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Article ; Online: Single-cell transcriptome analysis reveals cellular heterogeneity in mouse intra- and extra articular ligaments.

Ishibashi, Kyota / Ikegami, Kentaro / Shimbo, Takashi / Sasaki, Eiji / Kitayama, Tomomi / Nakamura, Yuzuru / Tsushima, Takahiro / Ishibashi, Yasuyuki / Tamai, Katsuto

Communications biology

2022 Volume 5, Issue 1, Page(s) 1233

Abstract: Ligaments are collagenous connective tissues that connect bones. Injury of knee ligaments, namely anterior cruciate ligament (ACL) and medial collateral ligament (MCL), is common in athletes. Both ligaments have important functions, but distinct ... ...

Abstract	Ligaments are collagenous connective tissues that connect bones. Injury of knee ligaments, namely anterior cruciate ligament (ACL) and medial collateral ligament (MCL), is common in athletes. Both ligaments have important functions, but distinct regeneration capacities. The capacity for recovery after injury also diminishes with age. However, cellular heterogeneity in the ligaments remains unclear. Here, we profiled the transcriptional signatures of ACL and MCL cells in mice using single-cell RNA sequencing. These ligaments comprise three fibroblast types expressing Col22a1, Col12a1, or Col14a1, but have distinct localizations in the tissue. We found substantial heterogeneity in Col12a1- and Col14a1-positive cells between ACL and MCL. Gene Ontology analysis revealed that angiogenesis- and collagen regulation-related genes were specifically enriched in MCL cells. Furthermore, we identified age-related changes in cell composition and gene expression in the ligaments. This study delineates cellular heterogeneity in ligaments, serving as a foundation for identifying potential therapeutic targets for ligament injuries.
MeSH term(s)	Mice ; Animals ; Anterior Cruciate Ligament ; Knee Joint ; Fibroblasts ; Gene Expression Profiling
Language	English
Publishing date	2022-11-12
Publishing country	England
Document type	Journal Article
ISSN	2399-3642
ISSN (online)	2399-3642
DOI	10.1038/s42003-022-04196-w
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Article ; Online: Generation of a recessive dystrophic epidermolysis bullosa mouse model with patient-derived compound heterozygous mutations.

Takaki, Satoshi / Shimbo, Takashi / Ikegami, Kentaro / Kitayama, Tomomi / Yamamoto, Yukari / Yamazaki, Sho / Mori, Shiho / Tamai, Katsuto

Laboratory investigation; a journal of technical methods and pathology

2022 Volume 102, Issue 6, Page(s) 574–580

Abstract: Recessive dystrophic epidermolysis bullosa (RDEB) is an intractable genetic disease of the skin caused by mutations in the COL7A1 gene. The majority of patients with RDEB harbor compound heterozygous mutations-two distinct mutations on each chromosome- ... ...

Abstract	Recessive dystrophic epidermolysis bullosa (RDEB) is an intractable genetic disease of the skin caused by mutations in the COL7A1 gene. The majority of patients with RDEB harbor compound heterozygous mutations-two distinct mutations on each chromosome-without any apparent hotspots in the COL7A1 mutation pattern. This situation has made it challenging to establish a reliable RDEB mouse model with mutations that accurately mimic the genomic background of patients. Here, we established an RDEB mouse model harboring patient-type mutations in a compound heterozygous manner, using the CRISPR-based genome-editing technology i-GONAD. We selected two mutations, c.5818delC and E2857X, that have frequently been identified in cohorts of Japanese patients with RDEB. These mutations were introduced into the mouse genome at locations corresponding to those identified in patients. Mice homozygous for the 5818delC mutation developed severe RDEB-like phenotypes and died immediately after birth, whereas E2857X homozygous mice did not have a shortened lifespan compared to wild-type mice. Adult E2857X homozygous mice showed hair abnormalities, syndactyly, and nail dystrophy; these findings indicate that E2857X is indeed pathogenic in mice. Mice with the c.5818delC/E2857X compound heterozygous mutation presented an intermediate phenotype between the c.5818delC and E2857X homozygous mice. Single-cell RNA sequencing further clarified that the intrafollicular keratinocytes in c.5818delC/E2857X compound heterozygous mice exhibited abnormalities in cell cycle regulation. The proposed strategy to produce compound heterozygous mice, in addition to the established mouse line, will facilitate research on RDEB pathogenesis to develop a cure for this devastating disease.
MeSH term(s)	Animals ; Collagen Type VII/genetics ; Disease Models, Animal ; Epidermolysis Bullosa Dystrophica/genetics ; Epidermolysis Bullosa Dystrophica/pathology ; Genes, Recessive ; Homozygote ; Humans ; Mice ; Mutation ; Phenotype
Chemical Substances	COL7A1 protein, human ; Collagen Type VII
Language	English
Publishing date	2022-02-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80178-1
ISSN	1530-0307 ; 0023-6837
ISSN (online)	1530-0307
ISSN	0023-6837
DOI	10.1038/s41374-022-00735-5
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Article ; Online: Hot Spot Mutagenesis Improves the Functional Expression of Unique Mammalian Odorant Receptors.

