Faculty, Staff and Student Publications

Language

English

Publication Date

12-1-2024

Journal

Journal of Respiratory Biology and Translational Medicine

DOI

10.70322/jrbtm.2024.10017

PMID

39553282

PMCID

PMC11565471

PubMedCentral® Posted Date

12-1-2024

PubMedCentral® Full Text Version

Author MSS

Abstract

Background: Deficiency of surfactant protein-C (SPC) increases susceptibility to lung infections and injury, and suppressed expression of SPC has been associated with the severity of acute respiratory distress syndrome (ARDS). Alveolar type 2 epithelial cells (AT2) are critical for maintenance and repair of the lung. However, the role of the SPC in the regulation of AT2 cell lineage and the underlying mechanisms are not completely understood.

Methods: This study aimed to investigate the mechanisms by which SPC regulates AT2 lineages. Sftpc-/- mice were used to model the SPC deficiency in ARDS patients. We utilized three-dimensional (3D) organoids to compare AT2 lineage characteristics between wild type (WT) and Sftpc-/- mice by analyzing AT2 proliferation, alveolar type 1 cells (AT1) differentiation and CD74 expression, using colony-formation assay, immunofluorescence, flow cytometry, and immunoblots.

Results: The results showed that Sftpc-/- mice demonstrated a reduced AT2 cell population. Influenza A virus subtype H1N1 (H1N1) infected Sftpc-/- mice demonstrated reduced AT2 proliferation and AT1 differentiation. Western blot indicated elevated levels of CD74 protein in AT2 cells of Sftpc-/- mice. Colony-forming efficiency was significantly attenuated in AT2 cells isolated from Sftpc-/- mice compared to the WT controls. Podoplanin (PDPN, a marker of AT1 cells) expression and transient cell count significantly increased in Sftpc-/- organoids. Moreover, siRNA-mediated gene silencing of CD74 in AT2 cells significantly increased AT2 proliferation and AT1 differentiation in Sftpc-/- organoids.

Conclusions: This study suggests that SPC regulates AT2 lineage in vitro and in vivo. The SPC might influence AT2 lineage during the lung epithelium repair by activating signaling mechanism involving CD74 receptor.

Keywords

Alveolar type 2 cell, Surfactant protein-C, ARDS, Differentiation, Proliferation, Re-alveolarization

Published Open-Access

yes

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