Project description:Targeting senescent cells for therapeutic purposes is gaining momentum across various organ systems. However, concerns about potential off-target effects have been raised. Previous studies have shown that removing senescent cells expressing high levels of p16 (p16high) can hinder processes like wound healing. Here, we identify a distinct senescent cell population during dermal wound healing characterized by high expression level of p21 (p21high) using the p21-Cre mouse model. Using a standard cutaneous injury model, we find that eliminating p21high cells can expedite wound closure, in contrast to the effects of removing p16high cells. Through Xenium, a single cell spatial imaging platform, we show that p21high cells are distinct from p16high cells, with p21high cells mainly comprising fibroblasts, immune cells, keratinocytes, and endothelial cells with a pro-inflammatory profile. Moreover, inhibition of NF-kB signaling specifically from p21high cells partially contributes to the accelerated wound healing rates. These findings highlight the heterogeneity of senescent cells during wound healing responses within the skin and likely in other conditions.
Project description:Targeting senescent cells for therapeutic purposes is gaining momentum across various organ systems. However, concerns about potential off-target effects have been raised. Previous studies have shown that removing senescent cells expressing high levels of p16 (p16high) can hinder processes like wound healing. Here, we identify a distinct senescent cell population during dermal wound healing characterized by high expression level of p21 (p21high) using the p21-Cre mouse model. Using a standard cutaneous injury model, we find that eliminating p21high cells can expedite wound closure, in contrast to the effects of removing p16high cells. Through Xenium, a single cell spatial imaging platform, we show that p21high cells are distinct from p16high cells, with p21high cells mainly comprising fibroblasts, immune cells, keratinocytes, and endothelial cells with a pro-inflammatory profile. Moreover, inhibition of NF-kB signaling specifically from p21high cells partially contributes to the accelerated wound healing rates. These findings highlight the heterogeneity of senescent cells during wound healing responses within the skin and likely in other conditions.
Project description:The accumulation of senescent cells can drive many age-associated phenotypes and pathologies. Consequently, it has been proposed that removing senescent cells might extend lifespan. Here we generated two knock-in mouse models targeting the best-characterized marker of senescence, p16Ink4a. Using a genetic lineage tracing approach, we found that age-induced p16High senescence is a slow process that manifests around 10-12 months of age. The majority of p16High cells were vascular endothelial cells mostly in liver sinusoids (LSECs), and to lesser extent macrophages and adipocytes. In turn, continuous or acute elimination of p16High senescent cells disrupted blood–tissue barriers with subsequent liver and peri-vascular tissue fibrosis and health deterioration. Our data show that senescent LSECs are not replaced after removal and have important structural and functional roles in the aging organism. In turn, delaying senescence or replacement of senescent LSECs could represent a powerful tool in slowing down aging.
Project description:We used scRNA-seq analysis to investigate the expression profiles of p16high adipocyte progenitor cells compared with p16low adipocyte progenitor cells in the gonadal adipose tissue of aging mice.
Project description:We used bulk RNA-seq analysis to investigate the gene expression patterns of p16high adipocyte progenitor cells compared with p16low adipocyte progenitor cells in the gonadal adipose tissue of tumor bearing mice.
Project description:In our laboratory, we developed a new knock-in murine model to trace p16 cells ex vivo using EGFP as a reporter gene under the control of the endogenous promoter (exon 3) of the p16 locus from the CDKN2A gene (p16-Cre/Rosa26-mtmg). We showed previously that cells positive for p16-EGFP accumulated during natural aging. We previously reported (Grosse et al, 2020) that among this cells, liver endothelial cells and macrophages from liver and other tissues are the main population going into p16 activation. We are now analyzing the characteristics of p16High tissue resident peritoneal macrophages to understant the roll they have during adulhood and aging.
Project description:Gene expression profile of LysMCre/Cre and KLF2∆/∆ primary peritoneal macrophages following 6 hours of LPS treatment. We used microarrays to detail the global program of gene expression following LPS stimulation of LysMCre/Cre and KLF2∆/∆ primary peritoneal macrophages. We identified distinct classes of genes that were altered following LPS stimulation.
