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

Eskiocak, Onur, Gewolb, Joseph, Shah, Vyom, Rouse, James A, Chowdhury, Saria, Akyildiz, Erdogan O, Fernández-Maestre, Inés, Boyer, Jacob A, Filliol, Aveline, Harris, Alexander S, Utama, Raditya, Guo, Guangran, Castro-Hernández, Carolina, Nnuji-John, Emmanuella, Chung, Charlie, Anderson, Arianna, Flowers, Sara, Habel, Jill, Romesser, Paul B, Levine, Ross L, Lowe, Scott W, Sadelain, Michel, Beyaz, Semir, Amor, Corina (November 2025) Anti-uPAR CAR T cells reverse and prevent aging-associated defects in intestinal regeneration and fitness. Nature Aging. ISSN 2662-8465

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URL: https://www.ncbi.nlm.nih.gov/pubmed/41291258

DOI: 10.1038/s43587-025-01022-w

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.

Item Type:	Paper
Subjects:	organs, tissues, organelles, cell types and functions > cell types and functions > cell types > T cells organs, tissues, organelles, cell types and functions > cell types and functions > cell types > T cells organs, tissues, organelles, cell types and functions > cell types and functions > cell types > T cells organs, tissues, organelles, cell types and functions > cell types and functions > cell functions organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions organs, tissues, organelles, cell types and functions organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > senescence
CSHL Authors:	Eskiocak, Onur Utama, Raditya Nnuji-John, Emmanuella Chung, Charlie Habel, Jill Beyaz, Semir Gewolb, Joseph Shah, Vyom Rouse, James Chowdhury, Saria Akyildiz, Erdogan Fernandez Maestre, Ines Harris, Alexander Guo, Guangran Castro Hernandez, Carolina Anderson, Arianna Amor, Corina
Communities:	CSHL Cancer Center Program > Cancer Genetics and Genomics Program CSHL labs > Beyaz lab CSHL labs > Koo Lab CSHL labs > Meyer Lab CSHL Post Doctoral Fellows School of Biological Sciences > Publications
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	25 November 2025
Date Deposited:	26 Nov 2025 13:52
Last Modified:	26 Nov 2025 13:52
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/42012

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