Pulmonary neuroendocrine cells: crucial players in respiratory function and airway-nerve communication

Abstract

Pulmonary neuroendocrine cells (PNECs) are unique airway epithelial cells that blend neuronal and endocrine functions, acting as key sensors in the lung. They respond to environmental stimuli like allergens by releasing neuropeptides and neurotransmitters. PNECs stand out as the only lung epithelial cells innervated by neurons, suggesting a significant role in airway-nerve communication via direct neural pathways and hormone release. Pathological conditions such as asthma are linked to increased PNECs counts and elevated calcitonin gene-related peptide (CGRP) production, which may affect neuroprotection and brain function. CGRP is also associated with neurodegenerative diseases, including Parkinson's and Alzheimer's, potentially due to its influence on inflammation and cholinergic activity. Despite their low numbers, PNECs are crucial for a wide range of functions, highlighting the importance of further research. Advances in technology for producing and culturing human PNECs enable the exploration of new mechanisms and cell-specific responses to targeted therapies for PNEC-focused treatments.

Keywords: HPSC; IPSC; brain; lung; pulmonary neuroendocrine cells; stem cells.

FIGURE 1

Role of PNECs in physiological and pathological conditions in lung. PNECs play crucial role in lung physiology and pathology. They function as sensory components, sensing oxygen and chemical stimuli, and are involved in oxygen sensing and mechano-transduction. PNECs are implicated in various lung diseases, regulating immune responses and tissue remodeling. Their diverse signaling output and release of neuropeptides make them critical sensors in the lung, influencing respiratory function and disease pathogenesis.

FIGURE 2

Timeline of PNECs research. 1949: PNECs were first characterized as ‘bright cells’ (Frohlich, 1949). 1954: The concept of the diffuse neuroendocrine system was established (Feyrter, 1954). 1970s: Innervated NEBs were identified in human infant or rabbit lungs (Lauweryns and Peuskens, 1972; Lauweryns et al., 1973). 1996: The proportion of PNECs in normal human airway epithelium was first quantified as less than 0.5% (Boers et al., 1996). 2011: PNEC was recognized as putative cell of origin of SCLC (Sutherland et al., 2011). 2012: PNECs were identified as a stem cell population to contribute to lung development and regeneration (Song et al., 2012). 2013: PNECs function as sensory cells in response to hypoxia, environmental stimuli, and mechanical stresses (Cutz et al., 2013). 2015: PNECs may originate from airway epithelial progenitor cells (Kuo and Krasnow, 2015). 2018: PNECs were reported to play an important role in asthmatic diseases (Sui et al., 2018). 2019.03: Protocols were initially developed for generating PNECs from hESCs (Chen et al., 2019). 2019.10: Notch activated-PNECs have been found as NE^stem to initiate reprogramming in SCLC cells (Ouadah et al., 2019). 2020: DISCO was employed to study PNECs in airways (Liu et al., 2020). 2023: Spatial transcriptomics, in conjunction with scRNA-seq, was employed to investigate PNECs (Sountoulidis et al., 2023).

FIGURE 3

Potential role of PNECs in brain diseases. PNECs have been implicated in neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD). While direct evidence is lacking, PNECs appear to modulate neural activity through the release of CGRP, a neuropeptide that serves as a potent mediator of various physiological processes, including inflammation and cholinergic neurotransmission. In the context of AD, CGRP enhances cholinergic activity and acts as an anti-inflammatory agent, which may be relevant to AD pathogenesis. In PD, PNECs’ ability to modulate neuronal sensitivity through CGRP may have downstream effects on α-Synuclein aggregation, contributing to PD pathology. Several studies indicate the role of CGRP in different neuropathological conditions in the brain, suggesting a potential role for PNEC-derived secretory molecules in neurodegenerative diseases. However, further research is needed to explore the exact role of PNECs in these conditions.