Lung regeneration and the stem cell niche

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DESCRIPTION (provided by applicant): During lung development FGF10 (Fibroblast growth factor 10) is secreted by the parabronchial smooth muscle cell (PSMC) progenitors in the distal mesenchyme and activates the canonical WNT signaling pathway in the distally located epithelial progenitors to maintain them and sustain their proliferation. Our recently published results indicate that in the embryonic lung, (-catenin signaling in the PSMC progenitors is also essential for their maintenance and proliferation. The goal in this proposal is to determine if this pathway can be reactivated in adults to promote reepithelialization of damaged airway epithelium. Our preliminary findings illustrate reactivation of this embryonic signaling cascade in the mature PSMCs shortly after naphthalene injury. After naphthalene injury some of the PSMCs show activated TOPGAL activity, as a readout for activated (-catenin signaling, undergo massive proliferation as monitored by BrdU incorporation and reexpress Fgf10. Our data suggest that this paracrine FGF10 signaling by the PSMCs is critical for epithelial repair after naphthalene injury possibly by activating the latent bronchioalveolar stem cells (BASCs) at the Bronchio-alveolar duct junctions (BADJs). Our preliminary data also indicate an additional cellular contribution by the PSMCs in epithelial repair after naphthalene injury. We show that mature PSMCs can dedifferentiate and undergo Mesenchymal to Epithelial Transition (MET) to contribute directly to the epithelial repair process. This suggests a dual major role for the PSMCs in epithelial repair after naphthalene injury. Hypothesis: Dedifferentiation of parabronchial smooth muscle cells and/or their recapitulation of a progenitor like phenotype, is critical for epithelial regeneration after injury. Aim 1: To determine the differentiation status of the surrounding (non-epithelial) "niche" cells after naphthalene injury and their potential paracrine role in epithelial regeneration after naphthalene injury. Aim 2: To determine the differentiation status and cellular contribution of the PSMCs to epithelial repair after naphthalene injury. PUBLIC HEALTH RELEVANCE: Remodeling of the airway epithelium is a common pathological feature in chronic lung disease and a predisposing factor in the development of lung cancer. Accordingly, understanding cellular and molecular mechanisms of epithelial maintenance and repair are fundamental to the development of improved therapeutic modalities for the treatment of chronic lung disease. We hypothesize that after epithelial injury, the surrounding non-epithelial cells get reprogrammed to contribute, directly and indirectly be secreting growth factors, to the epithelial repair.