Lung transplantation is often the only viable therapeutic option for end-stage pulmonary disorders. Unfortunately, lung transplantation is associated with numerous serious complications including acute rejection and bronchiolitis obliterans syndrome (BOS). Studies have indicated that immune-mediated injury and loss of airway epithelial cells is critical in the pathogenesis of BOS. Targeting this biology could therefore provide a major breakthrough for developing new therapeutic strategies for preventing rejection in lung transplantation. We have identified circulating epithelial progenitor cells (CEPC) that are recruited to the injured airway and aid in repair of the epithelium. These cells express cytokeratin 5, a marker of progenitor basal epithelial cells in the airway, and traffic via the CXCR4/CXCL12 biological axis. Consistent with the importance of CEPC in airway repair, blocking the recruitment of CEPC with neutralizing antibodies to CXCL12 resulted in the phenotype of squamous metaplasia. This implies that the interaction between circulating and resident progenitor epithelial cells in the airway niche is critical for normal airway repair. We hypothesize that enhancing engraftment of recipient CEPC into donor airway epithelium after lung transplantation will improve epithelial repair, result in less allo-recognition of the donor lung and ultimately reduce BOS. The goal of this proposal is to: 1) investigate the role of resident and circulating epithelial progenitor cell populations in the development of BOS by selectively eliminating these cell populations, 2) examine the effect of enhanced mobilization of CEPC on the development of BOS and 3) use patient lung transplant blood samples to determine whether CEPC correlate with patient outcome. The proposed studies will allow us to further understanding of the role of epithelial progenitor cells in the airway and will enable the harnessing of the therapeutic potential of CEPC.

Public Health Relevance

Adult stem cells hold great promise for repair of the lungs and we have discovered adult stem cells in the blood that contribute to repair of the lungs. Lung transplants are performed for many patients with end stage lung diseases, but are associated with many complications. We hypothesize that mobilizing adult stem cells after lung transplantation will improve the repair of the injured donor lungs and reduce the complications of lung transplantation. We plan to test this hypothesis in preclinical models and in lung transplant patient samples.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL094561-05
Application #
8528692
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Lin, Sara
Project Start
2009-09-01
Project End
2014-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2013
Total Cost
$362,855
Indirect Cost
$127,235
Name
University of California Los Angeles
Department
Pediatrics
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Ooi, Aik T; Gower, Adam C; Zhang, Kelvin X et al. (2014) Molecular profiling of premalignant lesions in lung squamous cell carcinomas identifies mechanisms involved in stepwise carcinogenesis. Cancer Prev Res (Phila) 7:487-95
Paul, Manash K; Bisht, Bharti; Darmawan, Daphne O et al. (2014) Dynamic changes in intracellular ROS levels regulate airway basal stem cell homeostasis through Nrf2-dependent Notch signaling. Cell Stem Cell 15:199-214
Hegab, Ahmed E; Ha, Vi Luan; Bisht, Bharti et al. (2014) Aldehyde dehydrogenase activity enriches for proximal airway basal stem cells and promotes their proliferation. Stem Cells Dev 23:664-75