CGRP induction in cystic fibrosis airways alters the submucosal gland progenitor cell niche in mice
Weiliang Xie, … , Xiaoming Liu, John F. Engelhardt
Weiliang Xie, … , Xiaoming Liu, John F. Engelhardt
Published July 18, 2011
Citation Information: J Clin Invest. 2011;121(8):3144-3158. https://doi.org/10.1172/JCI41857.
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Research Article

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

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

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Figure 11

Working model for CGRP regulation of CFTR-dependent airway gland functions.

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Working model for CGRP regulation of CFTR-dependent airway gland functio...
SMG secretions are controlled by parasympathetic and sympathetic innervation from the CNS. Afferent nerve fibers sense changes in the airway and SMGs, while efferent nerve fibers carry regulatory signals away from the CNS to the airways and SMGs. (A) In the uninjured homeostatic state, nerves produce little CGRP (purple circles), which maintains low-level CFTR-dependent fluid secretion and quiescent LRC progenitors (light green). (B) Following airway injury, sensory neurons send signals to the CNS to enhance CGRP production, which then simulates CFTR-dependent glandular fluid secretion and likely protects the airway from secondary infection. Enhanced CGRP expression also signals glandular LRC progenitors to enter the cell cycle and produce transient amplifying cells (dark green) that affect airway repair. Since CGRP expression is transient, slow-cycling progenitor cells maintain their phenotype within the glandular niche. As shown, the signal to active replication of LRCs is mediated through a second unknown mitogen (small blue circles), since CGRP receptors are very infrequently observed on LRCs. (C) In the CF airway, impaired homeostatic SMG secretions (due to the lack of CFTR) inform the CNS to enhance CGRP production at sites of SMG innervation. Since there is no CFTR to stimulate secretions, feedback signals for production of CGRP remain abnormally high. Prolonged induction of CGRP leads to sustained mitogenic signals in the glandular LRC progenitor niche, and this dysregulation leads to adaptive LRC niche expansion in the SAE.