Rising Star Presentation: Dr. Kostas Alysandratos

Pluripotent stem cells to model and treat pulmonary fibrosis

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease marked by progressive fibrosis and limited survival. A key challenge in developing effective therapies is the inadequate understanding of IPF pathogenesis, partly due to the lack of reliable human models. Recent studies identify dysfunction in alveolar epithelial type 2 (AT2) cells as a potential proximal disease driver. In this presentation, we showcase the use of patient-specific induced pluripotent stem cell (iPSC) models to study and treat pulmonary fibrosis. Our findings reveal that dysfunctional AT2 cells exhibit altered metabolism, including increased glycolysis, reduced mitochondrial biogenesis, and impaired fatty acid oxidation, leading to decreased self-renewal and accumulation of aberrant epithelial cells. We identify deficient AMP-kinase signaling as a critical factor in these metabolic disruptions and demonstrate that enhancing this pathway can restore AT2 cell function and alleviate fibrosis in vivo. Furthermore, we describe the development of a novel co-culture system combining iPSC-derived AT2 cells with lung-specific mesenchyme. This model uncovers key epithelial-mesenchymal interactions and signaling pathways, providing a platform for identifying new therapeutic targets and developing treatments for IPF.