To what extent mesothelial-derived cells contribute to lung development and post-natal repair is an open and basic question for the field. The objectives of this grant are to address this fundamental issue and to assess the key role of the Wilm's tumor 1 transcription factor (WT1) in these events. Using mouse lines that carry WT1 alleles with a knock-in Cre recombinase and GFP genes, we generated preliminary data leading to 3 hypotheses that will be examined: 1) the fetal mesothelium contains progenitors for differentiated mesenchymal lung cells 2) WT1 controls the expression of key genes, such as hedgehog (Hh) pathway constituents that control mesothelial migration into the fetal lung, and 3) mesothelium-derived cells contribute to post-natal lung repair and re-growth. To summarize, we found that WT1 is selectively expressed in the lung mesothelium from E11.5 to E16 and is undetectable in the adult. We identified a similar temporal pattern of WT1 expression in the primate lung, suggesting a conserved mesothelial WT1 program across mammalian species. Lineage tracing showed that mesothelium-derived cells give rise to a substantial number of bronchial smooth muscle cells (BSM), along with other parenchymal lung cells whose identities will be established (Aim 1). We observed that WT1 expression coincides with mesothelial cell entry into the underlying lung and active Hh signaling. Mechanistically, we found that WT1 binds to the promoters of multiple Hh pathway genes in mesothelial cells, and that selective loss of mesothelial Hh signaling markedly attenuates entry into the underlying lung in association with diminished expression of EMT genes. These data point to a key role for WT1 in the fetal mesothelium, controlling pathways such as Hh signaling that are involved in migration and EMT, which will be further explored (Aim 2). Interestingly, preliminary data indicate that WT1 is reactivated during lung re-growth post-pneumonectomy whereas WT1 is not re-activated in inflammatory lung injuries, such as asthma and fibrosis. These findings suggest 2 models for how the mesothelium may contribute to lung remodeling in post-natal life. In model 1, the fetal WT1-regulated mesothelial program is re-activated. In model 2, parenchymal cells that arise from the fetal mesothelium in development contribute to repair. To what degree these models are involved in lung re- growth and remodeling in post-natal life will be further examined (Aim 3). We expect that completion of these studies will establish a firm foundation for future work in this new area of lung biology.

Public Health Relevance

The lung is surrounded by a thin layer of cells called the mesothelium. The overall goal of this proposal is to determine whether cells that originate from the mesothelium contribute to lung development and repair of the injured adult lung. A particular emphasis of the planned experiments is to understand the key signals controlling these events.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL116163-03
Application #
8854132
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Lin, Sara
Project Start
2013-08-05
Project End
2016-05-31
Budget Start
2015-06-01
Budget End
2016-05-31
Support Year
3
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Boston University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
Chen, Felicia; Shao, Fengzhi; Hinds, Anne et al. (2018) Retinoic acid signaling is essential for airway smooth muscle homeostasis. JCI Insight 3:
Barrios, Juliana; Patel, Kruti R; Aven, Linh et al. (2017) Early life allergen-induced mucus overproduction requires augmented neural stimulation of pulmonary neuroendocrine cell secretion. FASEB J 31:4117-4128
Patel, Kruti R; Bai, Yan; Trieu, Kenneth G et al. (2017) Targeting acetylcholine receptor M3 prevents the progression of airway hyperreactivity in a mouse model of childhood asthma. FASEB J 31:4335-4346
Patel, K R; Aven, L; Shao, F et al. (2016) Mast cell-derived neurotrophin 4 mediates allergen-induced airway hyperinnervation in early life. Mucosal Immunol 9:1466-1476
Bai, Yan; Krishnamoorthy, Nandini; Patel, Kruti R et al. (2016) Cryopreserved Human Precision-Cut Lung Slices as a Bioassay for Live Tissue Banking. A Viability Study of Bronchodilation with Bitter-Taste Receptor Agonists. Am J Respir Cell Mol Biol 54:656-63
Chen, Felicia; Fine, Alan (2016) Stem Cells in Lung Injury and Repair. Am J Pathol 186:2544-50
Chen, Felicia; Marquez, Hector; Kim, Youn-Kyung et al. (2014) Prenatal retinoid deficiency leads to airway hyperresponsiveness in adult mice. J Clin Invest 124:801-11
Aven, Linh; Paez-Cortez, Jesus; Achey, Rebecca et al. (2014) An NT4/TrkB-dependent increase in innervation links early-life allergen exposure to persistent airway hyperreactivity. FASEB J 28:897-907
Rosner, Sonia R; Ram-Mohan, Sumati; Paez-Cortez, Jesus R et al. (2014) Airway contractility in the precision-cut lung slice after cryopreservation. Am J Respir Cell Mol Biol 50:876-81
Dixit, Radhika; Ai, Xingbin; Fine, Alan (2013) Derivation of lung mesenchymal lineages from the fetal mesothelium requires hedgehog signaling for mesothelial cell entry. Development 140:4398-406