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

Abstract

Emphysema is characterized by chronic alveolar destruction. Lipofibroblasts (LIF) are crucial in the stem cell niche surrounding alveolar type II (AT2) cells and may contribute to alveolar regeneration. We aim to determine whether emphysema is associated with LIF reduction and whether Sterol regulatory binding protein (SREBP) activation promotes LIF differentiation and fibroblast stem cell niche properties. We quantified LIF in the lungs of patients with emphysema compared to controls by co-staining Vimentin/Adipose differentiation-related protein (ADFP). Using available datasets, we explored the expression level of lipogenic pathways in mesenchymal cells. Fibroblasts from patients were isolated and SREBP-mediated signaling was activated with a Liver X receptor (LXR) agonist T0901317, and compared with Rosiglitazone, a Peroxisome proliferator-activated receptor gamma (PPARγ) agonist (gene expression and lipidomic analysis). The stem cell niche properties of fibroblasts were evaluated through coculture with the H441 cell line or primary AT2 in organoid assays. Patients with emphysema had two times fewer LIF compared to controls. T0901317 induced lipogenic differentiation of human lung fibroblasts and increased triglycerides contents and several phosphatidylcholine forms, particularly Dipalmitoylphosphatidylcholine (PC32_0), one of the main surfactant components. Rosiglitazone only increased ADFP expression with minor effects on lipid components. SREBP mediated signalling in fibroblasts, and to a lesser extent PPARγ activation, increased their stem cell niche properties through the increase of organoid number. LIF are decreased in the alveoli of emphysematous patients. Activation of SREBP-mediated signaling promotes lipogenic differentiation of fibroblasts and enhances their stem cell niche properties.

Keywords: Alveolar regeneration; Emphysema; Lipofibroblast; SREBP; Stem cell niche.