Department of Pediatrics, Stanford University School of Medicine, Stanford, United States; Department of Biochemistry and Howard Hughes Medical Institute, Stanford University, Stanford, United States
Spyros Darmanis
Department of Bioengineering, Stanford University, Stanford, United States
Alex Diaz de Arce
Department of Biochemistry and Howard Hughes Medical Institute, Stanford University, Stanford, United States
Yin Liu
Department of Biochemistry and Howard Hughes Medical Institute, Stanford University, Stanford, United States
Nicole Almanzar
Department of Pediatrics, Stanford University School of Medicine, Stanford, United States
Pulmonary neuroendocrine cells (PNECs) are sensory epithelial cells that transmit airway status to the brain via sensory neurons and locally via calcitonin gene-related peptide (CGRP) and γ- aminobutyric acid (GABA). Several other neuropeptides and neurotransmitters have been detected in various species, but the number, targets, functions, and conservation of PNEC signals are largely unknown. We used scRNAseq to profile hundreds of the rare mouse and human PNECs. This revealed over 40 PNEC neuropeptide and peptide hormone genes, most cells expressing unique combinations of 5–18 genes. Peptides are packaged in separate vesicles, their release presumably regulated by the distinct, multimodal combinations of sensors we show are expressed by each PNEC. Expression of the peptide receptors predicts an array of local cell targets, and we show the new PNEC signal angiotensin directly activates one subtype of innervating sensory neuron. Many signals lack lung targets so may have endocrine activity like those of PNEC-derived carcinoid tumors. PNECs are an extraordinarily rich and diverse signaling hub rivaling the enteroendocrine system.
