SREBP-mediated Signaling Restores Stem Cell Niche Properties in Human Lung Fibroblasts

Area of Science:

• Pulmonary Medicine
• Cell Biology
• Regenerative Medicine

Background:

• Emphysema involves chronic alveolar destruction, impacting lung function.
• Lipofibroblasts (LIF) are vital for the stem cell niche supporting alveolar type II (AT2) cells and may aid regeneration.
• The role of LIF reduction and SREBP activation in emphysema pathogenesis is unclear.

Purpose of the Study:

• To investigate the association between emphysema and LIF reduction.
• To determine if Sterol regulatory binding protein (SREBP) activation promotes LIF differentiation and fibroblast stem cell niche properties.

Main Methods:

• Quantified LIF in emphysema patients versus controls using Vimentin/ADFP co-staining.
• Analyzed lipogenic pathway expression in mesenchymal cells from public datasets.
• Activated SREBP signaling with an LXR agonist (T0901317) in patient-derived fibroblasts, assessing gene expression, lipidomics, and stem cell niche properties via organoid assays.

Main Results:

• Emphysema patients exhibited a twofold reduction in LIF compared to controls.
• T0901317 significantly induced lipogenic differentiation in lung fibroblasts, increasing triglycerides and specific phosphatidylcholine forms.
• SREBP activation, and to a lesser extent PPARγ activation, enhanced fibroblast stem cell niche properties, evidenced by increased organoid formation.

Conclusions:

• Lipofibroblasts (LIF) are decreased in the lungs of emphysema patients.
• Activation of SREBP-mediated signaling promotes fibroblast lipogenic differentiation and improves their stem cell niche properties, suggesting a potential therapeutic avenue for emphysema.