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 UCSFs 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 its 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. Youd also    have to manipulate the milieu so that you get the sort of    engraftment you want, and I think thats true of any organ in    which youre trying to regenerate tissue.  
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New Type of Cell Found to Repair Lung Injury in Mice