Sftpc-KO Mouse

Sftpc, encoding surfactant protein C, is crucial for alveolar homeostasis as it is involved in surfactant biosynthesis in alveolar type 2 (AT2) cells [2,3,4]. Surfactant helps reduce surface tension in the alveoli, preventing their collapse during respiration. Dysregulation of Sftpc-related pathways can lead to various lung-related diseases. Genetic models, such as gene-edited induced pluripotent stem cells (iPSCs), are valuable for studying Sftpc function.

Patient-specific iPSCs carrying an SFTPCI73T mutation show that mutant iAEC2s (differentiated from iPSCs into AEC2s) accumulate misprocessed and mistrafficked pro-SFTPC protein. This leads to diminished AEC2 progenitor capacity, perturbed proteostasis, altered bioenergetic programs, metabolic reprogramming, and NF-κB pathway activation [1]. In a knockin mouse model with SftpcC121G mutation, expression during fetal development causes fatal postnatal respiratory failure, while induced expression in adult mice results in AT2 cell ER stress, followed by spontaneous pulmonary fibrosis and restrictive lung impairment [5].

In conclusion, Sftpc is essential for maintaining normal alveolar function through its role in surfactant production. Studies using genetic models, like the iPSCs and mouse models, have revealed its significance in the pathogenesis of interstitial lung diseases. Understanding Sftpc function provides insights into the mechanisms of these diseases and may offer potential therapeutic targets.

References:

1. Alysandratos, Konstantinos-Dionysios, Russo, Scott J, Petcherski, Anton, Beers, Michael F, Kotton, Darrell N. . Patient-specific iPSCs carrying an SFTPC mutation reveal the intrinsic alveolar epithelial dysfunction at the inception of interstitial lung disease. In Cell reports, 36, 109636. doi:10.1016/j.celrep.2021.109636. https://pubmed.ncbi.nlm.nih.gov/34469722/

2. Abdel Megeid, Azza K, Refeat, Miral M, Ashaat, Engy A, El Ruby, Mona O, Amr, Khalda S. 2022. Correlating SFTPC gene variants to interstitial lung disease in Egyptian children. In Journal, genetic engineering & biotechnology, 20, 117. doi:10.1186/s43141-022-00399-0. https://pubmed.ncbi.nlm.nih.gov/35939165/

3. Katzen, Jeremy, Beers, Michael F. . Contributions of alveolar epithelial cell quality control to pulmonary fibrosis. In The Journal of clinical investigation, 130, 5088-5099. doi:10.1172/JCI139519. https://pubmed.ncbi.nlm.nih.gov/32870817/

4. Barkauskas, Christina E, Cronce, Michael J, Rackley, Craig R, Noble, Paul W, Hogan, Brigid L M. 2013. Type 2 alveolar cells are stem cells in adult lung. In The Journal of clinical investigation, 123, 3025-36. doi:10.1172/JCI68782. https://pubmed.ncbi.nlm.nih.gov/23921127/

5. Katzen, Jeremy, Wagner, Brandie D, Venosa, Alessandro, Deterding, Robin R, Beers, Michael F. 2019. An SFTPC BRICHOS mutant links epithelial ER stress and spontaneous lung fibrosis. In JCI insight, 4, . doi:10.1172/jci.insight.126125. https://pubmed.ncbi.nlm.nih.gov/30721158/