PHILADELPHIA – Researchers from the University of Pennsylvania School of Medicine found that the activation of a molecular pathway important in stem cell and developmental biology leads to an increase in lung stem cells. Harnessing this knowledge could help develop therapies for lung-tissue repair after injury or disease. The investigators published their findings online last week in advance of print publication in Nature Genetics.
“The current findings show that increased activity of the Wnt pathway leads to expansion of a type of lung stem cell called bronchioalveolar stem cells,” says senior author Edward Morrisey, Ph.D., Associate Professor of Medicine and Cell and Developmental Biology.
“This information will give us a more extensive basic understanding of Wnt signaling in adult tissue repair in the lung and other tissues and also start to help us determine whether pharmacological activation or inhibition of this pathway can be utilized for treatments,” explains Morrisey, who is also the Scientific Director of the Penn Institute for Regenerative Medicine.
Activation of the Wnt signaling pathway leads to expansion, or increase in number, of bronchioalveolar stem cells in the lung. A protein called GATA6 inhibits Wnt signaling by directly regulating the expression of another protein in the Wnt pathway called frizzled 2 (Fzd2).
Wnt signaling is a major pathway in stem cell biology. The finding that GATA6 negatively regulates Wnt signaling and that GATA6 has been shown to play important roles in embryonic stem cell replication and differentiation suggests that these two pathways are linked not only in lung stem cells but in other tissues where they play important roles including the heart, gut, and pancreas.
“We were surprised by the robust activation of Wnt signaling after loss of GATA6 expression in the lung,” says Morrisey. “Such a robust activation is rarely observed.”
Wnt signaling can be pharmacologically modulated with compounds, including lithium, already approved by the FDA. Use of such compounds, both known and newly identified through ongoing screens, could allow for forced expansion and differentiation of key stem cell populations in the lung and other tissues for adult tissue repair after injury or disease.
Future directions of the Morrisey lab include not only a more extensive basic understanding of Wnt signaling in adult-tissue repair in the lung and other tissues, but also starting to determine whether pharmacological activation or inhibition of this pathway can really be utilized for treatments.
Penn co-authors are Yuzhen Zhang, Ashley M. Goss, Ethan David Cohen, Rachel Kadzik, John J. Lepore, Karthika Muthukumaraswamy. Jifu Yang, and Michael Parmacek. This work was funded by the National Institutes of Health.
PENN Medicine is a $3.5 billion enterprise dedicated to the related missions of medical education, biomedical research, and excellence in patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System.
Penn's School of Medicine is currently ranked #4 in the nation in U.S.News & World Report's survey of top research-oriented medical schools; and, according to most recent data from the National Institutes of Health, received over $379 million in NIH research funds in the 2006 fiscal year. Supporting 1,400 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.
The University of Pennsylvania Health System includes three hospitals — its flagship hospital, the Hospital of the University of Pennsylvania, rated one of the nation’s “Honor Roll” hospitals by U.S.News & World Report; Pennsylvania Hospital, the nation's first hospital; and Penn Presbyterian Medical Center — a faculty practice plan; a primary-care provider network; two multispecialty satellite facilities; and home care and hospice.
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 Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation’s first medical school) and the University of Pennsylvania Health System, which together form a $8.9 billion enterprise.
The Perelman School of Medicine has been ranked among the top medical schools in the United States for more than 20 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $496 million awarded in the 2020 fiscal year.
The University of Pennsylvania Health System’s patient care facilities include: the Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center—which are recognized as one of the nation’s top “Honor Roll” hospitals by U.S. News & World Report—Chester County Hospital; Lancaster General Health; Penn Medicine Princeton Health; and Pennsylvania Hospital, the nation’s first hospital, founded in 1751. Additional facilities and enterprises 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 44,000 people. The organization also has alliances with top community health systems across both Southeastern Pennsylvania and Southern New Jersey, creating more options for patients no matter where they live.
Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2020, Penn Medicine provided more than $563 million to benefit our community.