title: CGRP induction in cystic fibrosis airways alters the submucosal gland progenitor cell niche in mice.
abstract: In cystic fibrosis (CF), a lack of functional CF transmembrane conductance regulator (CFTR) chloride channels causes defective secretion by submucosal glands (SMGs), leading to persistent bacterial infection that damages airways and necessitates tissue repair. SMGs are also important niches for slow-cycling progenitor cells (SCPCs) in the proximal airways, which may be involved in disease-related airway repair. Here, we report that calcitonin gene-related peptide (CGRP) activates CFTR-dependent SMG secretions and that this signaling pathway is hyperactivated in CF human, pig, ferret, and mouse SMGs. 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 SCPCs 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 SCPCs, 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 SMGs 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.
authors.affiliation: Department of Anatomy and Cell Biology, The University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA.
authors.forename: Weiliang
authors.initials: W
authors.lastname: Xie
authors.forename: John T
authors.initials: JT
authors.lastname: Fisher
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Lynch
authors.forename: Meihui
authors.initials: M
authors.lastname: Luo
authors.forename: Turan I A
authors.initials: TI
authors.lastname: Evans
authors.forename: Traci L
authors.initials: TL
authors.lastname: Neff
authors.forename: Weihong
authors.initials: W
authors.lastname: Zhou
authors.forename: Yulong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yi
authors.initials: Y
authors.lastname: Ou
authors.forename: Nigel W
authors.initials: NW
authors.lastname: Bunnett
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Russo
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Goodheart
authors.forename: Kalpaj R
authors.initials: KR
authors.lastname: Parekh
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Liu
authors.forename: John F
authors.initials: JF
authors.lastname: Engelhardt
mesh_terms: D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000502:physiology*; D002712:Chlorides / Q000378:metabolism; D003550:Cystic Fibrosis / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism; D005289:Ferrets; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009092:Mucous Membrane / Q000378:metabolism*; D009281:Naphthalenes / Q000494:pharmacology; D012137:Respiratory System; D013234:Stem Cells / Q000166:cytology*; D013552:Swine; D014018:Tissue Distribution
chemical_list: D002712:Chlorides; D009281:Naphthalenes; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C031721:naphthalene; D015740:Calcitonin Gene-Related Peptide