Fukutani, Yosuke / Nakamura, Yuko / Muto, Nonoko / Miyanaga, Shunta / Kanemaki, Reina / Ikegami, Kentaro / Noguchi, Keiichi / Ohsawa, Ikuroh / Matsunami, Hiroaki / Yohda, Masafumi

International journal of molecular sciences

2021 Volume 23, Issue 1

Abstract: Vertebrate animals detect odors through olfactory receptors (ORs), members of the G protein-coupled receptor (GPCR) family. Due to the difficulty in the heterologous expression of ORs, studies of their odor molecule recognition mechanisms have progressed ...

Abstract	Vertebrate animals detect odors through olfactory receptors (ORs), members of the G protein-coupled receptor (GPCR) family. Due to the difficulty in the heterologous expression of ORs, studies of their odor molecule recognition mechanisms have progressed poorly. Functional expression of most ORs in heterologous cells requires the co-expression of their chaperone proteins, receptor transporting proteins (RTPs). Yet, some ORs were found to be functionally expressed without the support of RTP (RTP-independent ORs). In this study, we investigated whether amino acid residues highly conserved among RTP-independent ORs improve the functional expression of ORs in heterologous cells. We found that a single amino acid substitution at one of two sites (N
MeSH term(s)	Amino Acids/genetics ; Animals ; Gene Expression Regulation ; HEK293 Cells ; Humans ; Ligands ; Loss of Function Mutation/genetics ; Mammals/genetics ; Mice ; Mutagenesis/genetics ; Mutant Proteins/metabolism ; Mutation/genetics ; Receptors, Odorant/agonists ; Receptors, Odorant/chemistry ; Receptors, Odorant/genetics
Chemical Substances	Amino Acids ; Ligands ; Mutant Proteins ; Receptors, Odorant
Language	English
Publishing date	2021-12-28
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms23010277
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Article ; Online: Single-cell transcriptome analysis of fractional CO

Hasegawa, Kouichi / Fujimoto, Takahiro / Mita, Chihiro / Furumoto, Hidehiro / Inoue, Masako / Ikegami, Kentaro / Kitayama, Tomomi / Yamamoto, Yukari / Shimbo, Takashi / Yamazaki, Takehiko / Tamai, Katsuto

Lasers in surgery and medicine

2022 Volume 54, Issue 8, Page(s) 1167–1176

Abstract: Objectives: Hair loss, including alopecia, is a common dermatological issue worldwide. At present, the application of fractional carbon dioxide (CO: Methods: A fractional CO: Results: The effective irradiation condition for initiating the hair ... ...

Abstract	Objectives: Hair loss, including alopecia, is a common dermatological issue worldwide. At present, the application of fractional carbon dioxide (CO Methods: A fractional CO Results: The effective irradiation condition for initiating the hair cycle was found to be 15 mJ energy/spot, which generates approximately 500 μm depth columns, but does not penetrate the dermis, only reaching approximately 1 spot/mm Conclusions: We found that fractional CO
MeSH term(s)	Alopecia/genetics ; Alopecia/radiotherapy ; Animals ; Carbon Dioxide/pharmacology ; Disease Models, Animal ; Gene Expression Profiling ; Hair ; Humans ; Lasers, Gas/therapeutic use ; Mice
Chemical Substances	Carbon Dioxide (142M471B3J)
Language	English
Publishing date	2022-08-02
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	604493-1
ISSN	1096-9101 ; 0196-8092
ISSN (online)	1096-9101
ISSN	0196-8092
DOI	10.1002/lsm.23590
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Article ; Online: Plap-1 lineage tracing and single-cell transcriptomics reveal cellular dynamics in the periodontal ligament.

