / Kiyotoshi Sekiguchi / Koji Eto

Stem Cell Research, Vol 53, Iss , Pp 102287- (2021)

2021

Abstract: Recombinant matrices have enabled feeder cell-free maintenance cultures of human pluripotent stem cells (hPSCs), with laminin 511-E8 fragment (LM511-E8) being widely used. However, we herein report that hPSCs maintained on LM511-E8 resist differentiating ...

Abstract	Recombinant matrices have enabled feeder cell-free maintenance cultures of human pluripotent stem cells (hPSCs), with laminin 511-E8 fragment (LM511-E8) being widely used. However, we herein report that hPSCs maintained on LM511-E8 resist differentiating to multipotent hematopoietic progenitor cells (HPCs), unlike hPSCs maintained on LM421-E8 or LM121-E8. The latter two LM-E8s bound weakly to hPSCs compared with LM511-E8 and activated the canonical Wnt/β-catenin signaling pathway. Moreover, the extracellular LM-E8-dependent preferential hematopoiesis was associated with a higher expression of integrin β1 (ITGB1) and downstream integrin-linked protein kinase (ILK), β-catenin and phosphorylated JUN. Accordingly, the lower coating concentration of LM511-E8 or addition of a Wnt/β-catenin signaling activator, CHIR99021, facilitated higher HPC yield. In contrast, the inhibition of ILK, Wnt or JNK by inhibitors or mRNA knockdown suppressed the HPC yield. These findings suggest that extracellular laminin scaffolds modulate the hematopoietic differentiation potential of hPSCs by activating the ITGB1-ILK-β-catenin-JUN axis at the undifferentiated stage. Finally, the combination of low-concentrated LM511-E8 and a revised hPSC-sac method, which adds bFGF, SB431542 and heparin to the conventional method, enabled a higher yield of HPCs and higher rate for definitive hematopoiesis, suggesting a useful protocol for obtaining differentiated hematopoietic cells from hPSCs in general.
Keywords	Hematopoietic cell differentiation ; Laminin ; Integrin β1 ; ILK ; Canonical Wnt/β-catenin pathway ; Pluripotent stem cells ; Biology (General) ; QH301-705.5
Subject code	500
Language	English
Publishing date	2021-05-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: MYCL promotes iPSC-like colony formation via MYC Box 0 and 2 domains

Chiaki Akifuji / Mio Iwasaki / Yuka Kawahara / Chiho Sakurai / Yu-Shen Cheng / Takahiko Imai / Masato Nakagawa

Scientific Reports, Vol 11, Iss 1, Pp 1-

2021 Volume 30

Abstract: Abstract Human induced pluripotent stem cells (hiPSCs) can differentiate into cells of the three germ layers and are promising cell sources for regenerative medicine therapies. However, current protocols generate hiPSCs with low efficiency, and the ... ...

Abstract	Abstract Human induced pluripotent stem cells (hiPSCs) can differentiate into cells of the three germ layers and are promising cell sources for regenerative medicine therapies. However, current protocols generate hiPSCs with low efficiency, and the generated iPSCs have variable differentiation capacity among different clones. Our previous study reported that MYC proteins (c-MYC and MYCL) are essential for reprogramming and germline transmission but that MYCL can generate hiPSC colonies more efficiently than c-MYC. The molecular underpinnings for the different reprogramming efficiencies between c-MYC and MYCL, however, are unknown. In this study, we found that MYC Box 0 (MB0) and MB2, two functional domains conserved in the MYC protein family, contribute to the phenotypic differences and promote hiPSC generation in MYCL-induced reprogramming. Proteome analyses suggested that in MYCL-induced reprogramming, cell adhesion-related cytoskeletal proteins are regulated by the MB0 domain, while the MB2 domain regulates RNA processes. These findings provide a molecular explanation for why MYCL has higher reprogramming efficiency than c-MYC.
Keywords	Medicine ; R ; Science ; Q
Subject code	500
Language	English
Publishing date	2021-12-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Multi-omics approach reveals posttranscriptionally regulated genes are essential for human pluripotent stem cells

Mio Iwasaki / Yuka Kawahara / Chikako Okubo / Tatsuya Yamakawa / Michiko Nakamura / Tsuyoshi Tabata / Yohei Nishi / Megumi Narita / Akira Ohta / Hirohide Saito / Takuya Yamamoto / Masato Nakagawa / Shinya Yamanaka / Kazutoshi Takahashi

iScience, Vol 25, Iss 5, Pp 104289- (2022)

2022

Abstract: Summary: The effects of transcription factors on the maintenance and differentiation of human-induced or embryonic pluripotent stem cells (iPSCs/ESCs) have been well studied. However, the importance of posttranscriptional regulatory mechanisms, which ... ...

