We and others have shown that epithelial cells lining the airways and the alveoli can be derived from bone marrow progenitor cells. These novel results have yet to be explored from an angle that addresses a functional role for these cells and the conditions that lead to their engraftment in the lung. To define the in vivo potential of bone marrow cells that differentiate into respiratory epithelium, we have designed experiments that combine quantification of engraftment with change in phenotype. We propose to investigate a role for bone marrow derived stem cells as progenitors of functional respiratory epithelium with the goal of using the results to develop novel and effective treatments for diseases of the lung. Specifically, we propose to test whether bone marrow transplantation can transfer a normally functioning gene to congenitally abnormal lungs, whether epithelial apoptosis is necessary for the engraftment of bone marrow cells as type I and type II cells, and whether these donor derived cells can reduce the lung damage associated with increased cell death. Using recipient mice whose pulmonary function is compromised due to knockout of the surfactant C protein, we will test the ability of bone marrow transplantation to confer normal phenotype to genetically abnormal lungs. To clarify the pathophysiology of the recipient lung tissue at the time of BMSC engraftment as epithelial cells, we will assess the necessity for epithelial apoptosis in the process of bone marrow engraftment as pneumocytes, and in order to gain a more fundamental understanding of the bone marrow derived stem cells that are capable of engraftment as epithelial cells, we will determine whether induction of stem cell proliferation is necessary for engraftment as lung epithelium.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL073742-04
Application #
7090728
Study Section
Special Emphasis Panel (ZHL1-CSR-J (M2))
Program Officer
Berberich, Mary Anne
Project Start
2003-07-01
Project End
2008-05-31
Budget Start
2006-07-01
Budget End
2008-05-31
Support Year
4
Fiscal Year
2006
Total Cost
$359,231
Indirect Cost
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
Kassmer, Susannah H; Jin, Huiyan; Zhang, Ping-Xia et al. (2013) Very small embryonic-like stem cells from the murine bone marrow differentiate into epithelial cells of the lung. Stem Cells 31:2759-66
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
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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