Iwayama, Tomoaki / Iwashita, Mizuho / Miyashita, Kazuya / Sakashita, Hiromi / Matsumoto, Shuji / Tomita, Kiwako / Bhongsatiern, Phan / Kitayama, Tomomi / Ikegami, Kentaro / Shimbo, Takashi / Tamai, Katsuto / Murayama, Masanori A / Ogawa, Shuhei / Iwakura, Yoichiro / Yamada, Satoru / Olson, Lorin E / Takedachi, Masahide / Murakami, Shinya

Development (Cambridge, England)

2022 Volume 149, Issue 19

Abstract: Periodontal tissue supports teeth in the alveolar bone socket via fibrous attachment of the periodontal ligament (PDL). The PDL contains periodontal fibroblasts and stem/progenitor cells, collectively known as PDL cells (PDLCs), on top of osteoblasts and ...

Abstract	Periodontal tissue supports teeth in the alveolar bone socket via fibrous attachment of the periodontal ligament (PDL). The PDL contains periodontal fibroblasts and stem/progenitor cells, collectively known as PDL cells (PDLCs), on top of osteoblasts and cementoblasts on the surface of alveolar bone and cementum, respectively. However, the characteristics and lineage hierarchy of each cell type remain poorly defined. This study identified periodontal ligament associated protein-1 (Plap-1) as a PDL-specific extracellular matrix protein. We generated knock-in mice expressing CreERT2 and GFP specifically in Plap-1-positive PDLCs. Genetic lineage tracing confirmed the long-standing hypothesis that PDLCs differentiate into osteoblasts and cementoblasts. A PDL single-cell atlas defined cementoblasts and osteoblasts as Plap-1-Ibsp+Sparcl1+ and Plap-1-Ibsp+Col11a2+, respectively. Other populations, such as Nes+ mural cells, S100B+ Schwann cells, and other non-stromal cells, were also identified. RNA velocity analysis suggested that a Plap-1highLy6a+ cell population was the source of PDLCs. Lineage tracing of Plap-1+ PDLCs during periodontal injury showed periodontal tissue regeneration by PDLCs. Our study defines diverse cell populations in PDL and clarifies the role of PDLCs in periodontal tissue homeostasis and repair.
MeSH term(s)	Animals ; Calcium-Binding Proteins/metabolism ; Cell Differentiation/genetics ; Extracellular Matrix Proteins/metabolism ; Mice ; Osteoblasts ; Periodontal Ligament ; RNA/metabolism ; Transcriptome
Chemical Substances	Calcium-Binding Proteins ; Extracellular Matrix Proteins ; Sparcl1 protein, mouse ; RNA (63231-63-0)
Language	English
Publishing date	2022-10-17
Publishing country	England
Document type	Journal Article
ZDB-ID	90607-4
ISSN	1477-9129 ; 0950-1991
ISSN (online)	1477-9129
ISSN	0950-1991
DOI	10.1242/dev.201203
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Article ; Online: The N-terminal region of RTP1S plays important roles in dimer formation and odorant receptor-trafficking.

Fukutani, Yosuke / Tamaki, Ryohei / Inoue, Ryosuke / Koshizawa, Tomoyo / Sakashita, Shuto / Ikegami, Kentaro / Ohsawa, Ikuroh / Matsunami, Hiroaki / Yohda, Masafumi

The Journal of biological chemistry

2019 Volume 294, Issue 40, Page(s) 14661–14673

Abstract: Receptor-transporting protein 1S (RTP1S) is an accessory protein that mediates the transport of mammalian odorant receptors (ORs) into the plasma membrane. Although most ORs fail to localize to the cell surface when expressed alone in nonolfactory cells, ...

Abstract	Receptor-transporting protein 1S (RTP1S) is an accessory protein that mediates the transport of mammalian odorant receptors (ORs) into the plasma membrane. Although most ORs fail to localize to the cell surface when expressed alone in nonolfactory cells, functional expression of ORs is achieved with the coexpression of RTP1S. However, the mechanism for RTP1S-mediated OR trafficking remains unclear. In this study, we attempted to reveal the mode of action and critical residues of RTP1S in OR trafficking. Experiments using N-terminal truncation and Ala substitution mutants of RTP1S demonstrated that four N-terminal amino acids have essential roles in OR trafficking. Additionally, using recombinant proteins and split luciferase assays in mammalian cells, we provided evidence for the dimer formation of RTP1S. Furthermore, we determined that the 2nd Cys residue is required for the efficient dimerization of RTP1S. Altogether, these findings provide insights into the mechanism for plasma membrane transport of ORs by RTP1S.
MeSH term(s)	Animals ; Cell Movement/genetics ; Dimerization ; Flow Cytometry ; HEK293 Cells ; Humans ; Membrane Transport Proteins/chemistry ; Membrane Transport Proteins/genetics ; Mice ; Molecular Chaperones/chemistry ; Molecular Chaperones/genetics ; Odorants/analysis ; Protein Transport/genetics ; Receptors, G-Protein-Coupled/chemistry ; Receptors, G-Protein-Coupled/genetics ; Receptors, Odorant/chemistry ; Receptors, Odorant/genetics
Chemical Substances	Membrane Transport Proteins ; Molecular Chaperones ; RTP1 protein, mouse ; Receptors, G-Protein-Coupled ; Receptors, Odorant
Language	English
Publishing date	2019-08-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.RA118.007110
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Article ; Online: Longitudinal Single-Cell Transcriptomics Reveals a Role for Serpina3n-Mediated Resolution of Inflammation in a Mouse Colitis Model.