Abstract	Summary: The effects of transcription factors on the maintenance and differentiation of human-induced or embryonic pluripotent stem cells (iPSCs/ESCs) have been well studied. However, the importance of posttranscriptional regulatory mechanisms, which cause the quantitative dissociation of mRNA and protein expression, has not been explored in detail. Here, by combining transcriptome and proteome profiling, we identified 228 posttranscriptionally regulated genes with strict upregulation of the protein level in iPSCs/ESCs. Among them, we found 84 genes were vital for the survival of iPSCs and HDFs, including 20 genes that were specifically necessary for iPSC survival. These 20 proteins were upregulated only in iPSCs/ESCs and not in differentiated cells derived from the three germ layers. Although there are still unknown mechanisms that downregulate protein levels in HDFs, these results reveal that posttranscriptionally regulated genes have a crucial role in iPSC survival.
Keywords	Biological sciences ; Stem cells research ; Omics ; Science ; Q
Subject code	570
Language	English
Publishing date	2022-05-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Inherent genomic properties underlie the epigenomic heterogeneity of human induced pluripotent stem cells

Shihori Yokobayashi / Yukihiro Yabuta / Masato Nakagawa / Keisuke Okita / Bo Hu / Yusuke Murase / Tomonori Nakamura / Guillaume Bourque / Jacek Majewski / Takuya Yamamoto / Mitinori Saitou

Cell Reports, Vol 37, Iss 5, Pp 109909- (2021)

2021

Abstract: Summary: Human induced pluripotent stem cells (hiPSCs) show variable differentiation potential due to their epigenomic heterogeneity, whose extent/attributes remain unclear, except for well-studied elements/chromosomes such as imprints and the X ... ...

Abstract	Summary: Human induced pluripotent stem cells (hiPSCs) show variable differentiation potential due to their epigenomic heterogeneity, whose extent/attributes remain unclear, except for well-studied elements/chromosomes such as imprints and the X chromosomes. Here, we show that seven hiPSC lines with variable germline potential exhibit substantial epigenomic heterogeneity, despite their uniform transcriptomes. Nearly a quarter of autosomal regions bear potentially differential chromatin modifications, with promoters/CpG islands for H3K27me3/H2AK119ub1 and evolutionarily young retrotransposons for H3K4me3. We identify 145 large autosomal blocks (≥100 kb) with differential H3K9me3 enrichment, many of which are lamina-associated domains (LADs) in somatic but not in embryonic stem cells. A majority of these epigenomic heterogeneities are independent of genetic variations. We identify an X chromosome state with chromosome-wide H3K9me3 that stably prevents X chromosome erosion. Importantly, the germline potential of female hiPSCs correlates with X chromosome inactivation. We propose that inherent genomic properties, including CpG density, transposons, and LADs, engender epigenomic heterogeneity in hiPSCs.
Keywords	human induced pluripotent stem cells ; clonal heterogeneity ; epigenome ; histone modifications ; DNA methylation ; X chromosome inactivation ; Biology (General) ; QH301-705.5
Subject code	571
Language	English
Publishing date	2021-11-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Derivation of induced pluripotent stem cells in Japanese macaque (Macaca fuscata)

Risako Nakai / Mari Ohnuki / Kota Kuroki / Haruka Ito / Hirohisa Hirai / Ryunosuke Kitajima / Toko Fujimoto / Masato Nakagawa / Wolfgang Enard / Masanori Imamura

Scientific Reports, Vol 8, Iss 1, Pp 1-

2018 Volume 9

Abstract: Abstract Non-human primates are our closest relatives and are of special interest for ecological, evolutionary and biomedical research. The Japanese macaque (Macaca fuscata) has contributed to the progress of primatology and neurosciences over 60 years. ... ...

