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Generation of a p16 Reporter Mouse and Its Use to Characterize and Target p16high Cells In Vivo
Open accessAbstract
Cell senescence plays a key role in age-associated organ dysfunction, but the in vivo pathogenesis is largely unclear. Here, we generated a p16-Cre ERT2-tdTomato mouse model to analyze the in vivo characteristics of p16 high cells at a single-cell level. We found tdTomato-positive p16 high cells detectable in all organs, which were enriched with age. We also found that these cells failed to proliferate and had half-lives ranging from 2.6 to 4.2 months, depending on the tissue examined. Single-cell transcriptomics in the liver and kidneys revealed that p16 high cells were present in various cell types, though most dominant in hepatic endothelium and in renal proximal and distal tubule epithelia, and that these cells exhibited heterogeneous senescence-associated phenotypes. Further, elimination of p16 high cells ameliorated nonalcoholic steatohepatitis-related hepatic lipidosis and immune cell infiltration. Our new mouse model and single-cell analysis provide a powerful resource to enable the discovery of previously unidentified senescence functions in vivo.
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Self-citationThree-Dimensional Visualization of Hypoxia-Induced Pulmonary Vascular Remodeling in Mice
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“For these studies, we utilized the recently characterized p16-Cre ERT2 /tdTomato mouse in which the fi rst exon of the endogenous p16 INK4a gene was substituted with a Cre ERT2 gene, which allowed us to identify p16 expressing cells (tdTom + ) at the single-cell level 19 .”
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“53,54 Therefore, P16 is widely used as a decisive marker for senescent cells.”
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“YB-1 is a DNA/RNA-binding protein ( Lyabin, Eliseeva & Ovchinnikov, 2014 ) and has been reported to bind to the promoter region of p16 INK 4 A and inhibit its expression ( Kotake et al., 2013 ; Xiao et al., 2020 ), a maker of cellular senescence ( Ogrodnik et al., 2019 ; Omori et al., 2020 ).”
Therapeutic Potential of a Senolytic Approach in a Murine Model of Chronic GVHD
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p16 Ink4a ‐Positive Hepatocytes Drive Liver Fibrosis Through Activation of LIFR Family Pathway
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Self-citationGeneration of mice for evaluating endogenous p16Ink4a protein expression
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“48,49 Previous studies have demonstrated significant age-dependent differences in cyclin-dependent kinase inhibitor 2A (CDKN2A) expression in the ascending and descending colon of older adults compared with younger adults.”
Deprivation of EGFR signal causes senolysis in PDAC with CDK4/6 inhibition
Zhang, Y., Kohno, S., Gao, K., Hasan, M., Baba, T., Zhang, Z., Sankoda, N., Yu, H., Pan, J., Gotoh, N., et al. (2025) · Cell Death and Differentiation · doi:10.1038/s41418-025-01634-0 · Cited by 2
“To examine whether the therapeutic dose of palbociclib induces cellular senescence in normal tissues, p16-Cre ERT2 - tdTomato mice [58] were treated either by vehicle or palbociclib (125 mg/kg body weight) for 28 days and two intraperitoneal injections of tamoxifen (80 mg/kg body weight)…”
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“To investigate this possibility, we reanalyzed the single-cell RNA sequencing (scRNA-seq) data from the livers and kidneys of p16-CreERT2-tdTomato mice previously reported by Omori et al (2020).”
Senotypes define the diverse landscape of senescent cells
Schafer, M. J., Basisty, N., Hertzel, A. V., Rindone, A. N., Elisseeff, J. H., Suryadevara, V., Aliferis, C., Robbins, P. D., Niedernhofer, L. J., Miller, K. N., et al. (2026) · Nature Aging · doi:10.1038/s43587-026-01148-5 · Cited by 2
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Cellular senescence during aging and chronic liver diseases
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“28, 29 Thus, identifying and un - derstanding ageing-related markers is crucial for advancing ageing research and therapeutic strategies.”
BackgroundSugiyama, Y., Kawabe, Y., Harada, T., Aoki, Y., Tsuji, K., Sugiyama, D., & Maruyama, M. (2024) · Genes to Cells · doi:10.1111/gtc.13163 · Cited by 2
“Some groups have created knock-in models by accelerating the expression of diphtheria toxin A or diphtheria toxin receptors using strong promoters such as Gt (ROSA)26Sor or CAG under the control of Cre inserted into the endogenous Cdkn2a locus (Grosse et al., 2020; Omori et al., 2020).”
Current Methodologies to Assess Cellular Senescence in Cancer
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“Instead, we traced pre-existed p16 Ink4a + somatic cells and PD-L1 + subpopulation by fate-mapping approaches (Omori et al, 2020), observing their selective depletion following PD-1 blockade.”
Self-citationResponse to: Limitations of the p16-3MR mouse model for detecting and eliminating senescent cells
Wang, B., Nehme, J., & Demaria, M. (2026) · EMBO Reports · doi:10.1038/s44319-026-00801-9 · Cited by 1
“Recent work highlighting immune modulation following p16 + -cell clearance underscores biological interconnectedness between senescence/ immunity rather than model failure (Omori et al, 2020; Zhao et al, 2024).”
