The absence of SRD5A2 regulates the heterotypic cell-cell communication in prostate
Christina Sharkey, MA1, Xingbo Long, MD2, Ra'ad Al-Faouri, MD1, Zongwei Wang, PhD1, Aria F. Olumi, MD1.
1Beth Israel Deaconess Medical Center, Boston, MA, USA, 2Sun Yat-sen University Cancer Center, Guangzhou, China.
BACKGROUND: Benign prostatic hyperplasia (BPH) is a heterogeneous disease that results from nonmalignant proliferation of both the prostate epithelial and stromal compartment. Steroid 5α reductase 2 (SRD5A2) is the predominant enzyme responsible for prostatic development and growth. We have shown that the expression of SRD5A2 is silenced in 30% of human adult prostate tissues by epigenetic regulation, and SRD5A2 is exclusively expressed in human and mouse prostatic stromal compartments. In SRD5A2 null (SRD5A2-/-) mice that were generated in our lab, the weight of the prostate gland decreased by ~50%. Here we wish to characterize the interacting signals between stromal cells and luminal epithelial cells (LE) in the absence of SRD5A2 by single-cell RNA sequencing (scRNA seq) analysis. METHODS: Prostatic single cells were digested from SRD5A2-/- mice and SRD5A2+/- littermate control mice. Unbiased scRNA seq with 10x genomics platform, followed by unsupervised clustering, was utilized to generate cell clusters based on differentially expressed (DE) gene profiles. The heterotypic cell-cell communication was analyzed using CellphoneDB2. Identified ligand-receptor pairs were validated by qPCR in human prostatic tissues collected from patients with BPH via transurethral resection of the prostate.
RESULTS: Sixteen cell subpopulations were transcriptomically identified from 23,000 single cells. The cellular expression of SRD5A2 was exclusively identified in fibroblasts and myofibroblasts. The absence of SRD5A2 induced a significant decrease in luminal cells (53.2% vs. 31.8%) but an increase in stromal cells (11.3% vs. 18.0%). Analysis of significantly-changed ligand-receptor pairs indicated that stromal cells were among the most prolific interactors, and myofibroblasts were the most "outbound" cells both in SRD5A2+/- and SRD5A2-/- animals. Meanwhile, the fibroblasts in SRD5A2-/- mice had the most significantly increased weighted value (366 vs. 493), and LE1, one subset of LE cells, had the most significantly decreased weighted value (205 vs. 96) when compared with SRD5A2+/- control mice. Furthermore, the most significantly changed ligand-receptor pairs were identified, including WNT5A/PTPRK, TGFB2/TGFBR1, and (NRP1, NRP2, FLT1)/VEGFA, which regulate the stromal cell and LE communication. In human prostatic tissues, the expressions of WNT5A and PTPRK were significantly associated with SRD5A2 expression.
CONCLUSIONS: Our data suggest that the heterotypic cell-cell communication is substantially changed in the absence of SRD5A2. The stroma-niched signaling might serve as a therapeutic target for managing BPH patients who lack SRD5A2 expression.
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