RV/PA Recoupling by Bone Marrow Derived Mesenchymal Stem Cells

描述（由申请人提供）：在健康和疾病中，肺循环与右心室（RV）功能耦合，而右心室功能衰竭（RVF）是特发性肺纤维化（IPF）患者死亡的直接原因。然而，在多环芳烃反应中，从代偿性右心室肥大到右心室衰竭的转变过程中，人们对其分子机制知之甚少。特别是，目前尚不清楚RV衰竭是否完全是后负荷效应的结果，或者肺血管疾病是否是裂谷热进展所必需的。为了解决这些局限性，并响应NHLBI RFA HL-12-021，我们组建了一个多学科的研究团队，他们在IPF生物学、肺血管生物学、心力衰竭、以及匹兹堡大学的骨髓衍生间充质干细胞（MSC）生物学，并与NIH HLBI赞助的明尼苏达大学细胞治疗项目的生产援助合作，为患有严重PAH的进行性IPF患者进行MSCs的一期临床试验，这些患者无法选择肺移植。MSCs表现出抗炎能力，我们已经用它来改善纤维化肺损伤。间充质干细胞能够将其线粒体转移到其他细胞中，并挤出外泌体（内吞起源的囊泡）来转移rna，作为细胞间遗传交换的机制。骨髓间充质干细胞分泌的外泌体减轻小鼠心肌缺血再灌注损伤。然而，间充质干细胞从未在RV/PA耦合受损的背景下进行过综合研究。我们提出了一个总体假设，即MSCs或其产物（外泌体或TSG-6）在纤维化肺部疾病的情况下，通过对肺循环的多向性作用和对RV肌细胞线粒体功能的独立改善，保护RV/PA偶联并防止RV衰竭。方法：我们将利用多学科方法来实现研究的两个主要目标：1)在已建立的肺损伤（博莱霉素诱导）和独立于肺循环损伤（PA带）的RV衰竭综合模型中，验证MSCs或其产品在预防和治疗纤维化肺病和RV衰竭中的应用；PAB)和2)表征了内源性TSG-6和RV线粒体功能障碍在人间质性肺疾病中的作用，以期验证MSC在这些疾病中的概念、转化安全性和人体机制研究。我们提出以下具体目标：1)确定MSCs在PAH动物模型中阻止RV从代偿到失效的作用；2)确定MSCs用于进行性IPF导致的PAH患者的安全性。这些目标的结论将增强我们目前对PAH动物模型和进行性ILD患者中失败RV的遗传学知识，并且我们将首次能够确定MSC在ipf相关PAH患者中的作用机制、安全性和潜在疗效。

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.