33 Development and maturation of human prostate from embryonic stem cells in vivo

Abstract

The study of human prostate development is limited by the availability of young normal tissue and the lengthy process from fetal development to maturation. The rodent is commonly used as a model to study human prostate development, maturation and disease, while immortalised or genetically modified cell lines are frequently used to study prostate differentiation and carcinogenesis. These approaches have limited utility when extrapolating findings to humans, however they have provided controversial evidence for the early origins of adult prostate disease specifically BPH, inflammation and prostate cancer. It is imperative we establish new models that accurately mimic human prostate development and maturation. Using rodent mesenchyme to establish reciprocal mesenchymal epithelial cell interactions with human embryonic stem cells (hESC) we report the development and maturation of undifferentiated hESC to fetal and mature human prostate tissue expressing PSA. hESC of different genetic sex generated ductal glandular structures expressing androgen receptor, estrogen receptors, Nkx3.1 and p63 and PSA. Seminal vesicle mesenchyme (SVM) recombined with hESC demonstrated the inductive properties of SVM across germ layers and predominantly generated prostatic tissue expressing PSA, rather than vesicular tissue expression lactoferrin. Androgen withdrawal caused tissue regression and atrophy. This model provides a novel model of human prostate development and maturation and shows species conserved signalling mechanisms that could extend to integumental, gastrointestinal and genital tissues.