Journal article
CGRP induction in cystic fibrosis airways alters the submucosal gland progenitor cell niche in mice
The Journal of clinical investigation, Vol.121(8), pp.3144-3158
07/18/2011
DOI: 10.1172/JCI41857
PMCID: PMC3148720
PMID: 21765217
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.
Details
- Title: Subtitle
- CGRP induction in cystic fibrosis airways alters the submucosal gland progenitor cell niche in mice
- Creators
- Weiliang XieJohn T FisherThomas J LynchMeihui LuoTuran I.A EvansTraci L NeffWeihong ZhouYulong ZhangYi OuNigel W BunnettAndrew F RussoMichael J GoodheartKalpaj R ParekhXiaoming LiuJohn F Engelhardt
- Resource Type
- Journal article
- Publication Details
- The Journal of clinical investigation, Vol.121(8), pp.3144-3158
- DOI
- 10.1172/JCI41857
- PMID
- 21765217
- PMCID
- PMC3148720
- NLM abbreviation
- J Clin Invest
- ISSN
- 0021-9738
- eISSN
- 1558-8238
- Language
- English
- Date published
- 07/18/2011
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Neurology; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Iowa Neuroscience Institute; Surgery; Radiation Oncology; Craniofacial Anomalies Research Center; Obstetrics and Gynecology; Cardiothoracic Surgery; Internal Medicine
- Record Identifier
- 9984070398102771
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