A group of researchers developed a new study model to identify disease-initiating mechanisms associated with adult and pediatric interstitial lung disease, including idiopathic pulmonary fibrosis (IPF). The study authors focused on alveolar epithelial type 2 cell (AEC2)-intrinsic mechanisms, which are far from being understood due to the inability to access primary AEC2s early on.

“Here, we present a human in vitro model permitting investigation of epithelial-intrinsic events culminating in AEC2 dysfunction, using patient-specific induced pluripotent stem cells (iPSCs) carrying an AEC2-exclusive disease-associated variant (SFTPCI73T),” Alysandratos et al wrote in the article recently published in Cell Reports.

Using different techniques and a gene-edited version of the cells with the altered gene corrected, they found that mutant cells mimicked in vivo alterations. They accumulated large amounts of abnormal proSFTPC protein, which decreased AEC2 progenitor capacity and compromised proteostasis.

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Moreover, it led to bioenergetic program alterations, time-dependent metabolic reprogramming, and inflammatory response via nuclear factor κB (NF-κB) signaling activation. Treating these cells with hydroxychloroquine worsened the observed perturbations.

According to Dr. Kotton, “Generating stem cell-based in vitro models of lung disease, using easily accessible blood or skin cells from these children that are then reprogrammed into induced pluripotent stem cells, remains a very attractive approach for studying pediatric lung disease because it avoids risky biopsies of the deep lung, yet provides a simulation in the laboratory dish of the same processes that we think are occurring in the in vivo lung tissue itself.”

Therefore, this cellular model can potentially be used to search for new therapeutic targets and test new drugs.


New study provides insight into lung scarring diseases without risky biopsy. News release. Boston University School of Medicine; August 31, 2021.

Alysandratos KD, Russo SJ, Petcherski A, et al. Patient-specific iPSCs carrying an SFTPC mutation reveal the intrinsic alveolar epithelial dysfunction at the inception of interstitial lung disease. Cell Rep. 2021;36(9):109636. doi:10.1016/j.celrep.2021.109636