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Secretory Cells Dominate Airway CFTR Expression and Function in Human Airway Superficial Epithelia.

Publication ,  Journal Article
Okuda, K; Dang, H; Kobayashi, Y; Carraro, G; Nakano, S; Chen, G; Kato, T; Asakura, T; Gilmore, RC; Morton, LC; Lee, RE; Mascenik, T; Yin, W-N ...
Published in: Am J Respir Crit Care Med
May 15, 2021

Rationale: Identification of the specific cell types expressing CFTR (cystic fibrosis [CF] transmembrane conductance regulator) is required for precision medicine therapies for CF. However, a full characterization of CFTR expression in normal human airway epithelia is missing. Objectives: To identify the cell types that contribute to CFTR expression and function within the proximal-distal axis of the normal human lung. Methods: Single-cell RNA (scRNA) sequencing (scRNA-seq) was performed on freshly isolated human large and small airway epithelial cells. scRNA in situ hybridization (ISH) and single-cell qRT-PCR were performed for validation. In vitro culture systems correlated CFTR function with cell types. Lentiviruses were used for cell type-specific transduction of wild-type CFTR in CF cells. Measurements and Main Results: scRNA-seq identified secretory cells as dominating CFTR expression in normal human large and, particularly, small airway superficial epithelia, followed by basal cells. Ionocytes expressed the highest CFTR levels but were rare, whereas the expression in ciliated cells was infrequent and low. scRNA ISH and single-cell qRT-PCR confirmed the scRNA-seq findings. CF lungs exhibited distributions of CFTR and ionocytes similar to those of normal control subjects. CFTR mediated Cl- secretion in cultures tracked secretory cell, but not ionocyte, densities. Furthermore, the nucleotide-purinergic regulatory system that controls CFTR-mediated hydration was associated with secretory cells and not with ionocytes. Lentiviral transduction of wild-type CFTR produced CFTR-mediated Cl- secretion in CF airway secretory cells but not in ciliated cells. Conclusions: Secretory cells dominate CFTR expression and function in human airway superficial epithelia. CFTR therapies may need to restore CFTR function to multiple cell types, with a focus on secretory cells.

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Published In

Am J Respir Crit Care Med

DOI

EISSN

1535-4970

Publication Date

May 15, 2021

Volume

203

Issue

10

Start / End Page

1275 / 1289

Location

United States

Related Subject Headings

  • Respiratory System
  • Respiratory Mucosa
  • Humans
  • Epithelial Cells
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Cystic Fibrosis
  • Cell Culture Techniques
  • Case-Control Studies
  • 3202 Clinical sciences
  • 3201 Cardiovascular medicine and haematology
 

Citation

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Okuda, K., Dang, H., Kobayashi, Y., Carraro, G., Nakano, S., Chen, G., … Boucher, R. C. (2021). Secretory Cells Dominate Airway CFTR Expression and Function in Human Airway Superficial Epithelia. Am J Respir Crit Care Med, 203(10), 1275–1289. https://doi.org/10.1164/rccm.202008-3198OC
Okuda, Kenichi, Hong Dang, Yoshihiko Kobayashi, Gianni Carraro, Satoko Nakano, Gang Chen, Takafumi Kato, et al. “Secretory Cells Dominate Airway CFTR Expression and Function in Human Airway Superficial Epithelia.Am J Respir Crit Care Med 203, no. 10 (May 15, 2021): 1275–89. https://doi.org/10.1164/rccm.202008-3198OC.
Okuda K, Dang H, Kobayashi Y, Carraro G, Nakano S, Chen G, et al. Secretory Cells Dominate Airway CFTR Expression and Function in Human Airway Superficial Epithelia. Am J Respir Crit Care Med. 2021 May 15;203(10):1275–89.
Okuda, Kenichi, et al. “Secretory Cells Dominate Airway CFTR Expression and Function in Human Airway Superficial Epithelia.Am J Respir Crit Care Med, vol. 203, no. 10, May 2021, pp. 1275–89. Pubmed, doi:10.1164/rccm.202008-3198OC.
Okuda K, Dang H, Kobayashi Y, Carraro G, Nakano S, Chen G, Kato T, Asakura T, Gilmore RC, Morton LC, Lee RE, Mascenik T, Yin W-N, Barbosa Cardenas SM, O’Neal YK, Minnick CE, Chua M, Quinney NL, Gentzsch M, Anderson CW, Ghio A, Matsui H, Nagase T, Ostrowski LE, Grubb BR, Olsen JC, Randell SH, Stripp BR, Tata PR, O’Neal WK, Boucher RC. Secretory Cells Dominate Airway CFTR Expression and Function in Human Airway Superficial Epithelia. Am J Respir Crit Care Med. 2021 May 15;203(10):1275–1289.

Published In

Am J Respir Crit Care Med

DOI

EISSN

1535-4970

Publication Date

May 15, 2021

Volume

203

Issue

10

Start / End Page

1275 / 1289

Location

United States

Related Subject Headings

  • Respiratory System
  • Respiratory Mucosa
  • Humans
  • Epithelial Cells
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Cystic Fibrosis
  • Cell Culture Techniques
  • Case-Control Studies
  • 3202 Clinical sciences
  • 3201 Cardiovascular medicine and haematology