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

Emphysema is characterized by chronic alveolar destruction. Lipofibroblasts (LIFs) are crucial in the stem cell niche surrounding alveolar type II cells and may contribute to alveolar regeneration. We aim to determine whether emphysema is associated with LIF reduction and whether SREBP (sterol regulatory element-binding protein) activation promotes LIF differentiation and fibroblast stem cell niche properties. We quantified LIFs in the lungs of patients with emphysema compared with controls by costaining vimentin and ADFP (adipose differentiation-related protein). 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 an LXR (liver X receptor) agonist, T0901317, and compared with rosiglitazone, a PPAR-γ (peroxisome proliferator-activated receptor γ) agonist (gene expression and lipidomic analysis). The stem cell niche properties of fibroblasts were evaluated through coculture with the H441 cell line or primary alveolar type II cells in organoid assays. Patients with emphysema had half as many LIFs as controls. T0901317 induced lipogenic differentiation of human lung fibroblasts and increased triglyceride contents and several phosphatidylcholine forms, particularly dipalmitoylphosphatidylcholine (PC32_0), one of the main surfactant components. Rosiglitazone increased only ADFP expression, with minor effects on lipid components. SREBP mediated signaling in fibroblasts and, to a lesser extent, PPAR-γ activation and increased their stem cell niche properties through the increase of organoid numbers. LIFs are decreased in the alveoli of patients with emphysema. Activation of SREBP-mediated signaling promotes lipogenic differentiation of fibroblasts and enhances their stem cell niche properties.