Biomimetic Coacervate Delivery of Muscle Stem Cell to Improve Cardiac Repair

肌肉干细胞的仿生凝聚层递送以改善心脏修复

• 批准号: 8636750
• 负责人: Johnny Huard
• 金额: $ 19.43万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-15 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8636750
• 关键词: Acute myocardial infarction; Antioxidants; Area; Biology; Biomimetics; Bladder; Bladder Dysfunction; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiomyoplasty; Cell Survival; Cell Therapy; Cells; Clinical; Clinical Trials; Congestive Heart Failure; Data; Development; Engraftment; Ethics; Exhibits; Experimental Animal Model; FGF2 gene; Fibroblast Growth Factor 2; Fibrosis; Heart; Heparin; Human; Imaging technology; Implant; In Vitro; Injection of therapeutic agent; Injury; Ischemia; Knowledge; Lead; Left Ventricular Remodeling; Modality; Mus; Muscle; Muscle satellite cell; Myoblasts; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardial tissue; Myocardium; Natural regeneration; Patients; Performance; Pluripotent Stem Cells; Population; Research; Research Personnel; Residual state; Resistance; Skeletal Muscle; Skeletal Myoblasts; Source; Stem cells; Stress; System; Technology; Testing; Therapeutic; Therapeutic Agents; Tissues; Transplantation; Ultrasonography; Viral; angiogenesis; cardiac regeneration; cardiac repair; cardiogenesis; cell type; clinically relevant; combinatorial; hypertensive heart disease; improved; in vivo; injured; innovation; mouse model; new technology; novel; novel therapeutics; paracrine; polycation; public health relevance; regenerative; repaired; research study; scaffold; stem cell therapy; success; tissue repair

DESCRIPTION (provided by applicant): Cellular cardiomyoplasty (CCM), which involves the transplantation of exogenous cells into the heart, is a promising approach to repair injured myocardium and improve cardiac function. We have isolated a population of muscle-derived stem cells (MDSCs) from the skeletal muscle of mice and humans, that when compared with myoblasts, display a significantly improved capacity for cardiac regeneration in a mouse model of acute myocardial infarction (AMI). Transplanted MDSCs survive significantly better than skeletal myoblasts due to their high expression of cellular antioxidants, which confers the cells with an increased resistance to stress, and through a paracrine effect which reduces myocardial fibrosis, promotes angiogenesis, and ameliorates left ventricular (LV) remodeling. We have successfully expanded human MDSCs, to clinically relevant numbers in culture and more importantly, human MDSCs have already entered the clinical arena for the treatment of bladder dysfunction & myocardial infarction, confirming that MDSCs represent a viable therapeutic cell source for CCM. However, several limitations, such as a poor delivery approach of the cells (direct intramyocardial injection in PBS) that leads to limited cell retention and survival as well as the low cardiomyogenic potential of the MDSCs, may still limit the cardiac regenerative potential of the MDSCs (Primary focus of the application). The use of FGF2-coacervate, as a novel delivery vehicle for the MDSCs, represents a new area of research that could not only promote cell retention, survival, and the cardiac regenerative potential of the MDSCs, but also synergistically enhance angiogenesis through the release of FGF2. We have shown that coacervate loaded with FGF2 was capable of enhancing cardiac repair and regeneration through the promotion of angiogenesis and supporting the survival of residual cardiomyocytes (preliminary data). Therefore, the focus of Aim 1 of this proposal will be to combine the new FGF2-coacervate technology with MDSCs to further improve cardiac repair. We will compare this combinatorial therapy to MDSCs and FGF2- coacervate therapies separately. Moreover, we have observed that the viral transduction of MDSCs with Wnt- 11, a molecule required for cardiogenesis, enhances the cardiomyogenic differentiation of the MDSCs in vitro and cardiac repair in vivo when injected directly into injured myocardium. In a second set of experiments (Aim 2), we will determine whether the intramyocardial injection of Wnt-11 transduced MDSCs (Wnt-11 MDSCs) in combination with FGF2 coacervate, can further enhance the cardiac regenerative potential of the Wnt-11 MDSCs when compared to non-transduced MDSCs and Inducible Pluripotent Stem Cell (iPSC)- derived cardiomyocytes delivered with FGF2-coacervate. The successful completion of these aims will increase our understanding of the basic biology of muscle-derived progenitor cell populations with enhanced cardiomyogenic potential for cardiac repair and facilitate the development of new therapeutic technologies that merge the merits of stem cell therapy with biomimetic coacervate to improve cardiac repair and regeneration.

描述（由申请人提供）：细胞心肌成形术（CCM）涉及将外源细胞移植到心脏中，是修复受损心肌和改善心脏功能的一种有前景的方法。我们从小鼠和人类的骨骼肌中分离出了一群肌肉源性干细胞 (MDSC)，与成肌细胞相比，它们在急性心肌梗死 (AMI) 小鼠模型中显示出显着改善的心脏再生能力。移植的 MDSC 的存活率明显优于骨骼肌成肌细胞，因为它们高表达细胞抗氧化剂，赋予细胞增强的抗应激能力，并通过旁分泌作用减少心肌纤维化，促进血管生成，改善左心室 (LV) 重塑。我们已经成功地将人类 MDSC 扩增至临床相关培养数量，更重要的是，人类 MDSC 已经进入治疗膀胱功能障碍和心肌梗死的临床领域，证实 MDSC 代表了 CCM 的可行治疗细胞来源。然而，存在一些局限性，例如细胞输送方法不佳（直接心肌内注射 PBS），导致细胞保留和存活有限 由于 MDSC 的心肌生成潜力较低，可能仍会限制 MDSC 的心脏再生潜力（本申请的主要焦点）。 FGF2-凝聚体作为 MDSC 的新型递送载体，代表了一个新的研究领域，它不仅可以促进 MDSC 的细胞保留、存活和心脏再生潜力，还可以通过释放FGF2。我们已经证明，负载 FGF2 的凝聚层能够通过促进血管生成和支持残余心肌细胞的存活来增强心脏修复和再生（初步数据）。因此，该提案的目标1的重点是将新的FGF2凝聚技术与MDSC相结合，以进一步改善心脏修复。我们将将此组合疗法分别与 MDSC 和 FGF2 凝聚疗法进行比较。此外，我们观察到，MDSC与心脏发生所需的分子Wnt-11的病毒转导，在直接注射到受损心肌时增强了MDSC的体外心肌分化和体内心脏修复。在第二组实验（目标 2）中，我们将确定心肌内注射 Wnt-11 转导的 MDSC（Wnt-11 MDSC）与 FGF2 凝聚物组合是否可以进一步增强 Wnt-11 MDSC 的心脏再生潜力。与非转导的 MDSC 和诱导多能干细胞 (iPSC) 衍生的心肌细胞相比FGF2-凝聚层。这些目标的成功完成将增加我们对肌肉源性祖细胞群基础生物学的理解，这些细胞群具有增强心脏修复的心肌生成潜力，并促进新的治疗技术的开发，将干细胞治疗与仿生凝聚的优点相结合，以改善心脏功能。修复和再生。