Study reveals role for stem cells in chronic lung diseasesby Leigh MacMillan | May. 25, 2017, 9:07 AM
A novel population of lung stem cells plays an important role in regulating the pulmonary microvasculature — the network of tiny blood vessels where oxygen and carbon dioxide exchange takes place.
The stem cells, called mesenchymal progenitor cells (MPCs), likely contribute to the pathobiology of chronic lung diseases, said Susan Majka, Ph.D., associate professor of Medicine.
Understanding the normal function and disease-associated dysfunction of MPCs could lead to earlier diagnosis and improved treatment for diseases such as pulmonary fibrosis, emphysema and pulmonary hypertension. The findings were reported this month in the Journal of Clinical Investigation.
Chronic lung diseases are marked by changes in lung tissue structure that include remodeling and loss of microvessels. The loss of microvessels impairs gas exchange, causing shortness of breath.
The vascular remodeling had been attributed to the endothelial cells that line blood vessels or the smooth muscle cells that surround them, Majka said. But endothelial and smooth muscle cells are “terminally differentiated” — they are not likely to become other types of cells — and Majka believed that unidentified stem cells, which can produce multiple types of “mature” cells with varied functions, were more likely to underlie tissue remodeling.
She and her colleagues had isolated vascular stem cells from mouse and human lungs and characterized them as MPCs that are located next to the microvasculature in the adult tissue. Now, they have used novel advanced lineage mapping tools to track the cells, under normal conditions and when signaling pathways associated with adult lung diseases are activated (Wnt signaling) or reduced (BMPR2 signaling).
“When these cells are abnormal, animals develop vasculopathy — a loss of structure in the microvessels and subsequently the lung. They lose the surfaces for gas exchange,” Majka said.
The investigators also followed the cells after lung injury — experimentally induced fibrosis (scarring). They discovered that the MPCs, which are abnormally activated after injury, formed an adaptive vascular structure that had never been previously characterized.
“It appears to be a form of ‘vascular mimicry,’ tubular structures that will circulate blood but are not normal blood vessels,” Majka said. “It’s a new form of angiogenesis that could get blood into the middle of fibrotic areas, but our studies ended early after the injury, during peak fibrosis, and we don’t know yet if it’s helping repair the injury or is actually detrimental.”
Majka and her colleagues also used human lung tissues obtained from transplant or other surgeries to isolate MPCs. They compared human and mouse MPCs from normal and diseased lung tissue and showed that the cells have similar characteristics and gene expression profiles, defining the work as relevant to human disease.
“It’s very exciting to discover something new like this cell type that is so important in maintaining microvascular and lung tissue structure and that has potential implications in disease and repair,” Majka said.
Understanding the MPCs, and other cell populations in the lung, is important for efforts to use stem cells to repair injured lung tissues, or to build lung tissue grafts.
“It’s critical to understand how different cells in the lung microenvironment regulate each other, and we really don’t know that yet,” Majka said.
By studying gene expression patterns in MPCs from normal and diseased or injured lungs, Majka and her colleagues have discovered new targets that may point to biomarkers for earlier detection of pulmonary diseases and that may guide the development of interventions that promote repair.
“With pulmonary vascular diseases, by the time a patient has symptoms, there’s already major damage to the microvasculature,” Majka said. Using new biomarkers to detect the disease before symptoms arise would allow for earlier treatment, which could be effective at decreasing progression or even reversing the disease process.
In addition, MPCs are present in many adult tissues, including skin, kidney and uterus, suggesting that the findings may improve understanding of the microvascular basis of disease pathophysiology in these tissues.
Christa Gaskill was the first author of the Journal of Clinical Investigation paper. Key collaborators included Timothy Blackwell, M.D., Jonathan Kropski, M.D., David Merryman, Ph.D., Anna Means, Ph.D. and the Pulmonary Hypertension Group at Vanderbilt University Medical Center, as well as Stijn DeLanghe from the University of Alabama at Birmingham and Dwight Klemm from the University of Colorado. The research was supported by grants from the National Institutes of Health (HL091105, HL116597, HL108800, TR000445).
Leigh MacMillan, (615) 322-4747