Enhanced Expression of a Novel Lamin A/C Splice Variant in IPF Lung.

In idiopathic pulmonary fibrosis (IPF), the normal delicate lung architecture is replaced with rigid extracellular matrix (ECM) due to accumulation of activated myofibroblasts and excessive deposition of ECM. Lamins have a role in fostering mechanosignaling from the ECM to the nucleus. Although there is a growing number of studies on lamins and associated diseases, there are no prior reports linking aberrations in lamins with pulmonary fibrosis. Here, we discovered through analysis of our RNA-seq data, a novel isoform of lamin A/C that is more highly expressed in IPF compared to control lung. This novel LMNA splice variant includes retained introns 10 and 11, and exons 11 and 12 as documented by RACE assay. We found that this novel isoform is induced by stiff extracellular matrix. To better clarify the specific effects of this novel isoform of lamin A/C and how it may contribute to the pathogenesis of IPF, we transduced the lamin transcript into primary lung fibroblasts and alveolar epithelial cells, and found that it impacts upon several biological effects, including cell proliferation, senescence, cell contraction, and the transition of fibroblasts to myofibroblasts. We also observed that type II epithelial cells and myofibroblasts, in IPF lung exhibited wrinkled nuclei, and this is notable because this has not been previously described and is consistent with laminopathy-mediated cellular effects.