| Until recently, local stem cells were thought to be the sole sources for epithelial repopulation following lung injury. However, an increasing body of data indicates a role for bone marrow derived stem cells (BMSCs) in this process. The scant literature in this area has been largely anecdotal. To date, no study has systematically analyzed the conditions necessary for the appearance of marrow derived lung epithelium (MDLE), or even confirmed that these cells are functional. Asking these questions is important because, if answered, they will yield information on how to use BMSCs as a renewable pool of pneumocyte precursors and open up new horizons of treatment for currently intractable respiratory disorders. Such a goal would include use of allogeneic marrow transplant or even genetically modified/peripherally mobilized autologous BMSCs to treat inherited or acquired diseases of the respiratory tract such as alpha-1 antitrypsin deficiency or pulmonary fibrosis.; To address these issues, this thesis details work to verify and evaluate the role that BMSCs play in lung repair. The aims herein investigate the capacity of BMSCs to adopt a functional phenotype in the alveolar epithelium. They also explore the lung conditions necessary for this change to occur, as well as the cellular mechanisms that enable the nuclear reprogramming of BMSC into MDLE. These questions are explored using transgenic mouse models, single cell analysis of pneumocytes using flow cytometry and in situ/immunohistochemical techniques, and evaluation of BMSC contributions to lung repair on a number of biochemical, molecular and functional levels. |
