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

Weiliang Xie, John T. Fisher, Thomas J. Lynch, Meihui Luo, Turan I.A. Evans, Traci L. Neff, Weihong Zhou, Yulong Zhang, Yi Ou, Nigel W. Bunnett, Andrew F. Russo, Michael J. Goodheart, Kalpaj R. Parekh, Xiaoming Liu, John F. Engelhardt

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)3144-3158
Number of pages15
JournalJournal of Clinical Investigation
Volume121
Issue number8
DOIs
StatePublished - Aug 1 2011

ASJC Scopus subject areas

  • Medicine(all)

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    Xie, W., Fisher, J. T., Lynch, T. J., Luo, M., Evans, T. I. A., Neff, T. L., Zhou, W., Zhang, Y., Ou, Y., Bunnett, N. W., Russo, A. F., Goodheart, M. J., Parekh, K. R., Liu, X., & Engelhardt, J. F. (2011). CGRP induction in cystic fibrosis airways alters the submucosal gland progenitor cell niche in mice. Journal of Clinical Investigation, 121(8), 3144-3158. https://doi.org/10.1172/JCI41857