Stem Cell Program | Lung Disease

Lung diseases are a diverse group of acute or chronic diseases that are caused by genetics or environmental causes and affect patients from neonates to the elderly. While premature babies commonly develop chronic respiratory problems (bronchopulmonary dysplasia), maladies like chronic obstructive pulmonary disease (COPD) and IPF (Idiopatic Pulmonary Fibrosis) are prevalent in the aging population. A specific genetic mutation is responsible for cystic fibrosis: one of the most common inherited disorders with childhood onset in the United States. Finally, viral infections of the lungs can cause acute or persistent damages to the lung architecture as in the current SARS-CoV2 pandemic.

Stem cells, the self-duplicating cells that maintain specialized cells within a tissue, are likely to be critical target cells in lung disease. In 2005, future Children’s Hospital Boston stem cell researcher Carla Kim, PhD, was the first person to discover a group of stem cells from the adult mouse lung called bronchioalveolar stem cells (BASCs). BASCs help to repair specialized lung cells needed for lung function if they are damaged.

Dr. Kim’s lab now studies the different interactions that regulate lung stem cells’ growth and activity within their surroundings in normal and pathological conditions. These studieswill help them in understanding and treating diseases such as broncho pulmonary dysplasia, emphysema, chronic lung disease, bronchiolitis obliterans and lung cancer. Dr. Kim is one of only a few scientists in the world who know how to isolate, cultivate and study lung stem cells.They have developed methods to culture lung stem cells in “organoids,” tiny versions of lung-like structures that grow in the laboratory dish.(see image that will be provided by Nella)

Very little is known about the very early events that transform a normal epithelial cell into a tumor cell or a cell in a pathological state of lung disease. Reasons for this are technical difficulties that come with studying early tumor stages. In humans, years can pass between the onset of cancer or disease and when a patient has obvious symptoms, by which time they usually already reached an advanced stage. Recently new diagnosis and screening methods have made it possible to detect lung tumors at an earlier stage, opening a window for early intervention.

The Kim Lab has established a lung tumor organoid system by turning primary lung epithelial cells into cancer cells in laboratory cultures. This is a rapid and physiologically relevant way to study tumor biology. The organoid approach can also be used to study human alveolar cells and their tumorigenic counterparts, making this system an invaluable tool that can be exploited for multiple applications in future, such as drug discovery studies in the form of large-scale small molecule screens. This work will help find vulnerabilities that can be exploited to target early stage tumors and prevent advanced lung cancer formation in the future.It also serves as a proof of principle that organoids can be used to study the earliest stages of any lung disease.In fact, Kim’s group has already been using organoids to study the effects of infection of lung cells with SARS-CoV-2, the virus that causes COVID-19 disease.

Kim’s lab is also developing ways to isolate mouse lung stem cells and re-grow them in other mice. Observing the ability of these cells to grow and produce more specialized lung cells in such a transplant setting will help scientists understand the specific traits of lung stem cell.

Once this method has been perfected, it can be used to do the same with human lung cells. This will make it possible to model lung diseases. In the long run, this work may help in creating ways to use knowledge of stem cells to treat diseases such as cystic fibrosis.

In the future, it may be possible to heal the fragile, underdeveloped lungs of premature babies using information learned from stem cell studies like that in the Kim Lab or the lab of Stella Kourembanas, MD, in the Division of Newborn Medicine at Children’s Hospital Boston and an affiliate member of the Stem Cell Program at Children’s. Dr. Kourembanas’ work shows that paracrine factors, chemical messengers one cell secretes to communicate with a neighboring cell, could be helpful in lung disease like that seen in premature infants. In experiments performed in mouse models of bronchopulmonary dysplasia, media containing paracrine factors was powerful enough to protect the lungs from inflammation and prevent chronic lung disease. The Kourembanas group is now leading studies to test the use of these factors in clinical studies.