Submucosal gland development in the human fetal trachea xenograft model: implications for fetal gene therapy

Abstract Background/Purpose Our previous work in a human-fetal trachea xenograft model suggests potential benefits of treating cystic fibrosis in utero. The target for postnatal gene therapy in cystic fibrosis is tracheal submucosal glands (SMGs). The aim of this study was to determine if SMG development in our model recapitulates normal trachea development and its validity for studying fetal gene transfer. Methods Fetal tracheas were divided into developmental phases: early, mid, and late. Fetal tracheas were xenografted onto immunocompromised mice and analyzed for SMG developmental staging and mucopolysaccharide production. Results There were no significant differences in gland number, size, or density from early through late phase between groups. Xenografted tracheas demonstrated a similar progression through the stages of SMG development as controls after an initial phase shift. Control and xenografted tracheas demonstrated characteristic patterns of acidic mucin production at the base of the SMGs. Conclusions Fetal trachea xenograft SMG recapitulates normal development and is a valid model for studying human fetal gene transfer. The accessibility of SMG stem cells in early tracheal development may afford a unique window of opportunity for gene transfer. This model has the benefit of providing access to human fetal tracheas in vivo and permits the study of novel fetal gene therapy strategies.