Journal article
Krt14 and Krt15 differentially regulate regenerative properties and differentiation potential of airway basal cells
JCI insight, Vol.8(2), e162041
2023
DOI: 10.1172/jci.insight.162041
PMCID: PMC9977304
PMID: 36512409
Abstract
Keratin expression dynamically changes in airway basal cells (BCs) following acute and chronic injury, yet the functional consequences of these changes on BC behavior remain unknown. In Bronchiolitis Obliterans (BO) following lung transplantation, BC clonogenicity declines which is associated with a switch from Keratin15 (Krt15) to Keratin14 (Krt14). We investigated the roles of these keratins using Crispr-KO in vitro and in vivo and found that Krt14-KO and Krt15-KO produce contrasting phenotypes in terms of differentiation and clonogenicity. Primary mouse Krt14-KO BCs failed to differentiate into club and ciliated cells, but had enhanced clonogenicity. By contrast, Krt15-KO did not alter BC differentiation, but impaired clonogenicity in vitro and reduced the number of label-retaining BCs in vivo following injury. Krt14, but not Krt15, bound the tumor suppressor Stratifin (Sfn). Disruption of Krt14, but not of Krt15, reduced Sfn protein abundance and increased expression of the oncogene dNp63a during BC differentiation, while dNp63a levels were reduced in Krt15-KO BCs. Overall, the phenotype of Krt15-KO BCs contrasts that of Krt14-KO and resembles the phenotype in BO with decreased clonogenicity, increased Krt14 and decreased dNp63a expression. This work demonstrates that Krt14 and Krt15 functionally regulate BC behavior which is relevant in chronic disease states like BO.
Details
- Title: Subtitle
- Krt14 and Krt15 differentially regulate regenerative properties and differentiation potential of airway basal cells
- Creators
- Vitaly Ievlev - Department of Anatomy and Cell Biology, The University of Iowa Carver College of Medicine, Iowa City, United States of AmericaThomas J Lynch - Department of Anatomy and Cell Biology, The University of Iowa Carver College of Medicine, Iowa City, United States of AmericaKyle W Freischlag - Department of Cardiothoracic Surgery, The University of Iowa Carver College of Medicine, Iowa City, United States of AmericaCaitlyn B Gries - Department of Cardiothoracic Surgery, The University of Iowa Carver College of Medicine, Iowa City, United States of AmericaAnit Shah - Department of Anatomy and Cell Biology, The University of Iowa Carver College of Medicine, Iowa City, United States of AmericaAlbert C Pai - Department of Cardiothoracic Surgery, The University of Iowa Carver College of Medicine, Iowa City, United States of AmericaBethany A Ahlers - Department of Cardiothoracic Surgery, The University of Iowa Carver College of Medicine, Iowa City, United States of AmericaSoo Yeun Park - Department of Anatomy and Cell Biology, The University of Iowa Carver College of Medicine, Iowa City, United States of AmericaJohn F Engelhardt - Department of Anatomy and Cell Biology, The University of Iowa Carver College of Medicine, Iowa City, United States of AmericaKalpaj R Parekh - Department of Cardiothoracic Surgery, The University of Iowa Carver College of Medicine, Iowa City, United States of America
- Resource Type
- Journal article
- Publication Details
- JCI insight, Vol.8(2), e162041
- DOI
- 10.1172/jci.insight.162041
- PMID
- 36512409
- PMCID
- PMC9977304
- NLM abbreviation
- JCI Insight
- ISSN
- 2379-3708
- Grant note
- name: NIH, award: R01 HL136370, P01 HL152960, NHLBI Contract 75N92019R0014, P30 DK054759, R01 HL165404, T32 HL007638, K99HL155843
- Language
- English
- Electronic publication date
- 12/13/2022
- Date published
- 2023
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Anatomy and Cell Biology; Radiation Oncology; Cardiothoracic Surgery; Internal Medicine
- Record Identifier
- 9984332737102771
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