Asthma is a common chronic illness that affects many children and adults worldwide. A major obstacle to prevention and treatment of asthma has been its diverse etiologies and our inadequate understanding of the biological mechanisms. Recent studies have changed our understanding of asthma as a purely inflammatory disease to a disease in which both inflammatory and structural components are equally involved. Allergen caused epithelial damage in early stages allows environmental allergens access to the airway tissue and may lead to the development of airway remodeling in chronic stages. Therefore, therapies that target the repair of the damaged epithelium in early stages could prevent the pathological airway remodeling and improve asthma control. Mesenchymal stem cells (MSCs) are adult connective tissue progenitor cells with multi-lineage differentiation potential and poten paracrine immunomodulatory properties. MSCs are significantly increased in the lungs after allergen challenge and may participate in airway repair/remodeling. Transforming growth factor ?1 (TGF?1) plays an important role in the recruitment of stem/progenitor cells for tissue repair, regeneration, and remodeling in various organs. Our previous studies have provided initial evidence that MSCs and active TGF?1 signaling are increased in airway in an allergen induced asthma model. Furthermore, conditioned medium (ECM) from cockroach extract challenged epithelium induces the migration of MSCs, while TGF?1 neutralizing antibody antagonized this migration. Recent studies in vitro have shown that MSCs can differentiate into epithelial cells in the presence of TGF?1. The stage is thus set to critically evaluate the functional effect on MSCs of TGF?1signaling in asthma. HYPOTHESIS: Active TGF?1 is an allergen-activated endogenous messenger that recruits bone marrow-derived MSCs to the injured airways, which differentiate into epithelial cells to repair the damaged epithelium in early stages or into fibroblasts/myofibroblasts contributing to fibrotic airway remodeling in chronic stage of asthma.
Aim 1 proposes experiments to determine the role of active TGF?1 in the recruitment of MSCs to the lung in asthma. We will determine the role of TGF?1 in migration of MSCs using our Air-Liquid Interface (ALI)-ECM-based cell migration system. We will further examine the recruitment of endogenous nestin+MSCs to the allergen-challenged airways during different stages of asthma using Nes-GFP mice, followed by the examination of the role of TGF?1 in the recruitment of MSCs using a TGF?1 neutralizing antibody or TGF-? receptor type I (T?RI) inhibitor. [Aim 2 proposes experiments to track the lineage commitment/differentiation of MSC recruited in lungs through TGF?1 signaling during acute and chronic stages of asthma]. We have established an inducible MSC lineage tracing mouse model (nestin-CreERT2;ROSA26-EGFP) that we will use to track the lineage commitment of recruited MSCs in airway of acute and chronic allergen-induced models of asthma. This will provide novel insights into the role of TGF-?1 signaling and MSCs in allergic asthma and offer an opportunity for novel therapies.
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