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Targeting Itga8 Mitigates Neurogenic Bladder Fibrosis Driven by Trem2(+) Macrophage-Derived Fn1 via FAK/RhoA/ROCK Signaling #MMPMID41355531
Wang J; Wang S; Ren L; Liu X; Zhang L; Hu P; Xu W; Zheng S; Liu J; Ling Q
Adv Sci (Weinh) 2025[Dec]; ? (?): e10631 PMID41355531show ga
Neurogenic bladder (NB)-induced fibrosis is the major cause of irreversible bladder dysfunction, yet the underlying mechanisms remain undefined. Here, leveraging single-cell RNA sequencing, the fibrotic landscape of NB is delineated and a distinct integrin alpha8 (Itga8) (+) fibroblast population. The Itga8(+) fibroblasts expand substantially during the acute phase post-injury and exhibit a fibrogenic transcriptional profile. Mechanistically, Itga8 is found to coordinate cytoskeletal remodeling via the FAK/RhoA/ROCK signaling to facilitate fibroblast activation. Moreover, fibroblast activation is orchestrated by Trem2(+) macrophages, which secrete Fn1 to engage Itga8 on fibroblasts, thereby reinforcing the pro-fibrotic communication between fibroblasts and macrophages. Notably, macrophage depletion markedly attenuates fibrosis and restores bladder function, underscoring their pivotal role in NB pathogenesis. In vivo, conditional deletion of Itga8 (Col1a2-CreERT; Itga8(fl/fl)) or local knockdown of Itga8 significantly attenuates collagen deposition and improves voiding efficiency. Collectively, this study reveals a novel Itga8-centered fibroinflammatory axis and nominates Itga8 as a promising therapeutic target for delaying fibrosis progression and restoring bladder function.
Adv+Sci+(Weinh) 2025 ; ? (?): e10631
