Human mesenchymal stem cell microvesicles for the treatment of acute lung injury

人间充质干细胞微泡治疗急性肺损伤

基本信息

批准号：
8661276
负责人：
Jae Woo Lee
金额：
$ 37.85万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-01 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8661276
关键词：
Actins Acute Lung Injury Acute Renal Failure with Renal Papillary Necrosis Acute respiratory failure Affect Alveolar Alveolar Macrophages Animals Anti-Inflammatory Agents Anti-inflammatory Apical Beds Biological Biology Bone Marrow CD44 gene Cell Therapy Cell membrane Cells Clinical Trials Critical Illness Data Development Edema Endothelial Cells Endothelium Endotoxins Epithelial Epithelial Cells Epithelium Escherichia coli Fibroblasts Fluid Balance Growth Growth Factor Guanosine Triphosphate Phosphohydrolases Human Human Activities In Vitro Infection Inflammation Inflammatory Inflammatory Response Injury Interferons Interleukin-1 Kidney Liquid substance Lung Malignant - descriptor Malignant Neoplasms Mediating Membrane Membrane Proteins Mesenchymal Stem Cells Messenger RNA MicroRNAs Mitochondria Modeling Mus Organelles Patients Permeability Phenotype Pre-Clinical Model Protein Biosynthesis Proteins Pulmonary Edema RNA Synthesis Inhibitors Receptor Cell Recovery of Function Reporting Research Research Personnel Resolution Role Safety Sodium Channel Stem cells Stress Fibers Surface Syndrome TNF gene Testing Therapeutic Therapeutic Effect Therapeutic Uses Tissues Translations Tubular formation Type II Epithelial Receptor Cell antimicrobial peptide apical membrane cytokine epithelial Na+ channel in vivo in vivo Model injured insight keratinocyte growth factor lung injury macrophage mortality novel novel strategies novel therapeutic intervention paracrine pre-clinical prevent receptor repaired tissue repair tumor growth

项目摘要

DESCRIPTION (provided by applicant): Acute lung injury (ALI) remains a devastating syndrome affecting more than 200,000 patients annually in the U.S. with a mortality rate approaching 40%. Currently, there are no pharmacologic therapies that reduce mortality. Consequently, further research into translational therapies is needed. Stem cell-based therapy with mesenchymal stem cells (MSC) is one attractive new approach. MSC have the capacity to secrete multiple paracrine factors that can regulate lung endothelial and epithelial permeability, decrease inflammation, enhance tissue repair, and inhibit bacterial growth. In over 150 clinical trials registered with clinicaltrials.gov using MSC as therapy, over 2000 patients have received the cells without any major complications. Despite a favorable safety profile, however, MSC have the capacity for spontaneous malignant transformation following multiple passages in vitro as well as the ability to promote tumor growth in vivo. Recently, some investigators have found that microvesicles (MV) released by human MSC are as biologically active as the stem cells in part through the transfer and expression of MV mRNA in the injured tissue bed. In this application, I propose to study the biology and test the potential therapeutic use of human bone-marrow derived MSC MV as an alternative to cellular therapy in models of ALI. The overall hypothesis is that human MSC MV are biologically active, and that their therapeutic activity is primarily mediated through transfer of mRNA from the MV to injured lung epithelium and lung endothelium. In Aim 1, the primary objective is to study the biology of MSC MV and determine which components of the MSC MV are functionally active, using inhibitors of RNA and protein synthesis and transport. I hypothesize that MSC MV require the transfer of mRNA for key paracrine soluble factors from the MV to the injured lung epithelium or endothelium using a cell membrane receptor, such as CD44, for their therapeutic effect. In Aim 2, I will test the functional activity of human MSC MV on net fluid transport in human alveolar epithelial type II cells and on lung endothelial permeability to protein in human lung microvascular endothelial cells injured by an inflammatory insult, the main pathological features of ALI. I hypothesize that MSC MV will prevent the decrease in net fluid transport in injured type II cells by restoring the apical membrane expression of the major epithelial sodium channel, ¿ENaC, and will reduce the increase in protein permeability in injured lung endothelial cells by preventing the formation of actin stress fibers. In Aim 3, I will determine if human MSC MV are biologically active in mice injured with E.coli endotoxin-induced ALI. I hypothesize that MSC MV will reduce endotoxin-induced ALI in mice by restoring lung endothelial and epithelial protein permeability, lung fluid balance and by reducing alveolar inflammation. These studies will provide novel insights into how MVs are released and the underlying mechanisms that explain why MSC MVs may be effective in tissue repair. Furthermore, the results may provide preclinical data that could facilitate development of MSC MV as a therapy for ALI.

描述（由适用提供）：急性肺损伤（ALI）仍然是一种毁灭性综合征，每年在美国影响20万多名患者，死亡率接近40％。当前，没有降低死亡率的药物疗法。因此，需要进一步研究转化疗法。间充质干细胞（MSC）基于干细胞的治疗是一种有吸引力的新方法。 MSC具有可以调节肺内皮和上皮渗透性，降低感染，增强组织修复并抑制细菌生长的多种旁分泌因子的能力。在通过临床试验注册的150次临床试验中。GOV使用MSC作为治疗，超过2000名患者没有任何重大并发症。但是，尽管有良好的安全性，但MSC在多次通过后具有赞助商自发性恶性转化的能力，并具有促进体内肿瘤生长的能力。最近，一些研究人员发现，人类MSC释放的微泡（MV）与干细胞一样活跃，部分通过受伤的组织床中MV mRNA的转移和表达。在此应用中，我建议研究生物学并测试人类骨髓衍生的MSC MV的潜在治疗用途，以替代ALI模型中的细胞疗法。总体假设是人类MSC MV具有生物活性，并且其治疗活性是通过将mRNA从MV转移到受伤的肺上皮和肺内皮的主要介导的。在AIM 1中，主要目的是研究MSC MV的生物学，并确定使用RNA和蛋白质合成和转运的抑制剂，MSC MV的哪些组成部分在功能上有效。我假设MSC MV需要使用细胞膜受体（例如CD44）将MRNA转移至关键的旁分泌固体因子从MV到受伤的肺上皮或内皮，以进行治疗作用。在AIM 2中，我将测试功能人类MSC MV对人肺泡上皮II型细胞中净流体转运的活性以及对炎症性损伤受伤的人肺微血管内皮细胞中对蛋白质的肺内皮通透性的活性，这是ALI的主要病理特征。我假设MSC MV将通过恢复主要上皮钠通道的顶膜表达损伤的II型细胞中净流体转运的降低，并将通过预防肌动蛋白压力纤维的形成，从而降低受伤的肺内皮细胞中受伤的肺内皮细胞中蛋白质渗透性的增加。在AIM 3中，我将确定人类MSC MV是否在用大肠杆菌内毒素诱导的ALI受伤的小鼠中具有生物活性。我假设MSC MV将通过恢复肺内皮和上皮蛋白渗透性，肺液平衡以及减少肺泡注射来减少内毒素诱导的小鼠诱导的ALI。这些研究将提供有关MV释放方式以及解释为什么MSC MV在组织修复中有效的基本机制的新见解。此外，结果可能会提供临床前数据，以促进MSC MVS作为ALI治疗。