Generation of alveolar epithelial type 2 cells from patient-derived induced pluripotent stem cells: A novel platform for exploring telomere biology in pulmonary fibrosis

<bold>Background:</bold> Idiopathic pulmonary fibrosis (IPF) is a complex, age-related lung disease. The exact cause of IPF is unknown, but short telomere length in alveolar epithelial type 2 cells (AT2)s are suspected key players in its pathogenesis. Approximately 25% of patients with IPF have a familial form of pulmonary fibrosis with the most common mutations identified in telomere related genes. Current models of pulmonary fibrosis fail to recapitulate many aspects of telomeropathies and primary alveolar cells are difficult to isolate from patients and culture for prolonged periods of time. <bold>Hypothesis:</bold> We hypothesise that induced pluripotent stem cell (iPSC) generated AT2 (iAT2) cells from patients with a telomere related gene mutation can be used as a model to explore telomere biology and determine its role in pulmonary fibrosis. <bold>Methods:</bold> PBMCs from a patient with telomere related mutation, RTEL1, were reprogrammed to iPSCs and pluripotency markers tested via immunostaining. Karyotyping was also performed. iPSCs were differentiated towards AT2 cell spheroids in 3D culture via a directed differentiation protocol which we have developed. <bold>Results:</bold> iPSCs were successfully generated from PBMCs isolated from a patient with an RTEL1 mutation. iPSCs express SSEA-4, TRA-1-60, and TRA-1-81, markers for pluripotency. The iPSCs are karyotypically normal and can be differentiated to AT2 spheroids. <bold>Conclusion:</bold> We have generated a novel model of pulmonary fibrosis from a patient with a telomere related gene mutation that will allow us to explore telomere biology and its role in pulmonary fibrosis.