Harnessing Paracrine Mechanisms of Stem Cell-mediated Cardiac Contractile Enhancement

利用干细胞介导的心脏收缩增强的旁分泌机制

• 批准号: 9910439
• 负责人: KEVIN D COSTA
• 金额: $ 42.12万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9910439
• 关键词: 3-Dimensional; Address; Alternative Therapies; Animal Model; Bathing; Biological Models; Biology; Biomimetics; Biophysics; Bioreactors; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular system; Cell Communication; Cell Culture Techniques; Cell Line; Cell Therapy; Cell Transplantation; Cells; Clinical Trials; Collagen; Conditioned Culture Media; Coupling; Data; Environment; Evaluation; Genetic; Heart; Heart failure; Human; Human Engineering; In Vitro; Individual; Injections; Interdisciplinary Study; Lead; Mediating; Mediator of activation protein; Mesenchymal Stem Cells; Modeling; Molecular; Myocardium; National Heart, Lung, and Blood Institute; Paracrine Communication; Patients; Performance; Pluripotent Stem Cells; Process; Recovery; Research; Risk; Role; Sampling; Signal Transduction; Species Specificity; Stimulus; System; Technology; Testing; Therapeutic; Therapeutic Agents; Tissue Engineering; Tissue Model; Tissues; Treatment Efficacy; Ursidae Family; angiogenesis; cardiac tissue engineering; clinically relevant; design; exosome; experimental study; immunoregulation; implantation; improved; in vitro Model; in vivo; in vivo Model; innovation; interest; microvesicles; mouse model; novel; paracrine; repaired; scaffold; self assembly; sensor technology; stem cell therapy; stem cells; success; therapeutic evaluation

An emerging approach to treat patients with heart failure from non-ischemic cardiomyopathy (NICM) involves delivery of mesenchymal stem cells (MSCs) that can that can improve CM performance in cell culture and in animal models, and are being tested in ongoing clinical trials. The functional benefits of MSC-therapy may involve a variety of mechanisms, but it remains unclear whether transplanted cells act primarily through direct cell-cell interactions, or through indirect paracrine signaling via soluble factors or via special microvesicles called exosomes that can transfer molecular cargo. Understanding MSC-enhanced CM function could lead to improved cardiotherapeutics, but progress has been hampered by the limits of existing models systems for understanding paracrine signaling in the cardiac niche environment. Directly addressing an NHLBI topic of special interest (HL-142) on the role of exosomes as paracrine signal mediators in cardiovascular disease, this proposal aims to use 3D human engineered cardiac tissue (hECT) as a controllable biomimetic in vitro model of native human myocardium in order to identify the primary factors underlying MSC-mediated effects on cardiomyocyte contractile function. A novel multi-hECT bioreactor system with integrated force-sensing technology has generated preliminary data supporting a predominant effect of extrinsic paracrine signaling mechanisms, including bioactive secreted exosomes, that significantly exceed the benefits of direct coupling between MSCs and hCMs in human engineered cardiac tissues. The governing hypothesis is that MSC treatment causes direct enhancement of cardiomyocyte contractile function primarily through paracrine signaling mechanisms involving secreted exosomes that can be identified, isolated, deconstructed and delivered as an alternative therapy for non-ischemic heart failure. Specific Aim 1 will resolve the environmental conditions that maximize MSC paracrine enhancement of hECT contractile performance, advancing our understanding of specific biophysical stimuli that modulate cardioactive signaling processes. Aim 2 will identify the role of exosomes and their molecular cargo in MSC-mediated contractile enhancement of hECTs by evaluating the potency of hMSC exosomes and cargo on hECT contractile function (Sub-aim 2a) and determining the molecular identity of lead inotropic compounds from hMSC exosome cargo (Sub-aim 2b). Finally, Aim 3 will evaluate the therapeutic efficacy of delivered hMSC exosome-derived cardiotropic factors on recovery of contractility using in vitro (Sub-aim 3a) and in vivo (Sub-aim 3b) models of non-ischemic heart failure. By capturing the benefits of MSC therapy while circumventing the potential risks of live cell implantation, this proposal may lead to improved treatment options for patients who suffer heart failure from non-ischemic cardiomyopathy.

