Stem cell regeneration of the airway: effects of smoke
Abstracts
Initial Award Abstract |
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A large literature links both prenatal and early childhood exposures to hazardous air pollutants, such as smoke, ozone and microorganisms, to decreased lung growth and increased rates of respiratory infections, otitis media, and early childhood asthma. The nature of the developmental effect by these environmental pollutants is incompletely understood. One of the major changes is the epigenomic change which affects the gene expression level in the absence of any genetic mutation or alteration.
The present system using embryonic stem (ES) cell-derived regeneration of matured airway epithelial cell types provides a great opportunity to study the nature of the epigenomic change associated with the airway cell development. ES cells are self-renewable and pluripotent cells derived from the inner cell mass of a blastocyst-stage embryo. Our laboratory has recently developed a defined serum-free hormone-supplemented medium that can direct the mouse ES cell line, the D3 cells, to express various airway epithelial cell markers, which include CC10, a Clara cell-specific marker, muc5b and muc5ac, the goblet and submucosal gland mucous cell markers, surfactant D and C, markers of alveolar epithelial cells, and Foxj1, a marker related to ciliogenesis. Preliminary studies, using smoke products as an example of environmental agents to regulate ES cell-derived airway epithelial cell regeneration. We observed smoke to stimulate muc5ac expression, but decrease muc5b and SPD expression. These changes are most effective in the early treatment of ES cell regeneration. Late smoke exposure has no effect. These results provided an evidence of epigenetic change associated with smoke-mediated ES cell regeneration.
The central hypothesis is that smokes as well as other air pollutants have a profoundly epigenetic effect on the regeneration of airway epithelial cells from ES cells. To test this hypothesis, we propose to use smoke exposure as the epigenetic agent to render ES cell differentiation and to examine what epigenetic changes occur in ES cells in relating to their ability to regenerate different airway mucous cell types. Three specific aims are proposed: 1) To test whether or not that changes in DNA methylation pattern at the promoter and first exon regions of muc5ac and muc5b genes occur in smoke-exposed ES cells; 2) To test whether or not that changes in chromatin structure of muc5ac and muc5b genes occur in smoke-exposed ES cells; and 3) To test whether or not that changes in cell signaling genes associated with the development of airway mucous cells occur in smoke-exposed ES cells. These studies should provide the basis of epigenetic change in airway cell regeneration. The information can also be applied to other hazardous air pollutants and human ES cell-based airway cell regeneration. |
Publications
| Regulation of Airway Mucin Gene Expression. |
| Periodical: Annual Review of Physiology |
Index Medicus: |
| Authors: P. Thai, A. Loukoianov, S. Wachi, and R. Wu. |
ART |
| Yr: 2008 |
Vol: 70 |
Nbr: |
Abs: |
Pg: 405-429 |
| Regulation of Airway Mucin Gene Expression. |
| Periodical: Annual Review of Physiology |
Index Medicus: |
| Authors: P. Thai, A. Loukoianov, S. Wachi, and R. Wu. |
ART |
| Yr: 2008 |
Vol: 70 |
Nbr: |
Abs: |
Pg: 405-429 |
