We and others have shown that bone marrow derived cells can take on the gene expression pattern and phenotype of alveolar type II pneumocytes. The mechanism(s) for this engraftment is(are) not yet known. One confirmed mechanism is fusion of marrow derived cells with mature non-hematopoietic cells under conditions of severe cellular injury. Using recipient mice whose pulmonary function is compromised due to knockout of surfactant protein C, we have confirmed the ability of bone marrow transplantation to restore type II pneumocytes that produce surfactant protein C in the lungs. In this application we propose to determine which BM subpopulations(s) become epithelial cells as well as the underlying mechanisms responsible. We will test the hypothesis that different BM subpopulations are capable of engraftment as type II pneumocytes, and that different degrees of tissue injury may promote engraftment of marrow derived epithelial cells via different mechanisms. Using the surfactant protein C knock-out model, we will compare the degree and kinetics of engraftment of type II pneumocytes from different BM subpopulations, assess the degree to which fusion is involved using Cre-lox and dual reporter mouse strains. These studies are critical for obtaining a better understanding of how BM derived cells in the adult take on the gene expression pattern of mature epithelial cells. The discoveries made could lead to novel therapeutic approaches for repair of tissues damaged by injury or disease. Project Narrative Studies to determine the mechanisms by which bone marrow derived cells engraft as functional epithelial cells in tissues after injury are important because this engraftment may represent a renewable source of stem cells that could be exploited for new cell- based therapies for tissue repair. The work proposed addresses these important issues in the setting of lung injury. This is an important phenomenon and if it could be harnessed for various clinical applications would be of potentially enormous benefit. Further, the cells could be used vehicles for gene therapy to treat pediatric lung diseases such as surfactant protein deficiency or alpha-1 anti-trypsin deficiency.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL073742-09
Application #
8286921
Study Section
Special Emphasis Panel (ZRG1-HEME-D (02))
Program Officer
Harabin, Andrea L
Project Start
2003-07-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
9
Fiscal Year
2012
Total Cost
$409,613
Indirect Cost
$162,113
Name
Yale University
Department
Pathology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Zhang, Ping-Xia; Murray, Thomas S; Villella, Valeria R et al. (2013) Reduced caveolin-1 promotes hyperinflammation due to abnormal heme oxygenase-1 localization in lipopolysaccharide-challenged macrophages with dysfunctional cystic fibrosis transmembrane conductance regulator. J Immunol 190:5196-206
Kassmer, Susannah H; Krause, Diane S (2013) Very small embryonic-like cells: biology and function of these potential endogenous pluripotent stem cells in adult tissues. Mol Reprod Dev 80:677-90
Qian, Lichuan; Krause, Diane S; Saltzman, W Mark (2012) Enhanced growth and hepatic differentiation of fetal liver epithelial cells through combinational and temporal adjustment of soluble factors. Biotechnol J 7:440-8
Kassmer, Susannah H; Bruscia, Emanuela M; Zhang, Ping-Xia et al. (2012) Nonhematopoietic cells are the primary source of bone marrow-derived lung epithelial cells. Stem Cells 30:491-9
Guo, Jian-Kan; Marlier, Arnaud; Shi, Hongmei et al. (2012) Increased tubular proliferation as an adaptive response to glomerular albuminuria. J Am Soc Nephrol 23:429-37
Bruscia, Emanuela M; Zhang, Ping-Xia; Satoh, Ayano et al. (2011) Abnormal trafficking and degradation of TLR4 underlie the elevated inflammatory response in cystic fibrosis. J Immunol 186:6990-8
Mohamadnejad, Mehdi; Sohail, Muhammad A; Watanabe, Azuma et al. (2010) Adenosine inhibits chemotaxis and induces hepatocyte-specific genes in bone marrow mesenchymal stem cells. Hepatology 51:963-73
Kassmer, Susannah H; Krause, Diane S (2010) Detection of bone marrow-derived lung epithelial cells. Exp Hematol 38:564-73
Bruscia, Emanuela M; Zhang, Ping-Xia; Ferreira, Elisa et al. (2009) Macrophages directly contribute to the exaggerated inflammatory response in cystic fibrosis transmembrane conductance regulator-/- mice. Am J Respir Cell Mol Biol 40:295-304
Swenson, E Scott; Xanthopoulos, Julie; Nottoli, Timothy et al. (2009) Chimeric mice reveal clonal development of pancreatic acini, but not islets. Biochem Biophys Res Commun 379:526-31

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