Abstract	Abstract Non-human primates are our closest relatives and are of special interest for ecological, evolutionary and biomedical research. The Japanese macaque (Macaca fuscata) has contributed to the progress of primatology and neurosciences over 60 years. Despite this importance, the molecular and cellular basis of the Japanese macaque remains unexplored since useful cellular tools are lacking. Here we generated induced pluripotent stem cells (iPSCs) from skin fibroblasts of the Japanese macaque with Sendai virus or plasmid vectors. The Japanese macaque iPSCs (jm-iPSCs) were established under feeder-free culture conditions, but feeder cells turned out to be essential for their maintenance. The jm-iPSCs formed human iPSC-like flat colonies which were positive for pluripotent antigens including alkaline phosphatase, SSEA4, and TRA-1-81. They also expressed endogenous OCT3/4, SOX2, L-MYC, and KLF4 and other pluripotent marker genes. The potential to differentiate into all three germ layers and neural stem cells was confirmed by embryoid body and neurosphere formation, respectively. The jm-iPSCs will provide a robust in vitro tool for investigating the underlying mechanisms of development and physiology studies with the Japanese macaque.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2018-08-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Human Pluripotent Stem Cell-Derived Tumor Model Uncovers the Embryonic Stem Cell Signature as a Key Driver in Atypical Teratoid/Rhabdoid Tumor

Yukinori Terada / Norihide Jo / Yoshiki Arakawa / Megumi Sakakura / Yosuke Yamada / Tomoyo Ukai / Mio Kabata / Kanae Mitsunaga / Yohei Mineharu / Sho Ohta / Masato Nakagawa / Susumu Miyamoto / Takuya Yamamoto / Yasuhiro Yamada

Cell Reports, Vol 26, Iss 10, Pp 2608-2621.e

2019 Volume 6

Abstract: Summary: Atypical teratoid/rhabdoid tumor (AT/RT), which harbors SMARCB1 mutation and exhibits a characteristic histology of rhabdoid cells, has a poor prognosis because of the lack of effective treatments. Here, we establish human SMARCB1-deficient ... ...

Abstract	Summary: Atypical teratoid/rhabdoid tumor (AT/RT), which harbors SMARCB1 mutation and exhibits a characteristic histology of rhabdoid cells, has a poor prognosis because of the lack of effective treatments. Here, we establish human SMARCB1-deficient pluripotent stem cells (hPSCs). SMARCB1-deficient hPSC-derived neural progenitor-like cells (NPLCs) efficiently give rise to brain tumors when transplanted into the mouse brain. Notably, activation of an embryonic stem cell (ESC)-like signature confers a rhabdoid histology in SMARCB1-deficient NPLC-derived tumors and causes a poor prognosis. Consistently, we find the activation of the ESC-like gene expression signature and an ESC-like DNA methylation landscape in clinical specimens of AT/RT. Finally, we identify candidate genes that maintain the activation of the ESC-like signature and the growth of AT/RT cells. Collectively, SMARCB1-deficient hPSCs offer the human models for AT/RT, which uncover the role of the activated ESC-like signature in the poor prognosis and unique histology of AT/RT. : Terada et al. present SMARCB1-deficient human pluripotent stem cell-derived atypical teratoid/rhabdoid tumor (AT/RT) models and show that ESC-like signature is a critical driver of malignant phenotypes of AT/RT. Genetic ablation targeting the maintenance of pluripotency inhibits AT/RT cell growth, suggesting that the ESC-like signature could be a promising therapeutic target for AT/RT. Keywords: atypical teratoid/rhabdoid tumor, pediatric tumor, embryonic stem cell, induced pluripotent stem cell, ESC-like signature, pluripotency, dedifferentiation, SMARCB1
Keywords	Biology (General) ; QH301-705.5
Subject code	572
Language	English
Publishing date	2019-03-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Retraction Notice to

Kohei Yamamizu / Mio Iwasaki / Hitomi Takakubo / Takumi Sakamoto / Takeshi Ikuno / Mami Miyoshi / Takayuki Kondo / Yoichi Nakao / Masato Nakagawa / Haruhisa Inoue / Jun K. Yamashita

Stem Cell Reports, Vol 10, Iss 2, Pp 674- (2018)

