Xenotransplantation · 2026
In Vitro and In Vivo Characterization of Porcine Urothelial Cells as an Intravesical Cellular Xenotransplantation Immunotherapeutic Agent for Bladder Cancer.
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Shyr Chih-Rong, Shih Chen-Kai, Wu Ching-Feng, Ma Wen-Lung, Huang Chi-Ping
Аннотация
BACKGROUND: Cellular xenotransplantation offers a unique immunotherapeutic strategy for cancer by utilizing xenogeneic cells to elicit robust host immune responses. Innovative treatments are required for non-muscle invasive bladder cancer (NMIBC) due to the limited effectiveness of current standard therapies. Intravesical xenogeneic porcine urothelial cell (PUC) immunotherapy provides a novel mechanism-of-action option.
OBJECTIVE: This study evaluates cellular xenotransplantation utilizing primary PUCs in vitro and in vivo to characterize their potential as an intravesical immunotherapeutic agent for NMIBC.
METHODS: Primary PUC phenotypic and transcriptomic identities were first characterized using flow cytometry and bulk RNA sequencing. Subsequently, the effects of basic fibroblast growth factor (bFGF) and the ROCK inhibitor Y-27632 on PUC expansion capacity, gene expression, and senescence were investigated. Immune-stimulatory potency was measured through cell-based co-culture bioassays, and in vivo biodistribution and immune recruitment were assessed in mice following intravesical instillation.
RESULTS: Expanded PUCs demonstrated high epithelial purity (92.16% ± 5.38% CD49f+). RNA-seq profiles confirmed a distinct urothelial identity (e.g., UPK3A, TP63, KRT7), with unsupervised clustering clearly separating PUCs from skeletal muscle comparators. Combined treatment with bFGF and Y-27632 synergistically promoted growth and upregulated differentiation markers while significantly suppressing p16-mediated senescence. PUCs significantly stimulated immune cell proliferation and IFN-γ/IL-2 secretion through direct, F-actin-polarized interactions. in vivo, PUCs remained localized and were cleared within 28 days, inducing a peak recruitment of CD4+ and CD8+ T cells at Day 14 and enhancing systemic cytotoxicity.
CONCLUSION: PUCs serve as a potent, localized, and transient cellular medicine that primes systemic antitumor-like immunity. The optimized expansion protocol facilitates the scalable production of non-senescent porcine cells for clinical applications in bladder cancer.
OBJECTIVE: This study evaluates cellular xenotransplantation utilizing primary PUCs in vitro and in vivo to characterize their potential as an intravesical immunotherapeutic agent for NMIBC.
METHODS: Primary PUC phenotypic and transcriptomic identities were first characterized using flow cytometry and bulk RNA sequencing. Subsequently, the effects of basic fibroblast growth factor (bFGF) and the ROCK inhibitor Y-27632 on PUC expansion capacity, gene expression, and senescence were investigated. Immune-stimulatory potency was measured through cell-based co-culture bioassays, and in vivo biodistribution and immune recruitment were assessed in mice following intravesical instillation.
RESULTS: Expanded PUCs demonstrated high epithelial purity (92.16% ± 5.38% CD49f+). RNA-seq profiles confirmed a distinct urothelial identity (e.g., UPK3A, TP63, KRT7), with unsupervised clustering clearly separating PUCs from skeletal muscle comparators. Combined treatment with bFGF and Y-27632 synergistically promoted growth and upregulated differentiation markers while significantly suppressing p16-mediated senescence. PUCs significantly stimulated immune cell proliferation and IFN-γ/IL-2 secretion through direct, F-actin-polarized interactions. in vivo, PUCs remained localized and were cleared within 28 days, inducing a peak recruitment of CD4+ and CD8+ T cells at Day 14 and enhancing systemic cytotoxicity.
CONCLUSION: PUCs serve as a potent, localized, and transient cellular medicine that primes systemic antitumor-like immunity. The optimized expansion protocol facilitates the scalable production of non-senescent porcine cells for clinical applications in bladder cancer.