An inducible <i>p21</i>-Cre mouse model to monitor and manipulate <i>p21</i>-highly-expressing senescent cells <i>in vivo</i>.

Abstract

The role of senescent cells has been implicated in various tissue dysfunction associated with aging, obesity, and other pathological conditions. Currently, most transgenic mouse models only target <i>p16</i> ^Ink4a-highly-expressing (<i>p16</i> ^high) cells. Here, we generated a <i>p21</i>-Cre mouse model, containing a <i>p21</i> promoter driving inducible Cre, enabling us to examine <i>p21</i> ^Cip1-highly-expressing (<i>p21</i> ^high) cells, a previously unexplored cell population exhibiting several characteristics typical of senescent cells. By crossing <i>p21</i>-Cre mice with different floxed mice, we managed to monitor, sort, image, eliminate, or modulate <i>p21</i> ^high cells <i>in vivo</i>. We showed <i>p21</i> ^high cells can be induced by various conditions, and percentages of <i>p21</i> ^high cells varied from 1.5 to 10% across different tissues in 23-month-old mice. Intermittent clearance of <i>p21</i> ^high cells improved physical function in 23-month-old mice. Our study demonstrates that the <i>p21</i>-Cre mouse model is a valuable and powerful tool for studying <i>p21</i> ^high cells to further understand the biology of senescent cells.