Generation of a p16 Reporter Mouse and Its Use to Characterize and Target p16^high Cells In Vivo

Satotaka Omori¹, Teh-Wei Wang¹, Yoshikazu Johmura², Tomomi Kanai¹, Yasuhiro Nakano³, Taketomo Kido³, Etsuo A Susaki⁴, Takuya Nakajima⁵, Shigeyuki Shichino⁵, Satoshi Ueha⁵, Manabu Ozawa⁶, Kisho Yokote¹, Soichiro Kumamoto¹, Atsuya Nishiyama¹, Takeharu Sakamoto⁷, Kiyoshi Yamaguchi⁸, Seira Hatakeyama⁸, Eigo Shimizu⁹, Kotoe Katayama⁹, Yasuhiro Yamada¹⁰, Satoshi Yamazaki¹¹, Kanako Iwasaki¹², Chika Miyoshi¹², Hiromasa Funato¹³, Masashi Yanagisawa¹⁴, Hiroo Ueno¹⁵, Seiya Imoto⁹, Yoichi Furukawa⁸, Nobuaki Yoshida¹⁶, Kouji Matsushima⁵, Hiroki R Ueda⁴, Atsushi Miyajima³, Makoto Nakanishi¹⁷

Affiliations

¹ Division of Cancer Cell Biology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
² Division of Cancer Cell Biology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. Electronic address: johmuray@g.ecc.u-tokyo.ac.jp.
³ Laboratory of Stem Cell Therapy, Institute for Quantitative Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
⁴ Department of Systems Pharmacology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; Laboratory for Synthetic Biology, RIKEN Center for Biosystems Dynamics Research, 1-3 Yamadaoka, Suita, Osaka 565-5241, Japan.
⁵ Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute of Biomedical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-0022, Japan.
⁶ Laboratory of Reproductive Systems Biology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
⁷ Department of System Biology, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8641, Japan.
⁸ Division of Clinical Genome Research, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
⁹ Division of Health Medical Intelligence, Human Genome Center, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
¹⁰ Division of Stem Cell Pathology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan; AMED-CREST, AMED, 1-7-1 Otemachi, Tokyo 100-0004, Japan.
¹¹ Division of Stem Cell Biology, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan; Laboratory of Stem Cell Therapy, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan.
¹² International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
¹³ International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan; Department of Anatomy, Faculty of Medicine, Toho University, 5-21-16 Omorinishi, Ota-ku, Tokyo 143-8540, Japan.
¹⁴ International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan; Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
¹⁵ Department of Stem Cell Pathology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan.
¹⁶ Laboratory of Developmental Genetics, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
¹⁷ Division of Cancer Cell Biology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. Electronic address: mkt-naka@g.ecc.u-tokyo.ac.jp.

PMID: 32949498
DOI: 10.1016/j.cmet.2020.09.006

Free article

Generation of a p16 Reporter Mouse and Its Use to Characterize and Target p16^high Cells In Vivo

Satotaka Omori et al. Cell Metab. 2020.

Free article

. 2020 Nov 3;32(5):814-828.e6.

doi: 10.1016/j.cmet.2020.09.006. Epub 2020 Sep 18.

Authors

Affiliations

¹ Division of Cancer Cell Biology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
² Division of Cancer Cell Biology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. Electronic address: johmuray@g.ecc.u-tokyo.ac.jp.
³ Laboratory of Stem Cell Therapy, Institute for Quantitative Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
⁴ Department of Systems Pharmacology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; Laboratory for Synthetic Biology, RIKEN Center for Biosystems Dynamics Research, 1-3 Yamadaoka, Suita, Osaka 565-5241, Japan.
⁵ Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute of Biomedical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-0022, Japan.
⁶ Laboratory of Reproductive Systems Biology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
⁷ Department of System Biology, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8641, Japan.
⁸ Division of Clinical Genome Research, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
⁹ Division of Health Medical Intelligence, Human Genome Center, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
¹⁰ Division of Stem Cell Pathology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan; AMED-CREST, AMED, 1-7-1 Otemachi, Tokyo 100-0004, Japan.
¹¹ Division of Stem Cell Biology, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan; Laboratory of Stem Cell Therapy, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan.
¹² International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
¹³ International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan; Department of Anatomy, Faculty of Medicine, Toho University, 5-21-16 Omorinishi, Ota-ku, Tokyo 143-8540, Japan.
¹⁴ International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan; Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
¹⁵ Department of Stem Cell Pathology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan.
¹⁶ Laboratory of Developmental Genetics, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
¹⁷ Division of Cancer Cell Biology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. Electronic address: mkt-naka@g.ecc.u-tokyo.ac.jp.

PMID: 32949498
DOI: 10.1016/j.cmet.2020.09.006

Abstract

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.

Keywords: NASH; aging; p16Ink4a; senescence; single-cell transcriptomics.

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Conflict of interest statement

Declaration of Interests The authors declare that they have no conflicts of interest with respect to the contents of this article. RIKEN has filed patents of CUBIC reagents in which E.A.S. and H.R.U. are co-inventors. Part of this study was performed in collaboration with Olympus Corporation.

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Generation of a p16 Reporter Mouse and Its Use to Characterize and Target p16^high Cells In Vivo

Affiliations

Generation of a p16 Reporter Mouse and Its Use to Characterize and Target p16^high Cells In Vivo

Authors

Affiliations

Abstract

Conflict of interest statement

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