My laboratory has recently demonstrated engraftment from bone marrow cells of fully differentiated pneumocytes in mice and hepatocytes in mice and humans. This remarkable discovery and those of others showing a previously unexpected level of differential plasticity of stem cell, open up many new avenues of research. In order to efficiently address the critical questions in this new broad field of stem cell plasticity, I have brought together a group of experienced researchers, each of whom has clinical or scientific expertise in a different organ system. The focus for this proposal is to determine the cellular and biological mechanisms that induce the bone marrow cells to differentiate into epithelial cell, and to use stem cell plasticity as a therapeutic moiety by autologous transplantation of gene modified cells. In order to dissect the mechanisms of this phenomenon in vivo, I will first determine whether epithelial engraftment as liver, lung, and skin cells can be directed in vivo in mice and in humans by induction of tissue repair mechanisms in response to injury or disease. Identification of the cellular and biological mechanisms by which bone marrow cells differentiate into hepatocytes will require the development of in vitro systems in which bone marrow derived cells become liver cells. I will use three dimensional collagen system and organ culture to achieve this differentiation in vitro. Finally, using viral vectors to infect bone marrow stem cells, I will use an autologous/syngeneic transplantation model to obtain liver specific gene expression in vivo.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK061846-02
Application #
6525206
Study Section
Special Emphasis Panel (ZHL1-CSR-J (S4))
Program Officer
Badman, David G
Project Start
2001-09-30
Project End
2005-07-31
Budget Start
2002-08-01
Budget End
2003-07-31
Support Year
2
Fiscal Year
2002
Total Cost
$408,750
Indirect Cost
Name
Yale University
Department
Pathology
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
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
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
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; Kuwahara, Reiichiro; Krause, Diane S et al. (2008) Physiological variations of stem cell factor and stromal-derived factor-1 in murine models of liver injury and regeneration. Liver Int 28:308-18

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