Anti-uPAR CAR T cells reverse and prevent aging-associated defects in intestinal regeneration and fitness

Abstract Intestinal stem cells (ISCs) drive the rapid regeneration of the gut epithelium. However, during aging, their regenerative capacity wanes, possibly through senescence and chronic inflammation, albeit little is known about how aging-associated dysfunction arises in the intestine. We previously identified the urokinase plasminogen activator receptor (uPAR) as a senescence-associated protein and developed CAR T cells able to efficiently target it. Harnessing them, here, we identify the accumulation of mostly epithelial uPAR-positive cells in the aging gut and uncover their detrimental impact on ISC function in aging. Thus, both therapeutic and prophylactic treatment with anti-uPAR CAR T cells improved barrier function, regenerative capacity, inflammation, mucosal immune function and microbiome composition in aged mice. Overall, these findings reveal the deleterious role of uPAR-positive cells on intestinal aging in vivo and provide proof of concept for the potential of targeted immune-based cell therapies to enhance tissue regeneration in aging organisms.