PD11-08 SINGLE CELL SEQUENCING REVEALS LUMINAL EPITHELIA PLASTICITY WITH FIBROBLAST ACTIVATION UPON SRD5A2 DELETION IN THE PROSTATE

Abstract

You have accessJournal of UrologyBenign Prostatic Hyperplasia: Basic Research & Pathophysiology (PD11)1 Sep 2021PD11-08 SINGLE CELL SEQUENCING REVEALS LUMINAL EPITHELIA PLASTICITY WITH FIBROBLAST ACTIVATION UPON SRD5A2 DELETION IN THE PROSTATE Xingbo Long, Christina Sharkey, Zongwei Wang, and Aria Olumi Xingbo LongXingbo Long More articles by this author , Christina SharkeyChristina Sharkey More articles by this author , Zongwei WangZongwei Wang More articles by this author , and Aria OlumiAria Olumi More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000001986.08AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Steroid 5α reductase 2 (SRD5A2) is the predominant enzyme responsible for prostatic development and growth. SRD5A2 inhibitors are the only class of benign prostate hyperplasia-related medications that reduce prostate size. However, patients respond variably to 5ARI therapies. Due to epigenetic modifications, we have previously demonstrated that 30% of adult human prostatic tissues do not express the SRD5A2 gene and protein. The goal of this study is to use single cell RNA sequencing (scRNA seq) to characterize the prostate cellular and transcriptomic changes when SRD5A2 is absent. METHODS: Homozygous SRD5A2-/- mice and littermate heterozygous SRD5A2+/- control were generated. The intact prostate tissues were collected from 8-16 weeks old mice and digested to single cells. ScRNA seq with 10x genomics platform, followed by unsupervised clustering, was utilized to generate cell clusters. A complete transcriptomic profile was obtained to identify cellular subsets and functional differentiation. RESULTS: ScRNA seq resulted in transcriptome data for clustering of 23,000 single cells, which were further annotated to 18 subpopulations demonstrating the heterogeneity within prostate. The SRD5A2 gene was identified to exclusively express in fibroblasts and myofibroblasts. Deletion of SRD5A2 induced a significant decrease of luminal cells (53.2% vs 31.8%), while there was a significant elevation of stromal (11.3% vs 18.0%) and immune cells (3% vs 6.6%). Further sub-clustering of luminal cells identified 3 unique subclusters with genetic signature of lineage, estrogen response and progenitor pathways. Luminal cells with lineage signature and progenitor signature diminished whereas luminal cells with estrogen response genetic signature stably survived after SRD5A2 deleted. Meanwhile, fibroblasts have broad ligand/receptor interactions with other cell populations. In particular, absence of SRD5A2 in fibroblasts exhibited significant increase of gene expression profiles of inflammatory, epithelial-mesenchymal transition and angiogenesis. Fibroblasts support the epithelial proliferation and immune cells recruitment of prostate through secretion of growth factors (EGF, FGF and TGF families) and cytokines (CXCL, CCL and HLA). CONCLUSIONS: Our data suggests that lack of SRD5A2 in fibroblasts might contributes to the plasticity of luminal cells with the genetic signature of estrogen response. Understanding the underlined mechanism may pave the way to find new therapeutic targets to the management of BPH patients who lack of SRD5A2 expression and are potentially resistant to 5ARI. Source of Funding: National Institutes of Health © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e201-e201 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Xingbo Long More articles by this author Christina Sharkey More articles by this author Zongwei Wang More articles by this author Aria Olumi More articles by this author Expand All Advertisement Loading ...