RV/PA Recoupling by Bone Marrow Derived Mesenchymal Stem Cells

DESCRIPTION (provided by applicant): The pulmonary circulation is coupled with the right ventricular (RV) function in health and disease and RV failure (RVF) is the immediate cause of death in patients with idiopathic pulmonary fibrosis (IPF). However, little is known about the molecular mechanisms operative during the transition from compensatory RV hypertrophy to RV failure in response to PAH. In particular, it is not clear whether RV failure develops exclusively as a consequence of afterload effects or whether disease of the lung vasculature is required for RVF progression. To address these limitations and in response to the NHLBI RFA HL-12-021 we assembled a multidisciplinary team of researchers with expertise in the biology of IPF, lung vascular biology, heart failure, and bone marrow derived mesenchymal stem cell (MSC) biology at the University of Pittsburgh and established a collaboration with the NIH HLBI sponsored Production Assistance for Cellular therapies program at the University of Minnesota to conduct a phase I clinical trial of MSCs for patients afflicted with progressive IPF who experience severe PAH and for whom lung transplantation in not an option. MSCs exhibit anti-inflammatory capacity that we have used to ameliorate fibrotic lung injury. MSCs are capable of transferring their mitochondria to other cells and to extrude exosomes, vesicles of endocytic origin, to transfer RNAs as a mechanism of genetic exchange between cells. Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury in mice. However, MSCs have never been studied in an integrated manner in the context of impaired RV/PA coupling. We propose the Overall Hypothesis that MSCs or their products (exosomes or TSG-6) preserve RV/PA coupling and prevents RV failure via pleotropic actions on both the pulmonary circulation and an independent improvement in the mitochondrial function of the RV myocyte in the setting of fibrotic lung disease. Approach: We will utilize a multidisciplinary approach to accomplish two main goals of the study: 1) To validate the use of MSCs or their products in the prevention and treatment of fibrotic lung disease and RV failure in established integrated models of lung injury (bleomycin-induced) and RV failure independent of injury in the pulmonary circulation (PA banding; PAB) and 2) characterize the role of endogenous TSG-6 and RV mitochondrial dysfunction in human interstitial lung disease in anticipation of a proof of concept translational safety and mechanistic human study of MSC in these diseases. We propose the following Specific Aims: 1) To determine the efficacy of MSCs in preventing the RV transition from compensation to failure in animal models of PAH; 2) To determine the safety of MSCs in patients with PAH as a result of progressive IPF. Conclusion of these Aims will enhance our current knowledge of the genetics of the failing RV in animal models of PAH and in subjects afflicted by progressive ILD and for the first time we will be able to determine the mechanisms of action and the safety and potential efficacy of MSC in patients with IPF-associated PAH. PUBLIC HEALTH RELEVANCE: Idiopathic pulmonary fibrosis and pulmonary arterial hypertension are lethal diseases for which no successful treatment is available. Bone marrow derived mesenchymal stem cells (MSC) are multi-potent cells that have the capacity to ameliorate lung injury. In this application we propose the hypothesis that MSCs are capable of inducing immune regulation by releasing anti inflammatory mediators (TSG-6), endosomal vesicles called exosomes in which they shuttle micro RNAs, and transfer mitochondria to other cells. Micro RNAs are powerful regulators of the expression of genes and Mitochondria are one of the most complex organelles found in eukaryotic cells and mitochondrial dysfunction has also been implicated in aging, cancer, Parkinson's, Alzheimer's, cardiovascular, and lung diseases.