MSC-derived microvesicles in metabolic syndrome and renovascular disease

 描述（由申请人提供）：本申请响应FOA PAR-13-114，“基于干细胞的再生医学动物模型的改进”，该申请鼓励R 01申请，旨在表征动物干细胞和改进现有的，并创建新的人类疾病动物模型。该倡议的目的是促进将干细胞疗法用于再生医学，包括证明特定干细胞或其衍生物的功能及其在改进的动物模型中的有效性。代谢综合征（MetS）是一系列心血管危险因素，其诱导肾脏损伤并增加慢性肾脏疾病的风险，部分原因是使其易受缺血影响。事实上，MetS与肾血管疾病（RVD）共存与血运重建后的不良结局有关，可能是由于MetS的特征性炎症。然而，削弱其肾脏效应的工具尚未确定，部分原因是缺乏MetS的转化动物模型和临床适用的治疗工具。脂肪组织来源的间充质干细胞（MSC）具有有效的旁分泌抗炎特性，最近的研究将其归因于它们释放的细胞外微泡（EV）。然而，EV递送的功效尚未在大型动物模型中进行测试。当前提案的目标是开发和评价这种新型平台在我们最近开发的新型MetS和RVD猪模型中改善肾脏活力的能力，该模型密切模拟人类病理生理学，并允许与人类临床医学相关的转化研究和干预。该项目的假设是，与其亲本MSC相似，MSC衍生的EV在减少单侧RVD并发MetS的肾脏损伤方面是独特且有效的。我们首先将EV的mRNA和micro-RNA表达模式与其亲本MSC进行比较，然后评估其在肾内注射后的作用。为此，我们将采用我们开发和完善的尖端生理成像技术，这些技术独特地适合于研究单肾，包括计算机断层扫描和磁共振成像。此外，我们还将研究EV介导其母体MSC所赋予的益处的机制。将追求三个具体目标：具体目标1将检验MSC衍生EV显示不同的mRNA和micro-RNA表达模式的假设，其中包括富集促血管生成货物。具体目标2将检验EV将减轻MetS-RVD肾脏损伤的假设。具体目标3将检验EV通过δ样4信号传导介导其亲本MSC的旁分泌血管生成效应的假设。在拟议的研究中开发和使用的新工具提供了一个独特的机会，以评估使用创新和临床适用的干预措施和治疗平台来改变MetS/RVD的肾脏结局的可行性，这可能有助于制定RVD和MetS患者的管理策略。

 DESCRIPTION (provided by applicant): This application responds to FOA PAR-13-114, "Improvement of Animal Models for Stem Cell-Based Regenerative Medicine", which encourages R01 applications aimed at characterizing animal stem cells and improving existing, and creating new, animal models for human disease. The intent of that initiative is to facilitate the use of stem cell-based therapies for regenerative medicine, including demonstration of the functionality of specific stem cells or their derivatives and their effectiveness in improved anima models. The metabolic syndrome (MetS) is a constellation of cardiovascular risk factors, which induces kidney damage and raises the risk for chronic kidney disease, partly by rendering it vulnerable to ischemia. Indeed, MetS co- existing with renovascular disease (RVD) is linked to poorer outcomes after revascularization, possibly due to inflammation that characterizes MetS. However, tools to blunt its renal effects are yet to be identified, partly due to the lack of translational animal models of MetS and clinically applicable therapeutic tools. Adipose tissue-derived Mesenchymal stem cells (MSC) have potent paracrine anti-inflammatory properties, which recent studies have attributed to extracellular microvesicles (EV) that they release. Yet, the efficacy of EV delivery has not been tested in a large animal model. The goal of the current proposal is to develop and evaluate the capability of this novel platform to improve kidney viability in a novel swine model of MetS and RVD that we recently developed which closely mimics human pathophysiology and allows translational studies and interventions relevant to human clinical medicine. The hypothesis underlying this project is that similar to their parent MSC, MSC-derived EV is distinct and effective in decreasing damage in the kidney in MetS complicated by unilateral RVD. We will initially characterize the mRNA and micro-RNA expression pattern of EV in comparison to their parent MSC, and then assess their effects after intra-renal injection. To this end we will employ cutting-edge physiologic imaging techniques that we developed and refined, which are uniquely suited for studying the single kidney, including computed tomography and magnetic resonance imaging. Moreover, we will study the mechanism by which EVs mediate the benefits conferred by their parent MSC. Three specific aims will be pursued: Specific Aim 1 will test the hypothesis that MSC-derived EV show distinct patterns of mRNA and micro-RNA expression, which include enrichment with pro-angiogenic cargo. Specific Aim 2 will test the hypothesis that EV will attenuate injury of MetS-RVD kidneys. Specific Aim 3 will test the hypothesis that EVs mediate the paracrine angiogenic effects of their parent MSC via delta-like-4 signaling. The novel tools developed and employed in the proposed studies provide a unique opportunity to assess the feasibility of modifying renal outcomes in MetS/RVD using innovative and clinically applicable interventions and treatment platforms, which will likely contribute towards management strategies for patients with RVD & MetS.