Senescent mast cells contribute to the progression of benign prostatic hyperplasia via SCF/c-KIT mediated endothelial-mesenchymal transition

Jing, Y., Li, L., Guo, W., Cao, T., Tang, J., Zhou, D., Yao, C., Xu, J., Liu, Y., Feng, C., Shi, Y., Wang, M., Chao, W., Liao, H., He, J., Qin, L., Luan, J., Wang, X., Cui, D., Zhu, Y., Ruan, Y., Xia, S., Han, B.

Department of Urology, Shanghai General 32 Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 33 200080, China · biorxiv

Paper

Abstract

Benign prostatic hyperplasia (BPH) is a common age-associated urological condition characterized by stromal expansion, but its cellular origins and regulatory mechanisms remain unclear. In this study, we identified endothelial-to-mesenchymal transition (EndMT) as a contributor to stromal cell accumulation in BPH. Using single-cell transcriptomic analysis, endothelial lineage tracing in mice, and validation in human samples, we showed that senescence-associated mast cells increased the expression of vascular endothelial growth factor A (VEGFA) and transforming growth factor-beta 1 (TGF-{beta}1) through the stem cell factor (SCF)/c-KIT-MAPK-JUND signaling pathway, thereby inducing EndMT in endothelial progenitor cells. Stromal fibroblasts express SCF, promoting mast cell activation and establishing a feedback loop that supports continued stromal proliferation. Intriguingly, inhibition of mast cell activation reduces EndMT and attenuates prostate enlargement in vivo.Thus, these findings revealed a senescence-linked immune - stromal interaction in the aging prostate and identify potential targets for therapeutic intervention in BPH.

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Research summary

Senescent mast cells promote endothelial-to-mesenchymal transition in benign prostatic hyperplasia through the SCF/c-KIT signaling pathway. This study addresses the role of cellular senescence in a specific age-related condition, linking immune responses to stromal changes, which could inform therapeutic strategies targeting aging mechanisms.

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