Penn researchers discover new cell type in human lung with regenerative properties

RASC-derived human ES cell (airway secretory cell) transitioning to type 2 alveolar cell over time in culture

PHILADELPHIA – A new type of cell that resides deep in human lungs and may play a key role in human lung disease has been discovered by researchers at the University of Pennsylvania’s Perelman School of Medicine.

The researchers, who today report their findings in Nature, analyzed human lung tissue to identify the new cells, which they call airway secretory cells (RASC). The cells line tiny branches of the airways, deep in the lungs, near the alveolar structures where oxygen is exchanged for carbon dioxide. Scientists have shown that RASCs have properties similar to stem cells allowing them to regenerate other cells essential for the normal functioning of the alveoli. They also found evidence that smoking and the common smoking-related disease called chronic obstructive pulmonary disease (COPD) can disrupt the regenerative functions of RASCs, suggesting that correcting this disruption could be a good way to treat COPD.

“COPD is a devastating and common disease, but we really don’t understand why or how some patients develop it. Identifying new cell types, especially new progenitor cells, that are injured in COPD could really speed up the development of new treatments,” said the study’s first author. Maria Basil, MD, Ph.D.a pulmonary medicine instructor.

COPD is typically characterized by progressive damage and loss of the alveoli, exacerbated by chronic inflammation. It is estimated to affect about 10% of people in parts of the United States and causes about 3 million deaths each year worldwide. Patients are often prescribed steroidal anti-inflammatory drugs and/or oxygen therapy, but these treatments can only slow the disease process rather than halting or reversing it. Progress in understanding COPD has been incremental in part because mice – the standard laboratory animal – have lungs that lack key features of human lungs.

In the new study, Morrisey and his team found evidence of RASC when examining gene activity signatures of lung cells taken from healthy human donors. They quickly recognized that RASCs, which do not exist in mouse lungs, are ‘secretory’ cells that reside near the alveoli and produce proteins necessary for the fluid lining of the airways.

“With studies like this, we’re starting to get a sense, at a cell biology level, of what’s really going on in this very common disease,” the lead author said. Edward Morrisey, Ph.D.professor of medicine at the Robinette Foundation, professor of cell and developmental biology and director of the Penn-CHOP Lung Biology Institute of Penn Medicine.

Observations of similarities in gene activity between RASCs and an important progenitor cell in the alveoli called AT2 cells led the team to another discovery: RASCs, in addition to their secretory function, serve as predecessors to AT2 cells, regenerating them to maintain the AT2 population and keep the alveoli healthy.

AT2 cells are known to become abnormal in COPD and other lung diseases, and researchers have found evidence that defects in RASCs may be an upstream cause of these abnormalities. In the lung tissues of people with COPD, as well as people without COPD who have a history of smoking, they observed many AT2 cells that were altered in a way that suggests defective transformation of RASC to AT2.

More research is needed, Morrisey said, but the findings point to the possibility of future COPD treatments that work by restoring the normal RASC-AT2 differentiation process, or even replenishing the normal RASC population in damaged lungs.

The research was supported by the National Institutes of Health (HL148857, HL087825, HL134745, HL132999, 5T32HL007586-35, 5R03HL135227-02, K23 HL121406, HL150226 K08, DK047967, HL152960, R35HL135816, P30DK072482, U01HL152978), the Consortium BREATH / Longfunds from the Netherlands, the Parker B. Francis Foundation and GlaxoSmithKline.

Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the University of Pennsylvania Raymond and Ruth Perelman School of Medicine (founded in 1765 as the first medical school in the country) and the University of Pennsylvania Health Systemwhich together make up a $9.9 billion business.

The Perelman School of Medicine has been ranked among the top medical schools in the United States for more than 20 years, according to US News & World Report’s survey of research-intensive medical schools. The school is consistently among the top recipients of funding from the nation’s National Institutes of Health, with $546 million awarded in fiscal year 2021.

Patient care facilities in the University of Pennsylvania Health System include: University of Pennsylvania Hospital and Penn Presbyterian Medical Center – which are recognized as one of the top “Honor Roll” hospitals in the nation by US News & World Report – Chester County Hospital; Lancaster General Health; Penn Medicine Princeton Health; and Pennsylvania Hospital, the nation’s first hospital, founded in 1751. Other facilities and businesses include Good Shepherd Penn Partners, Penn Medicine at Home, Lancaster Behavioral Health Hospital, and Princeton House Behavioral Health, among others.

Penn Medicine is powered by a talented and dedicated workforce of more than 52,000 people. The organization also has alliances with top community health systems in southeastern Pennsylvania and southern New Jersey, creating more options for patients, wherever they live.

Penn Medicine is committed to improving lives and health through a variety of community programs and activities. In fiscal year 2021, Penn Medicine provided more than $619 million to benefit our community.

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