Researchers at Boston University have discovered a set of signals that control the generation of mucus-secreting goblet cells in the major air passages of the lung that are often found in inflated numbers in lung diseases such as asthma, COPD (Chronic obstructive pulmonary disease), cystic fibrosis, and chronic bronchitis.
“By altering the proteins that control these signals we are able to either increase or decrease the production of goblet cells which offers potential new avenues for therapeutically targeting goblet cells in lung disease,” says Bob (Xaralabos) Varelas, PhD, associate professor of biochemistry at Boston University School of Medicine.
Varelas is senior author on the research article, “Yap/Taz inhibit goblet cell fate to maintain lung epithelial homeostasis” in the journal Cell Reports, that reports these novel findings. The work is financially supported by the Boston University, the National Institutes of Health, an ACS Research Scholar Grant, Find the Cause Breast Cancer Foundation, Moorman-Simon Fellowships and Janssen Pharmaceuticals.
Healthy lungs regulate the production of specialized epithelial cells (cells that line internal and external surfaces of the body) to maintain physiological equilibrium. Mucus secreted by the specialized epithelial cell called the goblet cell helps protect the lining of the bronchi (major air passages of the lung) by trapping microorganisms and dust particles. Signals that mediate the maintenance of this fine balance of goblet cell production had not been known until now.
The team of researcher led by Varelas use an experimental mouse model carrying a genetic deletion mutation in the lung epithelium of the genes Yap and Taz. These encode regulatory proteins that control the transcription of important components of signaling networks in the lung. The authors compare mutant and normal mice and observe that Yap/Taz mutant mice suffer severe lung damage, including disorganization of vascular alveolar sacs in the lungs and increased numbers of goblet cells that result in increased mucin production.
The investigators next probed into how the loss of the Yap and Taz genes increase goblet cell numbers. To answer this question, the researchers isolate cells from the mutant mouse and human lungs and culture them in the dish. Through lineage tracing experiments, gene expression studies and chromatin binding analyses they discover these proteins control a network of genes important for mucus production.
Their molecular studies reveal YAP and TAZ act cooperatively with TEA domain transcription factors (TEAD) and the NuRD complex to restrict the fate programming of the goblet cell lineage by directly repressing a gene called SPDEF which encodes a transcription factor necessary for the maturation of progenitor cells into airway goblet cells.
To identify therapeutic options, the researchers then use the mutant cells from the lung to test inhibitors that restrict goblet cell differentiation and mucus production.
“By identifying new regulators of goblet cell production, we offer insight into mechanisms that may contribute to these diseases. By targeting these signals, we can repress the production and maintenance of goblet cells and therefore may offer therapeutic directions for limiting the expansion of these cells in lung disease,” says Varelas.