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“In this model, the endogenous p16 promoter drives the expression of a tamoxifen-activated form of Cre recombinase (CreERT2), but without exogenously added elements that enhance transcriptional activity (Omori et al., 2020).”
BackgroundNetwork-community analysis of cellular senescencePreprint
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“Finally, to validate our findings further, we analyzed a previously published single-cell RNA-seq dataset in normal and fibrotic liver and kidney tissue [28].”
ResultSingle-cell-based evidence for GLS1 inhibitor as a bona fide senolytic agent in vivoPreprint
Okamura, Y. T., Wang, T.-W., Kawakami, S., Morimura, T., Johmura, Y., & Nakanishi, M. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.07.22.666220 · Cited by 1
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“Furthermore, we took advantage of p16 reporter mouse models (p16-Cre ERT2 -tdTomato) 23 to investigate the phenotypic effects and molecular mechanisms of IH-induced cardiovascular senescence, and their reversibility through selective targeting of senescent cells in the vasculature.”
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Stress-induced senescence of tubular cells
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P16 promotes aging-induced lipid droplet accumulation via up-regulation of PCSK9 in hepatocytesPreprint
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RPE Senescence and Its Implication in Age-Related Macular Degeneration
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Aging and rejuvenation of engineered cardiovascular tissues: from research to clinical application
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Does old-to-young kidney transplantation rejuvenate old donor kidneys?
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Metadata
- Authors
- Omori, S., Wang, T.-W., Johmura, Y., Kanai, T., Nakano, Y., Kido, T., Susaki, E. A., Nakajima, T., Shichino, S., Ueha, S., Ozawa, M., Yokote, K., Kumamoto, S., Nishiyama, A., Sakamoto, T., Yamaguchi, K., Hatakeyama, S., Shimizu, E., Katayama, K., Yamada, Y., Yamazaki, S., Iwasaki, K., Miyoshi, C., Funato, H., Yanagisawa, M., Ueno, H., Imoto, S., Furukawa, Y., Yoshida, N., Matsushima, K., Ueda, H. R., Miyajima, A., & Nakanishi, M.
- Affiliations
- Institute of Medical Science, The University of Tokyo (JP)
- Institute for Quantitative Biosciences, The University of Tokyo (JP)
- RIKEN Center for Biosystems Dynamics Research (JP)
- Tokyo University of Science (JP)
- Kanazawa University (JP)
- Japan Agency for Medical Research and Development (JP)
- University of Tsukuba (JP)
- Toho University (JP)
- Kansai Medical University (JP)
- Corresponding author
- Johmura, Yoshikazu
- Nakanishi, Makoto
- ORCID
- Omori, Satotaka
- Wang, Teh-Wei
- Johmura, Yoshikazu
- Kanai, Tomomi
- Nakano, Yasuhiro
- Kido, Taketomo
- Susaki, Etsuo A.
- Shichino, Shigeyuki
- Ueha, Satoshi
- Ozawa, Manabu
- Kumamoto, Soichiro
- Nishiyama, Atsuya
- Sakamoto, Takeharu
- Yamaguchi, Kiyoshi
- Hatakeyama, Seira
- Shimizu, Eigo
- Katayama, Kotoe
- Yamada, Yasuhiro
- Yamazaki, Satoshi
- Miyoshi, Chika
- Funato, Hiromasa
- Yanagisawa, Masashi
- Imoto, Seiya
- Furukawa, Yoichi
- Yoshida, Nobuaki
- Matsushima, Kouji
- Ueda, Hiroki R.
- Miyajima, Atsushi
- Nakanishi, Makoto
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2020-11
- Volume
- 32
- Issue
- 5
- Pages
- 814-828.e6
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W3087571995
- Cited by
- 194
- References
- 98
- Citations by year
- 2026: 30 · 2025: 32 · 2024: 43 · 2023: 37 · 2022: 26 · 2021: 23 · 2020: 3
- FWCI
- 13.38
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 367 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Princess Takamatsu Cancer Research Fund (17H06095, 19H03413, JP16H06276, JP18H05026m, JP19H03431, JP20H04940)
- Ministry of Education, Culture, Sports, Science and Technology
- Core Research for Evolutional Science and Technology (A3A28043, AMED JP20am0401411)
- Ono Medical Research Foundation
- Olympus
- Japan Society for the Promotion of Science (JP16K15239, JP17cm0106122, JP17fk0310111, JP17gm5010001, JP20ck0106550, JP22118003, JP26250027)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Keywords
- cellular senescence, nonalcoholic steatohepatitis, hepatic lipidosis, immune cell infiltration, single-cell analysis
- MeSH terms
- Animals, Cell Line, Humans, Mice, Inbred C57BL, Models, Biological, Cellular Senescence, Cyclin-Dependent Kinase Inhibitor p16, Mice, Single-Cell Analysis
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