Cell survival in engineered skeletal muscle: The role of complement

工程骨骼肌中的细胞存活：补体的作用

• 批准号: 10189582
• 负责人: Stephen Tomlinson
• 金额: $ 39.77万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-16 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10189582
• 关键词: Adipose tissue; Adopted; Affect; Anastomosis - action; Atrophic; Autologous; Blood; Blood Vessels; Cell Death; Cell Survival; Cells; Cicatrix; Clinic; Clinical; Complement; Complement 3a; Complement 5a; Complement Activation; Complement Inactivators; Complement Membrane Attack Complex; Congenital Abnormality; Contracts; Defect; Deformity; Emotional; Engineering; Engraftment; Event; Excision; Eye; Family; Fibroblasts; Food; Foreign Bodies; Genetically Engineered Mouse; Goals; Hemostatic function; Human; Human body; Immune; Immunologics; Implant; Indigenous; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Injury; Innate Immune Response; Investigation; Link; Mediating; Microcirculatory Bed; Modality; Modeling; Modernization; Mus; Muscle; Muscular Atrophy; Natural Immunity; Operative Surgical Procedures; Opsonin; Organ; Outcome; Pathway interactions; Patients; Peptides; Perfusion; Pharmaceutical Preparations; Play; Positioning Attribute; Process; Production; Proteins; Publishing; Regenerative capacity; Resolution; Role; Route; Site; Skeletal Muscle; Skin; Smiling; Surgical Flaps; Survival Rate; Techniques; Technology; Testing; Therapeutic; Tissue Engineering; Tissue Grafts; Tissue Survival; Tissues; Translating; Transplantation; Trauma; Treatment Protocols; Vascular Endothelium; Vascularization; Walking; activation product; angiogenesis; cell injury; clinically relevant; complement pathway; complement system; design; healing; implantation; improved; inhibitor/antagonist; injury and repair; innate immune mechanisms; innovative technologies; ischemic injury; loved ones; neovascular; new therapeutic target; novel; novel strategies; novel therapeutic intervention; pre-clinical; prototype; regenerative; repaired; satellite cell; scaffold; stem cells; stressor; tissue regeneration; tool; treatment planning; tumor; vascular tissue engineering

Abstract Muscle loss due to trauma, tumor resection or congenital malformation is devastating to the patient and their family. Current treatment regimens involve creative rearrangement of skin and muscle flaps to mitigate the deformity. However, these approaches are often sub-optimal as a percentage of mobilized flap tissues contract, atrophy and/or die and do not function like the original tissues. The field has long envisioned a treatment modality where using the patient's own cells to create tissue grafts, that can then be transplanted into a patient to restore form and function. However, unfortunately, there are numerous hurdles yet to be overcome for this new treatment plan to be broadly adopted in the clinic. One urgent and underappreciated hurdle is the poor survival rate of implanted cells which we hypothesize are killed by the innate immune response to the implanted graft. A major effector mechanism of innate immunity is the complement (Cp) system. The extent that early Cp inflammatory events kill a substantial number of cells within the TECs remains an important unanswered question in the tissue- engineering field. Even if cell death due to early inflammation can be avoided, there is insufficient vascular support. Techniques to generate pre-vascularized TECs which have rapid anastomotic potential would substantially improve cell survival and engraftment. These two highlighted events are intimately linked. Reduction of early inflammation without early vascular support or early vascular support in the presence of a substantial inflammatory response will still result in cell death and failed repair. Therefore, our central hypothesis is that; modulation of Cp effector pathways will promote survival of TEC by reducing inflammation, direct cell injury, and by promoting neovascularity. In this proposal we articulate a line of investigation that will lead to an enabling technology to improve the engraftment of cellularized implants by modulating the early inflammatory process and promoting nascent microvascular beds. Our lab has invented novel strategies and therapeutics that target the early inflammatory response. Additionally, we have recently developed a novel scaffold-free technology to generate Self-organizing Pre-vascularized Endothelial-fibroblast Constructs (SPECs). These engineered constructs can become perfused with blood very quickly once implanted. Using known mechanisms of inflammation, angiogenesis and anastomosis as our guide, we will systematically test these innovative technologies using specific inhibitors and genetically engineered mice in a sub-muscular implant model. The expected outcomes would significantly move the field forward by providing a workable solution to the principal hurdles facing tissue engineering - rapid vascularization and survival of implanted cells and tissues.

抽象的 由于创伤，肿瘤切除或先天性畸形引起的肌肉损失对患者及其 家庭。当前的治疗方案涉及皮肤和肌肉瓣的创造性重排以减轻 畸形。但是，这些方法通常是亚最佳的，因为动员皮瓣组织合同的百分比， 萎缩和/或死亡，不像原始组织那样起作用。该领域长期以来已经设想了一种治疗方式 在使用患者自己的细胞创建组织移植物的地方，可以将其移植到患者中以恢复 形式和功能。但是，不幸的是，这种新疗法尚未克服许多障碍 计划在诊所广泛采用。一个紧急和不足的障碍是生存率差 我们假设的植入细胞被对植入移植物的先天免疫反应杀死。专业 先天免疫的效应器机制是补体（CP）系统。早期CP炎症的程度 事件在TEC中杀死大量细胞仍然是组织中重要的未回答问题。 工程领域。即使可以避免因早期炎症引起的细胞死亡，血管也不足 支持。生成具有快速吻合潜力的血管前TEC的技术将 显着改善了细胞的存活和植入。这两个突出显示的事件密切相关。 在没有早期血管支持或早期血管支持的情况下减少早期炎症 大量炎症反应仍会导致细胞死亡和修复失败。因此，我们的中心假设 就是这样； CP效应途径的调节将通过减少炎症，直接促进TEC的存活 细胞损伤，并促进新生血管。在此提案中，我们阐明了一条调查，这将 导致一项使技术通过调节早期来改善细胞化植入物的植入 炎症过程并促进新生的微血管床。我们的实验室发明了新颖的策略， 针对早期炎症反应的治疗剂。此外，我们最近开发了一部小说 无脚手架的技术，以生成自组织的血管前内皮细胞构造 （规格）。一旦植入，这些工程构造就会很快被血液灌注。使用 已知的炎症，血管生成和吻合的机制作为我们的指南，我们将系统地测试 这些创新技术使用特定抑制剂和基因工程小鼠在亚肌肉植入物中 模型。预期的结果将通过提供可行的解决方案来大大推动该领域的前进 面对组织工程的主要障碍 - 植入细胞的快速血管化和存活 和组织。