Ho, Yen-Ting / Shimbo, Takashi / Wijaya, Edward / Kitayama, Tomomi / Takaki, Satoshi / Ikegami, Kentaro / Miyashita, Kazuya / Ouchi, Yuya / Takaki, Eiichi / Yamamoto, Ryoma / Kaneda, Yasufumi / Tamai, Katsuto

Cellular and molecular gastroenterology and hepatology

2021 Volume 12, Issue 2, Page(s) 547–566

Abstract: Background & aims: Proper resolution of inflammation is essential to maintaining homeostasis, which is important as a dysregulated inflammatory response has adverse consequences, even being regarded as a hallmark of cancer. However, our picture of ... ...

Abstract	Background & aims: Proper resolution of inflammation is essential to maintaining homeostasis, which is important as a dysregulated inflammatory response has adverse consequences, even being regarded as a hallmark of cancer. However, our picture of dynamic changes during inflammation remains far from comprehensive. Methods: Here we used single-cell transcriptomics to elucidate changes in distinct cell types and their interactions in a mouse model of chemically induced colitis. Results: Our analysis highlights the stromal cell population of the colon functions as a hub with dynamically changing roles over time. Importantly, we found that Serpina3n, a serine protease inhibitor, is specifically expressed in stromal cell clusters as inflammation resolves, interacting with a potential target, elastase. Indeed, genetic ablation of the Serpina3n gene delays resolution of induced inflammation. Furthermore, systemic Serpina3n administration promoted the resolution of inflammation, ameliorating colitis symptoms. Conclusions: This study provides a comprehensive, single-cell understanding of cell-cell interactions during colorectal inflammation and reveals a potential therapeutic target that leverages inflammation resolution.
MeSH term(s)	Acute-Phase Proteins/metabolism ; Animals ; Cell Communication ; Colitis/genetics ; Colitis/pathology ; Colon/pathology ; Dextran Sulfate ; Disease Models, Animal ; Genetic Predisposition to Disease ; Inflammation/genetics ; Inflammation/pathology ; Inflammatory Bowel Diseases/genetics ; Inflammatory Bowel Diseases/pathology ; Mice, Inbred C57BL ; Phenotype ; RNA-Seq ; Risk Factors ; Serpins/metabolism ; Single-Cell Analysis ; Stromal Cells/metabolism ; Transcriptome/genetics ; Mice
Chemical Substances	Acute-Phase Proteins ; Serpina3n protein, mouse ; Serpins ; Dextran Sulfate (9042-14-2)
Language	English
Publishing date	2021-04-13
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2819778-1
ISSN	2352-345X ; 2352-345X
ISSN (online)	2352-345X
ISSN	2352-345X
DOI	10.1016/j.jcmgh.2021.04.004
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Article ; Online: Odorant Receptor 7D4 Activation Dynamics.

de March, Claire A / Topin, Jérémie / Bruguera, Elise / Novikov, Gleb / Ikegami, Kentaro / Matsunami, Hiroaki / Golebiowski, Jérôme

Angewandte Chemie (International ed. in English)

2018 Volume 57, Issue 17, Page(s) 4554–4558

Abstract: Deciphering how an odorant activates an odorant receptor (OR) and how changes in specific OR residues affect its responsiveness are central to understanding our sense of smell. A joint approach combining site-directed mutagenesis and functional assays ... ...

