RhoA signaling controls mesenchymal stem cell lineage commitment via Lef-1 in asthma

Johns Hopkins University, Baltimore MD

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Abstract

ABSTRACT Asthma is a serious chronic illness, and a growing clinical and public health concern. A major obstacle to the prevention and treatment of asthma has been its diverse etiologies and our inadequate understanding of the biological mechanisms. Our long-term goals are to elucidate the fundamental underlying mechanisms and identify novel therapeutic targets for asthma. Recent studies suggest that allergen caused epithelial damage allows environmental allergens access to the airway tissue and may lead to the development of airway remodeling. Numerous studies have suggested that mesenchymal stem cells (MSCs), multipotent stem cells, can migrate to injured sites and differentiate into epithelial cells or fibroblasts/myofibroblasts that may contribute to airway repair/remodeling. However, these studies were performed either in cultured MSCs or transferred exogenous MSCs in mouse model of lung injury, and the primary endogenous factors that control MSC differentiation remain unclear. In this proposal, we aim to directly track the lineage commitment/differentiation of MSCs in mouse model of asthma over time using MSC lineage tracing mouse model and elucidate the underlying mechanisms. During the pilot stage, our group has made significant contributions to uncovering an important link between MSCs and asthma. We observed increased MSCs in the airways of asthma mouse model and demonstrated that active TGF?1 is essential for the recruitment of MSCs to the damaged airways. However, a major breakthrough came with our recent finding that TGF?1-activated RhoA functions as a molecular switch for the fate of MSCs during arterial repair/remodeling. This finding raises the possibility that RhoA signaling may also be critical in determining the lineage fate of MSCs for airway repair/remodeling. Indeed, we have utilized MSC lineage tracing model to track the RhoA-mediated MSC differentiation and found that inhibition of RhoA signaling suppressed MSC differentiation into myofibroblasts, but promoted MSC differentiation into epithelial cells in our mouse model. Furthermore, we identified the Wnt signaling lymphoid enhancer-binding factor 1 (Lef1) as the most up-regulated gene of RhoA-activation in MSCs. Intriguingly, knockdown of Lef1 induced MSC differentiation away from fibroblasts/myofibroblasts but towards airway epithelial cells. These exciting new data led us to test the hypothesis that RhoA signaling controls MSC lineage commitment/differentiation during airway repair/remodeling in asthma through Lef1. Three independent yet related specific aims are proposed. Aim 1 proposes experiments to define the role of RhoA signaling pathway in the lineage commitment/differentiation of MSCs in asthma mouse model over time using an established tamoxifen inducible MSC lineage tracing mouse model. Aim 2 will elucidate the molecular mechanisms underlying the RhoA signaling regulated lineage commitment/differentiation of MSCs. Aim 3 proposes studies to determine the role of RhoA-activated Lef1 in the lineage commitment/differentiation of MSCs. Collectively, these studies are significant in understanding of how environmental allergen-induced asthma occurs and in the development of new therapeutic targets for asthma.