Program Event: Jiang Yang
Cell Identity and Signaling (CIS) Chat
Jiang Yang, research associate professor in the department of comparative pathobiology at Purdue University, will be a speaker for the PICR Seminar Series.
Title: Chronic inflammation drives epithelial remodeling and therapy-resistant prostate hyperplasia
Chronic inflammation is strongly associated with human benign prostatic hyperplasia (BPH), yet the mechanisms by which immune activation drives epithelial expansion remain poorly understood. We previously demonstrated that mice lacking the Autoimmune Regulator (Aire) gene (Aire-/-) develop spontaneous, prostate-specific chronic inflammation that closely mirrors the inflammation in human BPH. In this study, we investigated in this unique model how chronic inflammation alters epithelial lineage behavior and androgen responsiveness. Prostates from Aire-/- and wild-type mice were analyzed by immunohistochemistry, flow cytometry, and single-cell RNA sequencing (scRNA-seq). Basal cell fate was assessed using lineage tracing, epithelial progenitor activity by 3D organoid assays, and androgen dependence by Dutasteride treatment.
Aire-/- prostates displayed dramatic glandular hyperplasia, with the basal-to-luminal ratio in the anterior lobes increasing from 1:6 to 1:1. Both basal and luminal epithelial cells exhibited robust upregulation of androgen receptor (AR). Ki67 staining and scRNA-seq identified luminal cells as the major proliferative population. Immunostaining revealed CK5 (Cytokeratin 5)+/CK8+ transitional cells in luminal layers, and lineage tracing confirmed that basalderived cells contributed to the luminal compartment only in inflamed prostates. Inflammation markedly expanded Sca-1 expression from 65% to 100% of basal cells and from 2% to 85% of luminal cells, consistent with a widespread progenitor-like state. Sca-1⁺ basal cells from inflamed prostates generated significantly larger colonies in organoid cultures, indicating enhanced progenitor potential. Treatment with the 5α-reductase inhibitor Dutasteride reduced prostate size in the Aire-/- mice but failed to reverse epithelial hyperplasia, suggesting partial androgen dependence sustained by inflammation. Together, these findings demonstrate that chronic prostate inflammation induces striking epithelial remodeling, including reprograming basal cells into Sca-1⁺, AR⁺ progenitors that drive both basal expansion and luminal proliferation, stimulating androgen-dependent hyperplasia that persists despite Dutasteride treatment. This work establishes a mechanistic link between inflammation, basal plasticity, and therapy-resistant epithelial hyperplasia, providing new insight into the pathogenesis of inflammation-associated BPH.
The event is hosted by Majid Kazemian.