Title: Generation of a p16 Reporter Mouse and Its Use to Characterize and Target p16high Cells In Vivo
Author: Satotaka Omori, Teh-Wei Wang, Yoshikazu Johmura, Tomomi Kanai, Yasuhiro Nakano, Taketomo Kido, Etsuo A. Susaki, Takuya Nakajima, Shigeyuki Shichino, Satoshi Ueha, Manabu Ozawa, Kisho Yokote, Soichiro Kumamoto, Atsuya Nishiyama, Takeharu Sakamoto, Kiyoshi Yamaguchi, Seira Hatakeyama, Eigo Shimizu, Kotoe Katayama, Yasuhiro Yamada, Satoshi Yamazaki, Kanako Iwasaki, Chika Miyoshi, Hiromasa Funato, Masashi Yanagisawa, Hiroo Ueno, Seiya Imoto, Yoichi Furukawa, Nobuaki Yoshida, Kouji Matsushima, Hiroki R. Ueda, Atsushi Miyajima, Makoto Nakanishi
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 thatthese 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 kidneysrevealed that p16high cells were present in various cell types, though most dominant in hepatic endotheliumand in renal proximal and distal tubule epithelia, and that these cells exhibitedheterogeneous senescence-associated phenotypes. Further, elimination of p16high cells ameliorated nonalcoholic steatohepatitis-related hepatic lipidosis and immunecell infiltration. Our new mouse model and single-cell analysis provide a powerfulresource to enable the discovery of previously unidentified senescence functions in vivo.