Bone Marrow Cells as Precursors of Alveolar Epithelium

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DESCRIPTION (provided by applicant): During lung injury, T1 cells, which represent most of the gas-exchanging surface of the lungs are preferentially injured. In the current paradigm, injury signals T2 cells, as the stem cell of the alveolus to proliferate and to differentiate into new T1 cells. The inability of this process to sufficiently replenish T1 cells is a leading factor in the mortality and morbidity of conditions such as ARDS and broncho-pulmonary dysplasia. To date, direct therapeutic delivery of replacement cells has not been feasible because of the lack of a reproducible source of alveolar epithelial progenitors. Recent work demonstrating that bone marrow cells can give rise to cell types previously held to originate from only one of the different embryonic cell layers, however, suggests the possibility of using cultured bone marrow cells as an alternative source of alveolar epithelial cell precursors. In this regard, we found that intravenously delivered plastic adherent bone marrow cells (marked with E. Coli beta-galactosidase), engrafted as clusters of cells with the morphological and molecular characteristics of T1 cells. During engraftment, we did not detect any labeled T2 cells at early and late time points after injection and found, that expression of the T1 cell specific surface marker T1a occurs after incorporation of cells into the alveolar surface. We also found that engraftment in large airway epithelium occurred after intra-tracheal injection of marrow cells. Our objective in this proposal is to extend this preliminary data by addressing fundamental questions relating to the patterning of lung engraftment, the assumption of a T1 cell phenotype, and the capacity of marrow cells to engraft as differentiated airway epithelium. To do this, we will determine the expression of specified marrow markers and lung epithelial markers as cells home to the lung and differentiate into T1 cells. This information will be correlated with marker analyses of marrow cells prior to injection to help develop strategies to enrich for cells with engraftment potential. In addition, the basis for type 1 cell cluster formation, and the role of different phases and types of acute lung injury on the pattern of lung engraftment will be determined. Lastly, we will characterize the kinetics, and we will further identify the marrow cell type that engrafts as airway epithelium. These studies, we believe, will help provide a foundation for the application of cell-based therapies for conditions associated with extensive damage to the epithelial surfaces of the lung.