Investigating the Role of Interferon Signaling in the Malformation of the Down Syndrome Lung 2260174

Abstract Introduction Down Syndrome (DS) is the most prevalent chromosomal abnormality worldwide, affecting 1 in every 700 live births. Although typically noted for its neurological implications, individuals with DS exhibit severe pulmonary malformations as well, including poor branching, impaired alveolar formation, and low lung mass. The triplication of chromosome 21 (HSA21) in DS results in the overexpression of several immunological genes found on HSA21, including four of the six interferon (IFN) receptor genes. Increased IFN receptor expression constitutively activates the IFN signaling pathway, fostering an antiproliferative environment during development. Given that dysregulated IFN signaling has been linked to impaired cardiogenesis in DS mouse models, we hypothesize that hyperactive IFN signaling similarly impairs human pulmonary development. Methods Although mechanistically useful, animal models prove incomplete in fully recapitulating a chromosomal disorder such as DS. Thus, we have utilized Trisomy HSA21 (T21) induced pluripotent stem cells (iPSCs) to establish a DS Branching Lung Organoid (BLO) model that recapitulates key hallmarks of pulmonary development, including branching, budding, and epithelial differentiation. Using this model, we aim to investigate how dysregulated IFN signaling contributes to pulmonary malformation in DS. Results iPSCs derived from an individual mosaic for DS, providing both diploid (D21) and triploid (T21) isogenic cell lines, were used to generate BLOs. We hypothesize that T21 induces impairments to healthy BLO morphogenesis that can be corrected when proper IFN signaling is restored. Conclusion Given that the lungs continue to form through early childhood, interventions given to infants immediately following birth have displayed efficacy in facilitating healthy pulmonary development. Thus, studying how lung malformations arise in the development of DS may offer insight into restorative therapies for these individuals, ultimately curbing high pulmonary associated mortality. Funding Source R01HL165259-03S1 Topic Categories Cytokines and Chemokines and their Receptors (CCR)