A new population of stem cells that appear to be important for regenerating the airway following severe injury has been identified by researchers at the University of Iowa. The cells, known as glandular myoepithelial cells (MECs), were found to be surprisingly flexible.
Our airway is a system of branching tubes that connects the nose and mouth with the lungs and allows us to inhale air, extract the vital oxygen, and exhale the waste product carbon dioxide. A layer of epithelial cells helps protect airways from harmful materials in the air we breathe.
However, the cells that make up this first line of defense are vulnerable to damage and rely on local stem cells to repair and renew the barrier after injury. This new study, conducted in lab mice, found that glandular myoepithelial cells are able to develop into new replacement cells within their local environment, known as submucosal glands.
More surprisingly, the MECs were also shown to be “reserve” stem cells for the lining of the airway, springing into action when the surface of the airway experiences severe damage, and developing into replacement cells there, too.
Glandular Myoepithelial Cells
Study co-first author Preston Anderson, a UI undergraduate working in the lab of John Engelhardt, UI professor and DEO of anatomy and cell biology, said:
“We demonstrated that MECs can self-renew and differentiate into seven distinct cell types in the airway. No other cell type in the lung has been identified with this much stem cell plasticity."
Because humans have submucosal glands throughout the airway, unlike mice, this specialized niche for MECs may play a significant role in lung regeneration and disease.
The team further investigated the signaling mechanisms controlling the MECs regenerative ability. Focusing on a transcription factor protein called Lef-1 that they had previously shown to be important in glandular development, the researchers found that upregulation of Lef-1 enhances the ability of MECs to migrate, proliferate, and differentiate.
Moreover, overexpression of Lef-1 in MECs was sufficient to activate the cells' regenerative response even in the absence of airway injury. Lymphoid enhancer-binding factor 1 (LEF1) is a protein that in humans is encoded by the LEF1 gene. It binds to a functionally important site in the T-cell receptor-alpha (TCRA) enhancer and confers maximal enhancer activity.
Stem Cell Regeneration
This new finding suggests that manipulating Lef-1 signaling in MECs could have major implications for developing practical regenerative medicine approaches to treat airway diseases, such as asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis.
There are different types of stem cells including embryonic stem (ES) cells, which during embryonic development generate every type of cell in the human body, and adult stem cells, which are tissue-specific. There are no adult stem cells that regenerate multiple tissue types.
“We have identified a potentially important stem cell target and defined a central mechanism that engages stem cell regeneration. We hope this new knowledge accelerates the development of regenerative medicines such as gene therapies and pharmaceuticals for lung diseases,"
said Thomas Lynch, PhD, UI postdoctoral researcher and co-first author of the study.
The work was supported by the NIH.
Thomas J. Lynch, Preston J. Anderson, Pavana G. Rotti, Scott R. Tyler, Adrianne K. Crooke, Soon H. Choi, Daniel T. Montoro, Carolyn L. Silverman, Weam Shahin, Rui Zhao, Chandler W. Jensen-Cody, Andrea Adamcakova-Dodd, T. Idil Apak Evans, Weiliang Xie, Yulong Zhang, Hongmei Mou, B. Paul Herring Submucosal Gland Myoepithelial Cells Are Reserve Stem Cells That Can Regenerate Mouse Tracheal Epithelium Cell Stem Cell (2018). DOI: 10.1016/j.stem.2018.03.017
Image: confocal microscopy shows MECs (green) on the surface airway epithelium following injury. Credit: Cell Stem Cell