In Vitro Modeling of Blood-Brain Barrier with Human iPSC-Derived Endothelial Cells, Pericytes, Neurons, and Astrocytes via Notch Signaling

2018

Keywords	Medicine (General) ; R5-920 ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2018-02-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Isolation of Human Induced Pluripotent Stem Cell-Derived Dopaminergic Progenitors by Cell Sorting for Successful Transplantation

Daisuke Doi / Bumpei Samata / Mitsuko Katsukawa / Tetsuhiro Kikuchi / Asuka Morizane / Yuichi Ono / Kiyotoshi Sekiguchi / Masato Nakagawa / Malin Parmar / Jun Takahashi

Stem Cell Reports, Vol 2, Iss 3, Pp 337-

2014 Volume 350

Abstract: Human induced pluripotent stem cells (iPSCs) can provide a promising source of midbrain dopaminergic (DA) neurons for cell replacement therapy for Parkinson’s disease. However, iPSC-derived donor cells inevitably contain tumorigenic or inappropriate ... ...

Abstract	Human induced pluripotent stem cells (iPSCs) can provide a promising source of midbrain dopaminergic (DA) neurons for cell replacement therapy for Parkinson’s disease. However, iPSC-derived donor cells inevitably contain tumorigenic or inappropriate cells. Here, we show that human iPSC-derived DA progenitor cells can be efficiently isolated by cell sorting using a floor plate marker, CORIN. We induced DA neurons using scalable culture conditions on human laminin fragment, and the sorted CORIN+ cells expressed the midbrain DA progenitor markers, FOXA2 and LMX1A. When transplanted into 6-OHDA-lesioned rats, the CORIN+ cells survived and differentiated into midbrain DA neurons in vivo, resulting in significant improvement of the motor behavior, without tumor formation. In particular, the CORIN+ cells in a NURR1+ cell-dominant stage exhibited the best survival and function as DA neurons. Our method is a favorable strategy in terms of scalability, safety, and efficiency and may be advantageous for clinical application.
Keywords	Medicine (General) ; R5-920 ; Biology (General) ; QH301-705.5
Subject code	571
Language	English
Publishing date	2014-03-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: In Vitro Modeling of Blood-Brain Barrier with Human iPSC-Derived Endothelial Cells, Pericytes, Neurons, and Astrocytes via Notch Signaling

Kohei Yamamizu / Mio Iwasaki / Hitomi Takakubo / Takumi Sakamoto / Takeshi Ikuno / Mami Miyoshi / Takayuki Kondo / Yoichi Nakao / Masato Nakagawa / Haruhisa Inoue / Jun K. Yamashita

Stem Cell Reports, Vol 8, Iss 3, Pp 634-

2017 Volume 647

Abstract: The blood-brain barrier (BBB) is composed of four cell populations, brain endothelial cells (BECs), pericytes, neurons, and astrocytes. Its role is to precisely regulate the microenvironment of the brain through selective substance crossing. Here we ... ...

Abstract	The blood-brain barrier (BBB) is composed of four cell populations, brain endothelial cells (BECs), pericytes, neurons, and astrocytes. Its role is to precisely regulate the microenvironment of the brain through selective substance crossing. Here we generated an in vitro model of the BBB by differentiating human induced pluripotent stem cells (hiPSCs) into all four populations. When the four hiPSC-derived populations were co-cultured, endothelial cells (ECs) were endowed with features consistent with BECs, including a high expression of nutrient transporters (CAT3, MFSD2A) and efflux transporters (ABCA1, BCRP, PGP, MRP5), and strong barrier function based on tight junctions. Neuron-derived Dll1, which activates Notch signaling in ECs, was essential for the BEC specification. We performed in vitro BBB permeability tests and assessed ten clinical drugs by nanoLC-MS/MS, finding a good correlation with the BBB permeability reported in previous cases. This technology should be useful for research on human BBB physiology, pathology, and drug development.
Keywords	induced pluripotent stem cells ; blood-brain barrier ; Notch signaling ; endothelial cells ; pericytes ; neurons ; astrocytes ; vasculature ; permeability ; drug kinetics ; Medicine (General) ; R5-920 ; Biology (General) ; QH301-705.5
Subject code	610
Language	English
Publishing date	2017-03-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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