IPF is a complex, age-related lung disease that leads to lung scarring, respiratory failure and death. Telomeres, repetitive DNA sequences, synthesised by telomerase protect chromosome ends from degradation. While the cause of IPF is unknown, short telomere length in type 2 alveolar epithelial (AT2) cells has been implicated as a key player. We hypothesise that iPSC derived AT2 (iAT2) can be used as a model to explore telomere biology to determine its role in IPF and identify new treatments.

DNA was collected at specific stages of iAT2 directed differentiation. Telomere length was measured by 3 methods. Telomerase expression and activity were measured by RT-qPCR and Q-TRAP. iAT2 were treated with chemicals known to affect telomere length to investigate their effect on telomere biology. Pro-fibrotic, inflammatory and senescence gene expression was measured by RT-qPCR.

Telomere length decreased throughout the different stages of iAT2 directed differentiation, whilst short telomere percentage increased. Telomere shortening was associated with decreased TERT expression, while TERC was only lowly expressed at all stages of differentiation. Treating iAT2 cells with chemicals altered their telomere biology. Telomere shortening was associated with increased expression of PRODH, CTGF and Bcl2 and decreased expression of p53 and Bax.

This is the first described model of telomere shortening in human iAT2 and explores the relationship of telomere length, telomerase activity and pro-fibrotic pathways in iAT2. Our data supports the applicability of our model in age related PF, and supports the hypothesis that telomere biology plays an important role in IPF.