Pritzker School of Molecular Engineering
Published April 10, 2026 | Version v1
Journal article Metadata-only

Pulmonary neuroendocrine cell–derived exosomes regulate iron homeostasis and oxidative stress in lung neurons

Creators

  • 1. University of Chicago
  • 2. University of Virginia
  • 3. Hong Kong Baptist University
  • 4. Icahn School of Medicine at Mount Sinai
  • 5. Chinese Academy of Sciences
  • 6. Shanghai Jiao Tong University

Description

Nicotine, the principal addictive component of cigarettes, is linked to cognitive decline and neurodegenerative alterations, likely through oxidative stress and impaired iron regulation in neurons. Yet, underlying molecular pathways remain unclear. This study examined the role of pulmonary neuroendocrine cells (PNECs) in smoke-induced neural changes. Using human pluripotent stem cells, we generated induced PNECs (iPNECs) to overcome culture limitations and performed mechanistic analyses. We found that nicotine exposure stimulates iPNECs to secrete exosomes enriched with serotransferrin, an iron-binding glycoprotein. Neurons internalizing these exosomes displayed elevated levels of transferrin receptor 1 (TFR1), divalent metal transporter 1, and duodenal cytochrome b, associated with ferritin accumulation, oxidative stress, and adenosine triphosphate depletion. Inhibition of TFR1 alleviated these effects. Furthermore, nicotine-triggered exosomes increased α-synuclein expression in neurons in a manner consistent with stress- and vulnerability-associated signatures observed in human lungs and nicotine-exposed mice, highlighting PNEC-derived exosomal signaling that may contribute to neuronal dysfunction.

Data availability

Single-cell RNA sequencing data of iLung (batches 1 and 2) used for Fig. 2 (D to I) and fig. S4 (A, B, and D) have been deposited in the Sequence Read Archive (SRA) database (BioProject accession number: PRJNA1219183; link: https://ncbi.nlm.nih.gov/sra/PRJNA1219183). For fig. S5 (A to E), we used public data GEO: GSE103354 (link: https://ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE103354) (75). For fig. 5 (A to C and I to N) and figs. S3 (A and B) and S17 (A to D), we used public data GEO: GSE122960 (link: https://ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE122960) (51). For fig. S19, the spatial transcriptomic data were obtained from the Single Cell Portal of Broad Institute, study# SCP1375 and Zenodo (DOI: https://doi.org/10.5281/zenodo.7332090) (69). For fig. S20, the spatial transcriptomic data were obtained from the STOmics of the brain tissue of control (dataset ID: STDS0000242; link: https://db.cngb.org/stomics/datasets/STDS0000242/) (70) and patients with AD (dataset ID: STDS0000188; link: https://db.cngb.org/stomics/datasets/STDS0000188/) (71). The HD10.6 cells can be provided by H.J.C. or A.C. pending scientific review and a completed material transfer agreement. Requests for the HD10.6 cells should be submitted to H.J.C. or A.C. All data and code needed to evaluate and reproduce the results in the paper are present in the paper and/or the Supplementary Materials. No new code and materials were generated during this study.

Additional details

Identifiers

DOI
10.1126/sciadv.ady2696
Other
oai:uchicago.tind.io:16962

Funding

National Institutes of Health
R21CA299377-01
National Institutes of Health
4R00CA226353-02
Neuroendocrine Tumor Research Foundation
Pilot Project Award
Lung Cancer Research Foundation
Pilot Project Award
United States Department of Defense
Idea Development Award

UChicago Information

Division(s)
Biological Sciences Division, Pritzker School of Molecular Engineering
Department(s)
Ben May Department for Cancer Research, Medicine