Rare Pulmonary Neuroendocrine Cells Are Stem Cells Regulated by Rb, p53, and Notch
Abstract
Pulmonary neuroendocrine (NE) cells are neurosensory cells sparsely distributed throughout the bronchial epithelium, many in innervated clusters of 20–30 cells. Following lung injury, NE cells proliferate and generate other cell types to promote epithelial repair. Here, we show that only rare NE cells, typically 2–4 per cluster, function as stem cells. These fully differentiated cells display features of classical stem cells. Most proliferate (self-renew) following injury, and some migrate into the injured area. A week later, individual cells, often just one per cluster, lose NE identity (deprogram), transit amplify, and reprogram to other fates, creating large clonal repair patches. Small cell lung cancer (SCLC) tumor suppressors regulate the stem cells: Rb and p53 suppress self-renewal, whereas Notch marks the stem cells and initiates deprogramming and transit amplification. We propose that NE stem cells give rise to SCLC, and transformation results from constitutive activation of stem cell renewal and inhibition of deprogramming.
Additional Information
© 2019 Elsevier Inc. Received 26 July 2018, Revised 29 April 2019, Accepted 5 September 2019, Available online 3 October 2019. Data and Code Availability: The scRNA-seq dataset generated during this study is available at Gene Expression Omnibus (GEO: GSE136580) with associated metadata file available as Table S3. For advice and assistance, we thank Maya Kumar (microscopy); Cathy Crumpton, Bianca Gomez, and Stanford FACS Facility (flow sorting); Spyros Darmanis, Neo Chung, Dominic Grün, Gary Mantalas, Norma Neff, Ben Passarelli, Sopheak Sim, Barbara Treutlein, Angela Wu, and Brian Yu (scRNA-seq); Pao-Tien Chuang, Tushar Desai, Jane Johnson, Julien Sage, and Irv Weissman (mouse lines); Jing Lim and Dian Yang (reagents, discussions); Tushar Desai, Maya Kumar, Ross Metzger, Lucy O'Brien, Julien Sage, Thomas Vierbuchen, and Kevin Yackle (comments on manuscript); and members of our lab (experiments, interpretations, comments on manuscript). This work was supported by NHLBI (U01-HL099995), NCI (U01-CA23185), HHMI, Virginia and D.K. Ludwig Fund for Cancer Research, an NSF Graduate Research Fellowship (Y.O.), Stanford Graduate Fellowship in Science and Engineering (Y.O.), and the Stanford Cancer Biology Program (NCI CA09302 to Y.O.). M.A.K. is an HHMI investigator. Author Contributions: Conceptualization, Y.O. and M.A.K.; Methodology, Y.O., E.R.R., D.P.R., S.C., and M.A.K.; Formal Analysis, Y.O., E.R.R., D.P.R., and S.C.; Investigation, Y.O.; Resources, C.S.K.; Writing – Original Draft, Y.O. and M.A.K.; Writing – Review & Editing, all authors; Supervision, M.A.K.; Funding Acquisition, Y.O., C.S.K., and M.A.K. The authors declare no competing interests.Attached Files
Accepted Version - nihms-1041360.pdf
Supplemental Material - 1-s2.0-S0092867419310165-mmc1.pdf
Supplemental Material - 1-s2.0-S0092867419310165-mmc2.xlsx
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Additional details
- Alternative title
- A subpopulation of pulmonary neuroendocrine cells are reserve stem cells regulated by the tumor suppressors Rb, p53, and Notch
- PMCID
- PMC6782070
- Eprint ID
- 99330
- Resolver ID
- CaltechAUTHORS:20191017-133800606
- U01-HL099995
- NIH
- U01-CA23185
- NIH
- National Cancer Institute
- Howard Hughes Medical Institute (HHMI)
- Virginia and D. K. Ludwig Fund for Cancer Research
- NSF Graduate Research Fellowship
- Stanford University
- CA09302
- NIH
- Created
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2019-10-22Created from EPrint's datestamp field
- Updated
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2021-11-16Created from EPrint's last_modified field