CGRP induction in cystic fibrosis airways alters the submucosal gland progenitor cell niche in mice

In cystic fibrosis (CF), a lack of functional CF transmembrane conductance regulator (CFTR) chloride channels causes defective secretion by submucosal glands (SM[G.sub.s]), leading to persistent bacterial infection that damages airways and necessitates tissue repair. SM[G.sub.s] are also important niches for slow-cycling progenitor cells (SCP[C.sub.s]) in the proximal airways, which may be involved in disease-related airway repair. Here, we report that calcitonin generelated peptide (CGRP) activates CFTR-dependent SMG secretions and that this signaling pathway is hyperactivated in CF human, pig, ferret, and mouse SM[G.sub.s]. Since CGRP-expressing neuroendocrine cells reside in bronchiolar SCPC niches, we hypothesized that the glandular SCPC niche may be dysfunctional in CF. Consistent with this hypothesis, CFTR-deficient mice failed to maintain glandular SCP[C.sub.s] following airway injury. In wild-type mice, CGRP levels increased following airway injury and functioned as an injury-induced mitogen that stimulated SMG progenitor cell proliferation in vivo and altered the proliferative potential of airway progenitors in vitro. Components of the receptor for CGRP (RAMP1 and CLR) were expressed in a very small subset of SCP[C.sub.s], suggesting that CGRP indirectly stimulates SCPC proliferation in a non-cell-autonomous manner. These findings demonstrate that CGRP-dependent pathways for CFTR activation are abnormally upregulated in CF SM[G.sub.s] and that this sustained mitogenic signal alters properties of the SMG progenitor cell niche in CF airways. This discovery may have important implications for injury/repair mechanisms in the CF airway.
Introduction Stem cell niches in adult organs play important roles in maintaining organ integrity in the setting of normal cellular turnover and injury. These microenvironments are unique and control intrinsic [...]