A Simple Cell Culture Assay for Human Prostatic Branching Morphogenesis Spotlights Bone Morphogenetic Protein Signaling as a Therapeutic Target in Benign Prostatic Hyperplasia

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BACKGROUND: Benign prostatic hyperplasia (BPH) leads to prostate enlargement and lower urinary tract symptoms that can resist treatment. A histologic hallmark of BPH is glandular epithelial hyperplasia with new ductal branching morphogenesis. The stromal inductive factors driving tissue morphogenesis may provide new therapeutic targets, but are incompletely known due in part to a paucity of cell culture model systems. We thus sought to create a reliable cell culture assay for human prostatic branching morphogenesis. METHODS: Various combinations of input cells, cell densities and cell culture medium were trialed. A robust solution comprised embedding BHPrE1 immortalized human prostatic epithelial cells in Matrigel, together with an inductive source of BPH stromal fibroblasts or their conditioned medium. Resultant spheroids were measured and budding/branching morphogenesis evaluated by brightfield microscopy and optionally immunofluorescence. Candidate paracrine signaling pathways were interrogated using small molecule inhibitors and neutralizing antibodies. RESULTS: We have detailed a simple, robust cell culture assay for human prostatic epithelial branching morphogenesis. Preliminary application of the assay to investigate signaling pathways previously implicated in developmental budding/branching morphogenesis identified functions of epidermal growth factor (EGF), insulin-like growth factors (IGFs), and bone morphogenetic proteins (BMPs) in stimulating prostatic spheroid growth. However, only BMP inhibition blocked prostatic epithelial budding/branching morphogenesis. CONCLUSIONS: We have described a straightforward cell culture assay for human prostatic budding/branching morphogenesis that in particular spotlights IGFs and BMPs as candidate therapeutic targets in BPH. Additional preclinical testing is warranted.

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