A previously unknown type of cell regenerates mouse lung tissue killed by the flu virus, according to a new study led by UC San Francisco scientists. In addition to its possible relevance to the hundreds of thousands of annual human deaths from flu, the work points toward a potential strategy for treating other forms of acute lung injury, as well as the cellular damage seen in end-stage pulmonary fibrosis.
The World Health Organization estimates that as many as 500,000 people per year die from influenza. But surprisingly little is known about how human lungs react to severe flu infections, in part because lung tissue from humans who die from flu is difficult to obtain for research, according to UCSF’s Hal Chapman, MD, professor of medicine and senior author of the new study.
The lining of hollow organs, such as the lungs and those that make up the gastrointestinal tract, is composed of a thin layer of cells known as epithelia, as is the surface of skin. The skin and gut heal rather quickly because they constantly regenerate epithelial cells and slough them off, but the turnover of epithelial cells in the lung is very slow, Chapman said, and lung injury caused by acute infections or by chronic disease is a pressing health problem.
It has generally been believed that surviving mature epithelial cells are the first responders following injury to the epithelial lining. But in the new study, led by postdoctoral fellow Andrew Vaughan, PhD, and published in the advance online edition of Nature on Dec. 24, infection with the flu virus instead activated a tiny population of cells in the mouse lung that were distinct from any mature epithelial cells.
After activation, these cells, dubbed LNEPs (lineage-negative epithelial stem/progenitor cells), greatly expanded in number and “became remarkably mobile,” Vaughan said, rapidly migrating to sites of injury. Once there, they began to differentiate into normal epithelial cells.
Moreover, when the researchers transplanted LNEPs they had isolated from the lungs of healthy mice into the lungs of mice infected with influenza, the cells differentiated into appropriate types of epithelial cells depending on the transplant location, and they integrated appropriately into lung tissue. These experiments demonstrated that LNEPs are “multipotent” – like stem cells, they have the capacity to transform into a range of cell types.
The scientists demonstrated that the proliferation of LNEPs is driven by signals from a protein called Notch, which governs cell growth in almost all animals. During development, a period of rapid cell proliferation, Notch eventually shuts down, prompting cells to differentiate into the range of distinctive cell types that make up various tissues. In the flu-infected mice, however, Notch signaling could sometimes remain activated, which hampered the formation of normal epithelium by LNEPs.
In the transplant experiments, for example, regions of the lung with high levels of Notch signaling formed honeycomb-like cysts of a sort seen in patients with advanced idiopathic pulmonary fibrosis (IPF) and in scleroderma, an autoimmune disease of connective tissue. When the researchers examined human lung tissue from IPF and scleroderma patients containing such cysts, they observed both high levels of Notch signaling and cells that bore markers also seen in mouse LNEPs, which suggests that some features of advanced lung disease may reflect a regenerative process gone awry.
It “remains to be seen” whether it’s a workable strategy to transplant human LNEPs into injured regions of the lung to repair damage from disease or infection, Chapman said, and it will be crucial to better understand how to tamp down Notch signaling to control the process.
“Treating lung injury using LNEPs would require more than just obtaining and transplanting the cells,” he said. “You’d also have to manipulate the milieu so that you get the sort of engraftment you want, and I think that’s true of any organ in which you’re trying to regenerate tissue.”
In addition to Chapman and Vaughan, UCSF scientists involved in the research were Alexis N. Brumwell, research associate; Ying Xi, PhD, postdoctoral fellow; Jeffrey Gotts, MD, PhD, assistant professor of medicine; Kevin Tan, research associate; Victor Tan, research associate; Feng Chun Liu, research specialist; Mark Looney, MD, associate professor of medicine; Michael Matthay, MD, professor of medicine; and Jason Rock, PhD, assistant professor of anatomy. They were joined by Doug G. Brownfield, PhD, postdoctoral fellow at Stanford School of Medicine, and Barbara Treutlein, PhD, of the Max Planck Institute for Evolutionary Anthropology, in Leipzig, Germany.
The research was funded by grants from the National Institutes of Health, through a research agreement with Daiichi-Sankyo, and with support from the Nina Ireland Program for Lung Health at UCSF.
UCSF is the nation’s leading university exclusively focused on health. Now celebrating the 150th anniversary of its founding as a medical college, UCSF is dedicated to transforming health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, nursing and pharmacy; a graduate division with world-renowned programs in the biological sciences, a preeminent biomedical research enterprise and two top-tier hospitals, UCSF Medical Center and UCSF Benioff Children’s Hospital San Francisco.