一种治疗非缺血性心肌病 (NICM) 心力衰竭患者的新兴方法 涉及间充质干细胞 (MSC) 的输送，可以改善细胞培养中的 CM 性能 以及动物模型，并且正在正在进行的临床试验中进行测试。间充质干细胞疗法的功能益处 可能涉及多种机制，但目前尚不清楚移植细胞是否主要通过 直接的细胞间相互作用，或通过可溶性因子或特殊的间接旁分泌信号传导 称为外泌体的微泡可以转移分子货物。了解MSC增强的CM功能 可能会改善心脏治疗，但现有模型的局限性阻碍了进展 用于理解心脏生态位环境中的旁分泌信号传导的系统。 直接讨论 NHLBI 特别感兴趣的主题 (HL-142)，即外泌体作为旁分泌信号的作用 心血管疾病的介质，该提案旨在使用 3D 人体工程心脏组织 (hECT) 作为 天然人类心肌的可控仿生体外模型，以确定主要因素 MSC 介导的对心肌细胞收缩功能的潜在影响。一种新型多hECT生物反应器 具有集成力传感技术的系统已生成支持主要数据的初步数据 外在旁分泌信号机制的影响，包括生物活性分泌的外泌体，显着 超过了人类工程心脏组织中 MSC 和 hCM 之间直接耦合的好处。 主要假设是 MSC 治疗导致心肌细胞收缩力直接增强 主要通过旁分泌信号传导机制发挥作用，涉及可识别的分泌外泌体， 分离、解构并作为非缺血性心力衰竭的替代疗法提供。具体目标 1 将解决最大化 MSC 旁分泌增强 hECT 收缩的环境条件 性能，增进我们对调节心脏活性信号传导的特定生物物理刺激的理解 流程。目标 2 将确定外泌体及其分子货物在 MSC 介导的收缩中的作用 通过评估 hMSC 外泌体和货物对 hECT 收缩功能的效力来增强 hECT （子目标 2a）并确定 hMSC 外泌体货物中铅正性肌力化合物的分子特性 （子目标 2b）。最后，目标 3 将评估递送的 hMSC 外泌体的治疗效果 使用体外（子目标 3a）和体内（子目标 3b）模型研究心肌因子对收缩力恢复的影响 非缺血性心力衰竭。通过捕捉 MSC 治疗的益处，同时规避潜在风险 活细胞植入，该提案可能会改善心力衰竭患者的治疗选择 来自非缺血性心肌病。

项目成果

Computational design of custom therapeutic cells to correct failing human cardiomyocytes.

定制治疗细胞的计算设计，以纠正衰竭的人类心肌细胞。

• DOI: 10.3389/fsysb.2023.1102467
• 发表时间: 2023
• 期刊: Frontiers in systems biology
• 作者: Tieu,Andrew;Phillips,KatherineG;Costa,KevinD;Mayourian,Joshua
• 通讯作者: Mayourian,Joshua

Cardiac Tissue Engineering Models of Inherited and Acquired Cardiomyopathies.

遗传性和获得性心肌病的心脏组织工程模型。

• DOI: 10.1007/978-1-4939-8597-5_11
• 发表时间: 2018
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Turnbull,IreneC;Mayourian,Joshua;Murphy,JackF;Stillitano,Francesca;Ceholski,DelaineK;Costa,KevinD
• 通讯作者: Costa,KevinD

In silico Cell Therapy Model Restores Failing Human Myocyte Electrophysiology and Calcium Cycling in Fibrotic Myocardium.

• DOI: 10.3389/fphys.2021.755881
• 发表时间: 2021
• 期刊: Frontiers in physiology
• 影响因子: 4
• 作者: Phillips KG;Turnbull IC;Hajjar RJ;Costa KD;Mayourian J
• 通讯作者: Mayourian J