Pulmonary neuroendocrine cells: physiology, tissue homeostasis and disease.

Masafumi Noguchi,Mitsuru Morimoto,Kana T Furukawa

doi:10.1242/dmm.046920

Abstract

ABSTRACTMammalian lungs have the ability to recognize external environments by sensing different compounds in inhaled air. Pulmonary neuroendocrine cells (PNECs) are rare, multi-functional epithelial cells currently garnering attention as intrapulmonary sensors; PNECs can detect hypoxic conditions through chemoreception. Because PNEC overactivation has been reported in patients suffering from respiratory diseases – such as asthma, chronic obstructive pulmonary disease, bronchopulmonary dysplasia and other congenital diseases – an improved understanding of the fundamental characteristics of PNECs is becoming crucial in pulmonary biology and pathology. During the past decade, murine genetics and disease models revealed the involvement of PNECs in lung ventilation dynamics, mechanosensing and the type 2 immune responses. Single-cell RNA sequencing further unveiled heterogeneous gene expression profiles in the PNEC population and revealed that a small number of PNECs undergo reprogramming during regeneration. Aberrant large clusters of PNECs have been observed in neuroendocrine tumors, including small-cell lung cancer (SCLC). Modern innovation of imaging analyses has enabled the discovery of dynamic migratory behaviors of PNECs during airway development, perhaps relating to SCLC malignancy. This Review summarizes the findings from research on PNECs, along with novel knowledge about their function. In addition, it thoroughly addresses the relevant questions concerning the molecular pathology of pulmonary diseases and related therapeutic approaches.

Highlights

Every time we take a breath to convey oxygen (O2) into our body, our respiratory tissues are exposed to external air, which contains ambient aerosols along with a multitude of pathogens, allergens and pollutants
This study discovered a peculiar subpopulation of club cells next to Pulmonary neuroendocrine cells (PNECs) at the bronchioalveolar–duct junctions, termed variant club cells, which act as transient-amplifying cells (Reynolds et al, 2000) (Fig. 4A)
The majority of small-cell lung cancer (SCLC) tumors had a low Notch pathway activity, including high expression of the Notch-inhibiting genes ASCL1 and DLK1 (George et al, 2015). Supporting this idea, conditional activation of the Notch pathway by N2ICD overexpression significantly suppressed the progression of tumors in transformation-related protein 53 (Trp53), retinoblastoma protein 1 (Rb1) and p130 triple-knockout mice, indicating a negative role of Notch signaling in SCLC development (George et al, 2015)

Summary

Introduction

Every time we take a breath to convey oxygen (O2) into our body, our respiratory tissues are exposed to external air, which contains ambient aerosols along with a multitude of pathogens, allergens and pollutants. Several pioneering studies on transgenic mice demonstrated that PNECs might be the origin of SCLCs. Meuwissen et al (2003) described the first SCLC model mouse, an adeno-Cre conditional double-knockout (DKO) of transformation-related protein 53 (Trp53) and retinoblastoma protein 1 (Rb1) within adult airway epithelial cells, which developed aggressive lung tumors, which appeared morphologically and immunophenotypically similar to SCLC. The majority of SCLC tumors had a low Notch pathway activity, including high expression of the Notch-inhibiting genes ASCL1 and DLK1 (George et al, 2015) Supporting this idea, conditional activation of the Notch pathway by N2ICD (the active form of Notch2) overexpression significantly suppressed the progression of tumors in Trp, Rb1 and p130 ( known as Nolc1) triple-knockout mice, indicating a negative role of Notch signaling in SCLC development (George et al, 2015). Improvement in deep-tissue 3D imaging would help to accurately map the spatial alterations in PNECs occurring during lung disease

Objective lens

Findings

Conclusions