Scientists at Boston University and the University of Pennsylvania have used patient-specific induced pluripotent stem cells (iPSCs) to model functional abnormalities of the highly specialized cells, called type-2 alveolar epithelial cells, that line the delicate air sacs of the lungs.

The findings published in a Cell Reports paper, “Patient-specific iPSCs carrying an SFTPC mutation reveal the intrinsic alveolar epithelial dysfunction at the inception of interstitial lung disease” will help develop effective therapies for adult and pediatric lung diseases, including idiopathic pulmonary fibrosis (IPF) and childhood interstitial lung disease (chILD)—lung diseases with poorly understood mechanisms of pathogenesis, largely due to the lack of access to type-2 alveolar epithelial cells adequate disease models. Type-2 alveolar epithelial cells initiate the fibrotic cascade that characterizes a number of adult and pediatric lung diseases, including IPF and chILD.

“Understanding how dysfunction of the highly specialized cells of the air sacs initiates the fibrotic cascade can result in development of novel targeted therapies for this devastating disease. Furthermore, this model has the potential to serve as a platform for testing new therapeutics,” says Kontantinos Alysandratos, MD, PhD, assistant professor of medicine at Boston University School of Medicine (BUSM) and first author on the paper.

The authors note studying lung diseases in children, particularly those diseases that affect the air sac cells that reside deep in the lung, is very difficult since it is hard to access those cells for biological studies. The team believes this model will now make it possible to adopt similar approaches to study many other types of interstitial lung diseases that arise from dysfunction in the air sacs and affect both children and adults.

“In this way, these in vitro models should really expand drug development efforts to treat these diseases that until now have suffered from a lack of access to living cells from patients,” says Alysandratos.

Scientists differentiate patient-specific induced pluripotent stem cells (iPSCs) carrying the SFTPC-I73T genetic variant associated with interstitial lung disease [Alysandratos, et al, Cell Reports]
IPF, the most common and severe form of lung disease is characterized by relentless scarring leading to death within an average of four years from the time of diagnosis. The poorly understood pathogenesis of IPF, in part due to the lack of human disease models, has been a major hurdle in developing effective therapies.

“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,” says Darrell Kotton, MD, the David C. Seldin Professor of Medicine at BUSM and Director of the BU/Boston Medical Center’s Center for Regenerative Medicine (CReM) and corresponding author of the paper.

The authors focus on a disease-associated variant in the surfactant protein C gene (SFTPC^I73T) because earlier studies have shown that the protein is expressed after birth, specifically in type-2 alveolar epithelial cells and can be edited to provide comparator cells, that are identical in all respects save for the specific mutation.

The authors first altered the gene by introducing the mutation to make it dysfunctional in one group of patient-specific cells and in a second group they edited the mutation to correct the altered gene. The authors show cells with the SFTPC^I73T variant have a buildup of large amounts of mis-processed and mis-localized pro-SFTPC protein. These mutant cells divide abnormally, aberrantly recycle unnecessary cellular components, bear altered metabolic profiles, and show inflammatory activation.

The researchers then expose both sets of cells to hydroxychloroquine, a drug commonly used in pediatric patients carrying this altered gene and show that the cellular disturbances are aggravated in mutant cells whereas no changes are seen in normal cells.

Financial support for the study came from The Pulmonary Fibrosis Foundation, NIH grants and an IDEAL Consortium Grant from Celgene/Bristol Myers Squibb.