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New stem cell identified for lung tissue regeneration

Mouse (left) and human (right) AEP cells grow into large lung organoids in culture and make multiple types of epithelial cells, including gas exchange type 1 cells (red) and surfactant-producing type 2 cells (green).Ed Morrisey lab, Perelman School of Medicine, University of Pennsylvania.

Breathing is a vital function of life. Your lungs allow your body to take in oxygen from the air and get rid of carbon dioxide, a waste gas that can be toxic.

The intake of oxygen and removal of carbon dioxide in the lung is called gas exchange. When you breathe in, air travels down your windpipe and into your lungs. After passing through your bronchial tubes, the air enters the alveoli (air sacs). Oxygen from the air passes through the very thin walls of the alveoli to the surrounding blood vessels. At the same time, carbon dioxide moves from the blood vessels into the air sacs to be exhaled.

Air sacs can be damaged from injuries, viruses, or lung disease. Damage to the air sacs can make it harder to breathe. Lung tissue is slow to regenerate. A team led by Dr. Edward E. Morrisey of the University of Pennsylvania characterized the molecular underpinnings of air sac regeneration in the lungs. The research was supported primarily by NIH’s National Heart, Lung, and Blood Institute (NHLBI). Results were published online in Nature on February 28, 2018.

The researchers compared alveoli cell activity over time in mice with lung damage from the influenza (flu) virus and healthy mice. They tracked cells that contained known markers of cells that turn into alveolar type 2 cells (AT2). AT2 cells produce the surfactant that protects alveolar type 1 (AT1) cells, which form the gas-exchange surface of the air sacs.

The team found that a month after an influenza-induced lung injury, the tracked cells rapidly expanded and produced a large increase in both AT2 and AT1 cells. The cells self-renewed and, after three months, the majority of AT2 and AT1 cells in the alveoli that had regenerated had come from the injury-induced cells, which the scientists now call alveolar epithelial progenitor (AEP) cells.

The team next characterized the gene and protein expression of the AEP cells from mouse lung. Using this information, they were able to isolate AEP cells from human lung tissue. The cells were used to grow 3D organ-like structures, called organoids, in the laboratory for further study. The researchers found molecular similarities in the cells that appear to be evolutionarily conserved between species.

“From our organoid culture system, we were able to show that AEPs are an evolutionarily conserved alveolar progenitor that represents a new target for human lung regeneration strategies,” Morrisey says.

“We are very excited at this novel finding,” says Dr. James P. Kiley, director of NHLBI’s Division of Lung Diseases. “Basic studies are fundamental stepping stones to advance our understanding of lung regeneration. Furthermore, the NHLBI support of investigators from basic to translational science helps promote collaborations that bring the field closer to regenerative strategies for both acute and chronic lung diseases."

—by Tianna Hicklin, Ph.D.