Chronic Obstructive Pulmonary Disease (Chronic Bronchitis & Emphysema) is a leading cause of morbidity & mortality in the United States. Emphysema is histologically defined as the destruction of alveolar walls without significant fibrosis. Regeneration of alveoli in the emphysematous lung should improve pulmonary function and lessen the burden of this common disease. Marrow Stromal Cells (MSCs) are pluripotent cells that can be harvested from adult bone marrow and can potentially be used in tissue repair. The currently achievable, low levels of engraftment in the lung are unlikely to result in clinically significant improvements in pulmonary function. Therefore this proposal focuses on enhancing recruitment and engraftment of MSCs to the lung. This proposal will test the hypothesis that population of """"""""stem sites"""""""" in the alveolar wall with bone marrow-derived stromal cells will allow """"""""neo-alveolarization"""""""" to occur in the emphysematous lung with restoration of alveolar morphology and function. The 1st specific aim of the project will confirm the hypothesis that homing of MSCs to the lung is increased in the elastase-induced rat model of emphysema. Administration techniques will be optimized. These interventions will be assessed by transplanting MSCs harvested from male rats into female rats previously treated with intratracheal elastase and quantitating engraftment by chimerism of the X- & Y-chromosomes. Engraftment will be confirmed by fluorescent microscopy (of EGFP-transgenic MSCs), immunohistochemistry & FACS analysis. The 2nd specific aim investigates the expression of chemokine receptors on MSCs and chemokine ligands by the injured lung.
Specific aim 3 will expand on this by exploring the effects of chemokines on MSC migration in vitro and lung recruitment in vivo by over expression of ligand through tetracycline-regulated gene therapy techniques. Finally, in Specific Aim 4 the benefits of enhancing recruitment to the lung will be defined by assessing the morphologic and functional impact of MSC transplantation. These studies will expand our understanding of the biology of MSCs & methods to improve recruitment to the lung, hopefully leading to novel therapies for emphysema.
| Siggins, Robert W; Hossain, Fokhrul; Rehman, Tayyab et al. (2014) Cigarette Smoke Alters the Hematopoietic Stem Cell Niche. Med Sci (Basel) 2:37-50 |
| Zhang, Ping; Welsh, David A; Siggins 2nd, Robert W et al. (2009) Acute alcohol intoxication inhibits the lineage- c-kit+ Sca-1+ cell response to Escherichia coli bacteremia. J Immunol 182:1568-76 |
| Zhang, Ping; Nelson, Steve; Bagby, Gregory J et al. (2008) The lineage-c-Kit+Sca-1+ cell response to Escherichia coli bacteremia in Balb/c mice. Stem Cells 26:1778-86 |
| Ricks, David M; Kutner, Robert; Zhang, Xian-Yang et al. (2008) Optimized lentiviral transduction of mouse bone marrow-derived mesenchymal stem cells. Stem Cells Dev 17:441-50 |
