Spontaneous lung fibrosis resolution reveals novel antifibrotic regulators

Qi Tan, Patrick A. Link, Jeffrey A. Meridew, Tho X. Pham, Nunzia Caporarello, Giovanni Ligresti, Daniel J. Tschumperlin

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

deposition, and collagen gel compaction, consistent with roles for these genes in fibroblast deactivation. This combination of RNA sequencing analysis of freshly sorted fibroblasts and hypothesis testing in cultured idiopathic pulmonary fibrosis fibroblasts offers a path toward identification of novel regulators of lung fibroblast deactivation, with potential relevance to understanding fibrosis resolution and its failure in human disease.

Fibroblast activation is transient in successful wound repair but persistent in fibrotic pathologies. Understanding fibroblast deactivation during successful wound healing may provide new approaches to therapeutically reverse fibroblast activation. To characterize the gene programs that accompany fibroblast activation and reversal during lung fibrosis resolution, we used RNA sequencing analysis of flow sorted Col1a1-GFP–positive and CD45-, CD31-, and CD326-negative cells isolated from the lungs of young mice exposed to bleomycin. We compared fibroblasts isolated from control mice with those isolated at Days 14 and 30 after bleomycin exposure, representing the peak of extracellular matrix deposition and an early stage of fibrosis resolution, respectively. Bleomycin exposure dramatically altered fibroblast gene programs at Day 14. Principal component and differential gene expression analyses demonstrated the predominant reversal of these trends at Day 30. Upstream regulator and pathway analyses of reversing “resolution” genes identified novel candidate antifibrotic genes and pathways. Two genes from these analyses that were decreased in expression at Day 14 and reversed at Day 30, Aldh2 and Nr3c1, were selected for further analysis. Enhancement of endogenous expression of either gene by CRISPR activation in cultured human idiopathic pulmonary fibrosis fibroblasts was sufficient to reduce profibrotic gene expression, fibronectin

Original languageEnglish (US)
Pages (from-to)453-464
Number of pages12
JournalAmerican journal of respiratory cell and molecular biology
Volume64
Issue number4
DOIs
StatePublished - Apr 2021

Keywords

  • Aldh2
  • CRISPR activation
  • Fibrosis resolution
  • Nr3c1
  • RNA-seq

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

Fingerprint Dive into the research topics of 'Spontaneous lung fibrosis resolution reveals novel antifibrotic regulators'. Together they form a unique fingerprint.

Cite this