CELL BIOLOGY & IMMUNOLOGY
Stem cells A new breath of life
The discovery of distal airway stem cells opens the door to new therapies for reversing pulmonary disease
The H1N1 virus is a subtype of the influenza A virus that caused the 1918 Spanish flu and the 2009 swine flu pandemics. It has the capacity to trigger acute respiratory distress syndrome (ARDS), a condition that causes extensive damage to the human lung. However, ARDS is not fatal to all patients who contract the virus. For those who survive the syndrome, the details of how their respiratory system recovers remains elusive. Frank McKeon at the A*STAR Genome Institute of
Singapore, Wa Xian at the A*STAR Institute of Medical Biology and co-workers1
have now identified stem cells in the airway that
are responsible for lung regeneration. “In response to damage, the stem cells undergo a robust regeneration process that could patch up the human lung within a few months — or less for a mouse lung,” says McKeon. To demonstrate this, McKeon, Xian and their team infected mice with sublethal doses of H1N1 to induce the kind of lung damage similar to that of ARDS in humans. They looked for cells that were responsible for the regeneration of tissues lining the oxygen exchange surfaces of the bronchioli and alveoli, and pinpointed a transient population of stem cells expressing two key cellular markers: the transcription factor p63 and the keratin protein krt5. These stem cells — called distal airway stem cells (DASCs) — assemble into growing clumps at the site of injury (see image), where they help the lungs rebuild those cells which were damaged by the virus. These findings in mice were also validated by the research- ers in human lung cultures. The team of researchers spent nine months devising ways to reliably maintain adult stem cells in the laboratory — something that few researchers have managed to achieve in the past — and ultimately succeeded in culturing human stem cells expressing the same hallmark gene signatures as those seen in the mouse DASCs. Using a three-dimensional growth medium, the researchers
coaxed the human DASCs to form alveoli-like structures, sug- gesting that the cells could one day be used to treat ARDS and other conditions marked by extensive airway damage, includ- ing pulmonary fibrosis and chronic obstructive pulmonary disease. “We can grow the stem cells from very small biopsies and
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Clumps of distal airway stem cells (green) assemble at the site of lung injury and express alveolar marker (red)
mass-produce them in vitro,” says Xian. “And because you can culture the same adult stem cells from the same patient, you can avoid a lot of immune issues after transplantation.” McKeon and Xian believe that DASCs have great poten- tial in regenerative therapies. They now aim to unravel the regulatory mechanisms that govern DASC prolifera- tion and differentiation.
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1. Kumar, P. A. et al. Distal airway stem cells yield alveoli in vitro and during lung regeneration following H1N1 influenza infection. Cell 147, 525–538 (2011).
A*STAR RESEARCH OCTOBER 2011– MARCH 2012
© 2012 Xian-McKeon Laboratory
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