@article{1c1cbf9084a744ab88ab59ae72b5357d,
title = "Generation of a p16 Reporter Mouse and Its Use to Characterize and Target p16high Cells In Vivo",
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-CreERT2-tdTomato mouse model to analyze the in vivo characteristics of p16high cells at a single-cell level. We found tdTomato-positive p16high 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 p16high 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 p16high 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",
author = "Satotaka Omori and Wang, {Teh Wei} and Yoshikazu Johmura and Tomomi Kanai and Yasuhiro Nakano and Taketomo Kido and Susaki, {Etsuo A.} and Takuya Nakajima and Shigeyuki Shichino and Satoshi Ueha and Manabu Ozawa and Kisho Yokote and Soichiro Kumamoto and Atsuya Nishiyama and Takeharu Sakamoto and Kiyoshi Yamaguchi and Seira Hatakeyama and Eigo Shimizu and Kotoe Katayama and Yasuhiro Yamada and Satoshi Yamazaki and Kanako Iwasaki and Chika Miyoshi and Hiromasa Funato and Masashi Yanagisawa and Hiroo Ueno and Seiya Imoto and Yoichi Furukawa and Nobuaki Yoshida and Kouji Matsushima and Ueda, {Hiroki R.} and Atsushi Miyajima and Makoto Nakanishi",
note = "Funding Information: We are grateful to Dr. C.E. Burd and Dr. N.E. Sharpless (University of North Carolina) for providing a p16-Luc targeting vector, and Mrs. Chieko Konishi, Yoshie Chiba, Miho Ishiura, Miho Kikuchi, and Tomoko Ando for technical assistance. Immunofluorescent images for liver sections were acquired with the help of the University of Tokyo IQB Olympus Bioimaging Center (TOBIC). The super-computing resource was provided by the Human Genome Center (the Univ. of Tokyo). This study was supported by MEXT/JSPS KAKENHI under grant numbers JP26250027, JP22118003, and JP16K15239; AMED under grant numbers JP17cm0106122, JP17fk0310111, JP17gm5010001, and JP20ck0106550; Ono Medical Research Foundation, Princess Takamatsu Cancer Research Fund, and RELAY FOR LIFE JAPAN CANCER SOCIETY to M.N.; JP18H05026m, JP19H03431, JP20H04940, and JP16H06276 (AdAMS) to Y.J.; 17H06095 to M.Y. and H.F. and 19H03413 to E.A.S.; JST CREST A3A28043 to M.Y.; the World Premier International Research Center Initiative (WPI) from MEXT to M.Y.; and AMED JP20am0401411 to H.R.U. S.O. was supported by JSPS as a Research Fellow. M.N. and Y.J. conceived the idea of the project; S.O. T.-W.W. Y.J. Y.N. T. Kido, E.A.S. M.O. N.Y. H.R.U. A.M. and M.N. planned the experiments; S.O. T.-W.W. Y.J. T. Kanai, Y.N. E.A.S. T.N. K. Yokote, S.K. A.N. K. Yamaguchi, and S.H. performed the experiments; S.O. T.-W.W. Y.J. Y.N. T. Kido, E.A.S. S.S. S.U. K. Yamaguchi, E.S. K.K. Y.Y. S.I. Y.F. N.Y. K.M. H.R.U. A.M. and M.N. analyzed the results; T.S. S.Y. C.M. K.I. M.Y. H.F. and H.U. provided the materials; and M.N. and T.-W.W. wrote the manuscript with editing by all the other authors. 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. Funding Information: We are grateful to Dr. C.E. Burd and Dr. N.E. Sharpless (University of North Carolina) for providing a p16-Luc targeting vector, and Mrs. Chieko Konishi, Yoshie Chiba, Miho Ishiura, Miho Kikuchi, and Tomoko Ando for technical assistance. Immunofluorescent images for liver sections were acquired with the help of the University of Tokyo IQB Olympus Bioimaging Center (TOBIC). The super-computing resource was provided by the Human Genome Center (the Univ. of Tokyo). This study was supported by MEXT /JSPS KAKENHI under grant numbers JP26250027 , JP22118003 , and JP16K15239 ; AMED under grant numbers JP17cm0106122 , JP17fk0310111 , JP17gm5010001 , and JP20ck0106550 ; Ono Medical Research Foundation , Princess Takamatsu Cancer Research Fund , and RELAY FOR LIFE JAPAN CANCER SOCIETY to M.N.; JP18H05026m , JP19H03431 , JP20H04940 , and JP16H06276 (AdAMS) to Y.J.; 17H06095 to M.Y. and H.F. and 19H03413 to E.A.S.; JST CREST A3A28043 to M.Y.; the World Premier International Research Center Initiative (WPI) from MEXT to M.Y.; and AMED JP20am0401411 to H.R.U. S.O. was supported by JSPS as a Research Fellow. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",
year = "2020",
month = nov,
day = "3",
doi = "10.1016/j.cmet.2020.09.006",
language = "English (US)",
volume = "32",
pages = "814--828.e6",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "5",
}