The balance and distribution of epithelial cell types is required to maintain tissue homeostasis. A hallmark of airway diseases is epithelial remodeling, leading to increased goblet cell numbers and an overproduction of mucus. In the conducting airway, basal cells act as progenitors for both secretory and ciliated cells. To identify mechanisms regulating basal cell fate, we developed a screenable 3D culture system of airway epithelial morphogenesis. We performed a high-throughput screen using a collection of secreted proteins and identified inflammatory cytokines that specifically biased basal cell differentiation toward a goblet cell fate, culminating in enhanced mucus production. We also demonstrate a specific requirement for Notch2 in cytokine-induced goblet cell metaplasia in vitro and in vivo. We conclude that inhibition of Notch2 prevents goblet cell metaplasia induced by a broad range of stimuli and propose Notch2 neutralization as a therapeutic strategy for preventing goblet cell metaplasia in airway diseases.

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BACKGROUND Since prepubertal boys cannot benefit from sperm banking, a potential alternative strategy for fertility preservation involves immature testicular tissue (ITT) banking aimed at preservation of spermatogonial stem cells. Survival of spermatogonia has been demonstrated after ITT freezing, which is considered ethically acceptable. We report the results of a pilot program set up for fertility preservation in prepubertal boys. METHODS All boys undergoing ITT cryobanking from May 2005 were identified from our clinical register. Data were collected from medical files. RESULTS Testicular tissue was retrieved from 52 prepubertal patients under 12 years of age and 10 peripubertal patients aged between 12 and 16 years, in whom no spermatozoa were identified in testicular biopsies. Malignant disease accounted for 80.6% of cases; the remaining patients suffered from benign disorders requiring gonadotoxic treatments. Mean ages, Tanner stages and occurrence rates of urogenital pathology were 6.43 ± 3.32 and 14 ± 1.23 years, I and I-IV, and 13.5 and 20% for pre- and peripubertal patients, respectively. Mean volumes of removed tissue were 20.1 ± 8.6 and 42.4 ± 15.6 mm(3) for pre- and peripubertal patients, respectively. No complications occurred during or after tissue retrieval and 93.5% of referred patients accepted ITT storage. The presence of spermatogonia, and thus the potential for later tissue use, was established in all of these patients. CONCLUSIONS The majority of cryopreserved samples showed reproductive potential. Storage was accepted by most parents. All parents and children considered this fertility preservation strategy a positive approach.

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