This research is designed to test the central hypothesis that bone marrow-derived stromal stem cells engraft in the lung and differentiate to alveolar and airway epithelial and mesenchymal cells, consequently ameliorating or exacerbating the progression of fibroproliferative lung disease. Two well-characterized models of lung injury will be used: 1) Brief exposure to inhaled asbestos fibers rapidly causes injury of the bronchiolar-alveolar epithelium and a fibroproliferative lesion at the alveolar duct bifurcations. Studies were carried out in female rats that have undergone whole bone marrow transplantation from male green fluorescent protein (GFP)-transgenic syngeneic rats. The Preliminary Data shown here demonstrate that there are significantly increased numbers of GFP-positive, Y chromosome-positive bone marrow-derived cells in the asbestotic lesions compared with surrounding, uninjured tissues and with lungs from unexposed rats. Furthermore, the GFP-positive cells in the lung had both epithelial and mesenchymal phenotypes. Studies were also carried out in female rats injected intravascularly with 5 x 10[6] marrow stromal stem cells isolated from male GFP-transgenic rats. Our Preliminary Data demonstrate putative stem cells apparently attached to alveolar duct walls. Here we propose to define the subpopulations of stem cells that engraft and differentiate in injured lung and the effect they have on progression of asbestos-induced fibroproliferative lesions. 2) Denuded rat tracheae grafted into nude mice provide a milieu in which an epithelial lining can be reestablished, the characteristics of which is primarily determined by the differentiation potential of the inoculated cells. Our Preliminary Data show that purified populations of airway epithelial cells mixed with bone marrow-derived cells form a differentiated epithelium in the tracheal graft system. Furthermore the bone marrow-derived cells in the graft appear to differentiate into epithelial cells, as well as endothelial cells that participate in revascularization of the grafts. Some stem cells appear to differentiate as mesenchymal cells. This system will be ideal for testing the postulate since varying numbers of specific stem cell subpopulations in different stages of differentiation can be studied in combination with varying numbers and types of epithelial cells. There are no data available which allow us to predict whether or not the stem cells will play any role in the degree of lesion development or participate in populating the tracheo-bronchial and bronchiolar-alveolar duct walls. These studies will provide opportunities to develop therapeutic approaches through the use of adult bone marrow-derived stem cells because we know the precise anatomic and temporal distribution of the developing lesions. The stem cells will be characterized in, and we will be using the same populations of cells employed by investigators in the other projects. This will be a clear advantage for the final data analysis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL075161-03
Application #
7463756
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2007-06-01
Budget End
2008-05-31
Support Year
3
Fiscal Year
2007
Total Cost
$336,057
Indirect Cost
Name
Tulane University
Department
Type
DUNS #
053785812
City
New Orleans
State
LA
Country
United States
Zip Code
70118
Foskett, Andrea M; Bazhanov, Nikolay; Ti, Xinyu et al. (2014) Phase-directed therapy: TSG-6 targeted to early inflammation improves bleomycin-injured lungs. Am J Physiol Lung Cell Mol Physiol 306:L120-31
Krause, Ulf; Gregory, Carl A (2012) Potential of modulating Wnt signaling pathway toward the development of bone anabolic agent. Curr Mol Pharmacol 5:164-73
Prockop, Darwin J; Oh, Joo Youn (2012) Medical therapies with adult stem/progenitor cells (MSCs): a backward journey from dramatic results in vivo to the cellular and molecular explanations. J Cell Biochem 113:1460-9
Ohkouchi, Shinya; Block, Gregory J; Katsha, Ahmed M et al. (2012) Mesenchymal stromal cells protect cancer cells from ROS-induced apoptosis and enhance the Warburg effect by secreting STC1. Mol Ther 20:417-23
Danchuk, Svitlana; Ylostalo, Joni H; Hossain, Fokhrul et al. (2011) Human multipotent stromal cells attenuate lipopolysaccharide-induced acute lung injury in mice via secretion of tumor necrosis factor-?-induced protein 6. Stem Cell Res Ther 2:27
Pachón-Peña, G; Yu, G; Tucker, A et al. (2011) Stromal stem cells from adipose tissue and bone marrow of age-matched female donors display distinct immunophenotypic profiles. J Cell Physiol 226:843-51
Choi, Hosoon; Lee, Ryang Hwa; Bazhanov, Nikolay et al. (2011) Anti-inflammatory protein TSG-6 secreted by activated MSCs attenuates zymosan-induced mouse peritonitis by decreasing TLR2/NF-*B signaling in resident macrophages. Blood 118:330-8
Uccelli, Antonio; Prockop, Darwin J (2010) Why should mesenchymal stem cells (MSCs) cure autoimmune diseases? Curr Opin Immunol 22:768-74
Block, Gregory J; DiMattia, Gabriel D; Prockop, Darwin J (2010) Stanniocalcin-1 regulates extracellular ATP-induced calcium waves in human epithelial cancer cells by stimulating ATP release from bystander cells. PLoS One 5:e10237
Bartosh, Thomas J; Ylöstalo, Joni H; Mohammadipoor, Arezoo et al. (2010) Aggregation of human mesenchymal stromal cells (MSCs) into 3D spheroids enhances their antiinflammatory properties. Proc Natl Acad Sci U S A 107:13724-9

Showing the most recent 10 out of 27 publications