Related Experiment Video
Updated: May 28, 2026
Refined Murine Model of Idiopathic Pulmonary Fibrosis
Published on: June 17, 2025
KLF4 Initiates Dedifferentiation of Systemic Sclerosis Lung Fibroblasts
Ludivine Renaud1, Samantha Kotz1, Aravind Menon2
1Department of Medicine, Division of Rheumatology and Immunology, Medical University of South Carolina, 96 Jonathan Lucas Street, Suite 822, Charleston, SC 29425, USA.
Background:
Systemic sclerosis (SSc) is a systemic autoimmune disease leading to extensive fibrosis of the skin and many visceral organs, including the lungs. The need for effective treatments is urgent, as none exists today that can stop or reverse the progression of fibrosis. We examined the effect of restoring KLF4 levels in primary human lung fibroblasts of SSc patients with pulmonary fibrosis as a potential therapeutic strategy.
Methods:
We restored KLF4 levels in SSc lung fibroblasts by adenoviral infection and extracted total RNA for RNA sequencing. Genes and systems level analyses were performed, and selected genes of interest and markers of alveolar, inflammatory, and fibrotic fibroblasts were further validated at the mRNA and protein levels.
Results:
Our results showed that restoring KLF4 levels in SSc lung fibroblasts initiated dedifferentiation of αSMA and CTHRC1, expressing myofibroblasts by repressing markers of inflammatory and fibrotic fibroblasts while boosting markers of alveolar fibroblasts. Our data also revealed that restoring KLF4 levels prevented TGFβ1-induced fibrogenesis in normal lung fibroblasts, and reduced fibrosis in explanted human lungs in organ culture.
Conclusions:
Our results in human primary SSc lung fibroblasts showed that restoring KLF4 levels initiated dedifferentiation of fibrotic and inflammatory fibroblasts towards the phenotype of alveolar fibroblasts, their lineage precursors, highlighting the potential of KLF4 as a therapy to stop and reverse fibrosis.
Insights
Restoring KLF4 levels in systemic sclerosis (SSc) lung fibroblasts reversed fibrosis by dedifferentiating myofibroblasts. This highlights KLF4
Area of Science:
- Fibrosis research
- Autoimmune disease mechanisms
- Cellular reprogramming
Background:
- Systemic sclerosis (SSc) causes progressive fibrosis in organs like the lungs.
- Current treatments for SSc lack the ability to halt or reverse fibrosis.
- Pulmonary fibrosis in SSc is a critical unmet medical need.
Purpose of the Study:
- To investigate KLF4's therapeutic potential in SSc-associated pulmonary fibrosis.
- To determine if restoring KLF4 levels can reverse lung fibroblast-induced fibrosis.
Main Methods:
- Adenoviral delivery used to restore KLF4 in SSc lung fibroblasts.
- RNA sequencing and gene expression analysis performed.
- Validation of key markers at mRNA and protein levels.
Main Results:
- Restored KLF4 induced dedifferentiation of myofibroblasts (αSMA+, CTHRC1+).
- KLF4 suppressed inflammatory and fibrotic fibroblast markers, promoting alveolar fibroblast markers.
- KLF4 inhibited TGFβ1-induced fibrogenesis and reduced fibrosis in human lung organ cultures.
Conclusions:
- Restoring KLF4 promotes dedifferentiation of fibrotic/inflammatory fibroblasts to alveolar fibroblast precursors.
- KLF4 shows potential as a therapeutic agent to halt and reverse SSc-related fibrosis.
- Targeting KLF4 offers a novel strategy for treating pulmonary fibrosis in systemic sclerosis.
