Modulating Exosome Cargos and Surfaces for Precision Heart Repair

调节外泌体货物和表面以实现精密心脏修复

• 批准号: 9904177
• 负责人: Ke Cheng
• 金额: $ 38万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9904177
• 关键词: Acute myocardial infarction; Animal Model; Animals; Behavior; Cardiac; Cardiomyopathies; Cardiovascular Diseases; Cardiovascular system; Caring; Cell Death; Cell Therapy; Cell Transplantation; Cells; Development; Disease; Engineering; Ensure; Failure; Family suidae; Functional disorder; Future; Goals; Heart; Heart Diseases; Heart Injuries; Heart failure; Histology; Homing; Human; Impairment; In Vitro; Injections; Injury; Intravenous; Ischemia; Lead; MAP2K1 gene; Measures; Mediating; Medical; MicroRNAs; Modeling; Modification; Morbidity - disease rate; Morphology; Mus; Myocardial Infarction; Myocardial dysfunction; N-octanoylglucosylamine; Names; PTEN gene; Palliative Care; Patients; Peptides; Property; Proteins; Proto-Oncogene Proteins c-akt; RNA; Recovery of Function; Regenerative Medicine; Reperfusion Therapy; Risk; Signal Pathway; Societies; Standardization; Stem cell transplant; Stromal Cells; Surface; Survivors; System; Techniques; Testing; Therapeutic; Therapeutic Agents; Thoracic Surgical Procedures; Time; Transplantation; United States; Vesicle; base; cardiac regeneration; cardiac repair; cell type; clinical translation; exosome; experience; experimental study; functional loss; healing; in vivo; knock-down; loss of function; mortality; mouse model; neoplastic cell; paracrine; preservation; regenerative; repaired; stem cells; therapeutic candidate; therapeutic miRNA; transcriptome sequencing

It has been established that most of the beneficial effects of transplanted cells are indirect: injected cells secrete paracrine factors that promote endogenous heart repair. Among those secreted substances, exosomes are 30-100 nm vesicles secreted by a wide range of cell types including tumor cells and stem cells. Exosomes can transport microRNAs (miRs) that enable cells to communicate with neighboring cells to change their behavior. The essential miR cargos underlying the therapeutic potencies of exosomes have yet to be determined. In addition, unlike stem cells, exosomes do not have migratory ability therefore local injections are performed to ensure delivery. However, direction injection into the heart is not trivial, normally requiring open- chest surgery or sophisticated endomyocardial injection setups such as the NOGA mapping system. It is crucial to develop techniques to target systemically delivered exosomes to the heart injury. Our long-term goal is to create exosomes with optimized cargos and surfaces for precision cardiac repair. In our preliminary studies, we compared cultured cardiac stromal cells from normal and failing human hearts, and isolated exosomes from these cells. In vitro experiments and animal studies indicate an impaired regenerative activity of exosomes from heart failure patients. In addition, miR array revealed dysregulation of miR-21 in heart failure exosomes. Based on those preliminary results, we hypothesize that: i) there is a loss of therapeutic properties in exosomes from heart failure and such functional loss is due to alterations in repertoire miRs such as miR-21; ii) modulating such miR cargos could rescue the regenerative potential of the diseased exosomes; iii) efficient systemic delivery and injury targeting can be achieved by exosomal surface modification. Studies proposed in this proposal are highly significant since they aim to enhance our fundamental understating of mechanisms underlying exosomes' reparative function but may also pave the way for future clinical translation.

已经确定，移植细胞的大部分益处是间接的： 注射的细胞分泌旁分泌因子，促进内源性心脏修复。其中包括 分泌物，外体是由多种细胞类型分泌的30-100 nm的小泡 包括肿瘤细胞和干细胞。Exosome可以运输microRNAs(MiRs)，使其能够 细胞与相邻细胞通信以改变其行为。最基本的MIR货物 外切体的潜在治疗潜力还有待确定。此外，不同于 干细胞，外体不具有迁移能力，因此进行局部注射以 确保送货。然而，心脏的定向注射并不是微不足道的，通常需要打开- 胸部手术或复杂的心内膜心肌注射装置，如NOGA标测 系统。开发以系统递送的外体为靶点的技术至关重要。 心脏受伤。我们的长期目标是创造具有优化的货物和表面的外体 精确的心脏修复。在我们的初步研究中，我们比较了培养的心脏基质细胞 从正常和衰竭的人类心脏中分离出来，并从这些细胞中分离出外切体。离体 实验和动物研究表明外切体的再生活性受损 心力衰竭患者。此外，miR阵列显示在心力衰竭中miR-21的调节失调。 外显体。根据这些初步结果，我们假设：i)存在以下损失 心力衰竭和这种功能丧失的外体的治疗特性是由于 对miR-21等曲目miR进行更改；ii)调制此类miR货物可以挽救 疾病外切体的再生潜力；iii)有效的全身递送和损伤 靶向可通过胞外表面修饰来实现。这项建议中建议的研究 具有非常重要的意义，因为它们旨在加强我们对机制的根本低估 潜在的外切体的修复功能，但也可能为未来的临床铺平道路 翻译。