Abstract	Deciphering how an odorant activates an odorant receptor (OR) and how changes in specific OR residues affect its responsiveness are central to understanding our sense of smell. A joint approach combining site-directed mutagenesis and functional assays with computational modeling has been used to explore the signaling mechanics of OR7D4. In this OR, a genetic polymorphism affects our perception of androstenone. Molecular simulations totaling 0.12 ms predicted that, similarly to observations for other G-protein-coupled receptors with known experimental structures, an activation pathway connects the ligand and the G-protein binding site. The 3D model activation mechanism correlates with in vitro data and notably predicts that the OR7D4 WM variant is not activated. Upon activation, an OR-specific sequence motif is the convergence point of the mechanism. Our study suggests that robust homology modeling can serve as a powerful tool to capture OR dynamics related to smell perception.
MeSH term(s)	Crystallography, X-Ray ; Humans ; Molecular Conformation ; Molecular Dynamics Simulation ; Receptors, Odorant/agonists ; Receptors, Odorant/chemistry ; Receptors, Odorant/metabolism
Chemical Substances	OR7D4 receptor protein, human ; Receptors, Odorant
Language	English
Publishing date	2018-03-24
Publishing country	Germany
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2011836-3
ISSN	1521-3773 ; 1433-7851
ISSN (online)	1521-3773
ISSN	1433-7851
DOI	10.1002/anie.201713065
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Article ; Online: Concentration-Dependent Recruitment of Mammalian Odorant Receptors.

Hu, Xiaoyang Serene / Ikegami, Kentaro / Vihani, Aashutosh / Zhu, Kevin W / Zapata, Marcelo / de March, Claire A / Do, Matthew / Vaidya, Natasha / Kucera, Gary / Bock, Cheryl / Jiang, Yue / Yohda, Masafumi / Matsunami, Hiroaki

eNeuro

2020 Volume 7, Issue 2

Abstract: A fundamental challenge in studying principles of organization used by the olfactory system to encode odor concentration information has been identifying comprehensive sets of activated odorant receptors (ORs) across a broad concentration range inside ... ...

Abstract	A fundamental challenge in studying principles of organization used by the olfactory system to encode odor concentration information has been identifying comprehensive sets of activated odorant receptors (ORs) across a broad concentration range inside freely behaving animals. In mammals, this has recently become feasible with high-throughput sequencing-based methods that identify populations of activated ORs
MeSH term(s)	Animals ; Mammals/metabolism ; Odorants ; Olfactory Bulb/metabolism ; Olfactory Receptor Neurons/metabolism ; Receptors, Odorant/genetics ; Receptors, Odorant/metabolism ; Smell
Chemical Substances	Receptors, Odorant
Language	English
Publishing date	2020-04-23
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2800598-3
ISSN	2373-2822 ; 2373-2822
ISSN (online)	2373-2822
ISSN	2373-2822
DOI	10.1523/ENEURO.0103-19.2019
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Article ; Online: Structural instability and divergence from conserved residues underlie intracellular retention of mammalian odorant receptors.

Ikegami, Kentaro / de March, Claire A / Nagai, Maira H / Ghosh, Soumadwip / Do, Matthew / Sharma, Ruchira / Bruguera, Elise S / Lu, Yueyang Eric / Fukutani, Yosuke / Vaidehi, Nagarajan / Yohda, Masafumi / Matsunami, Hiroaki

Proceedings of the National Academy of Sciences of the United States of America

2020 Volume 117, Issue 6, Page(s) 2957–2967

Abstract: Mammalian odorant receptors are a diverse and rapidly evolving set of G protein-coupled receptors expressed in olfactory cilia membranes. Most odorant receptors show little to no cell surface expression in nonolfactory cells due to endoplasmic reticulum ... ...

Abstract	Mammalian odorant receptors are a diverse and rapidly evolving set of G protein-coupled receptors expressed in olfactory cilia membranes. Most odorant receptors show little to no cell surface expression in nonolfactory cells due to endoplasmic reticulum retention, which has slowed down biochemical studies. Here we provide evidence that structural instability and divergence from conserved residues of individual odorant receptors underlie intracellular retention using a combination of large-scale screening of odorant receptors cell surface expression in heterologous cells, point mutations, structural modeling, and machine learning techniques. We demonstrate the importance of conserved residues by synthesizing consensus odorant receptors that show high levels of cell surface expression similar to conventional G protein-coupled receptors. Furthermore, we associate in silico structural instability with poor cell surface expression using molecular dynamics simulations. We propose an enhanced evolutionary capacitance of olfactory sensory neurons that enable the functional expression of odorant receptors with cryptic mutations.
MeSH term(s)	Animals ; Cell Line ; Humans ; Mice ; Molecular Dynamics Simulation ; Olfactory Receptor Neurons/chemistry ; Olfactory Receptor Neurons/metabolism ; Protein Stability ; Receptors, Odorant/chemistry ; Receptors, Odorant/genetics ; Receptors, Odorant/metabolism
Chemical Substances	Receptors, Odorant
Language	English
Publishing date	2020-01-23
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1915520117
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