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: 10017965
• 负责人: Stephen Tomlinson
• 金额: $ 40.58万
• 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/10017965
• 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; 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 therapeutics; 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 由于外伤、肿瘤切除或先天畸形而导致的肌肉损失对患者及其家人来说是毁灭性的 家庭。目前的治疗方案包括创造性地重新排列皮肤和肌肉瓣，以减轻 畸形。然而，这些方法通常不是最佳的，因为动员的皮瓣组织的百分比会收缩， 萎缩和/或死亡并且不能像原始组织一样发挥作用。该领域很早就设想了一种治疗方式 使用患者自身的细胞创建组织移植物，然后将其移植到患者体内以恢复健康 形式和功能。然而，不幸的是，这种新疗法还有许多障碍有待克服 计划在临床上广泛采用。一个紧迫且未被充分认识的障碍是低生存率 我们假设植入的细胞被对植入移植物的先天免疫反应杀死。一个专业 先天免疫的效应机制是补体（Cp）系统。早期 Cp 炎症的程度 事件杀死了 TEC 内的大量细胞，这仍然是组织中一个未解答的重要问题—— 工程领域。即使可以避免早期炎症导致的细胞死亡，但血管供应不足 支持。产生具有快速吻合潜力的预血管化 TEC 的技术将 显着提高细胞存活率和植入率。这两个突出事件密切相关。 在没有早期血管支持或存在早期血管支持的情况下减少早期炎症 大量的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 是那个； Cp 效应通路的调节将通过减少炎症、直接促进 TEC 的存活 细胞损伤，并促进新血管形成。在本提案中，我们阐明了一系列调查，将 导致一种通过调节早期细胞来改善细胞化植入物的植入的使能技术 炎症过程并促进新生微血管床。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方法。另外，我们最近还开发了一本小说 无支架技术生成自组织预血管化内皮成纤维细胞构建体 （规格）。这些工程结构一旦植入，就可以很快被血液灌注。使用 以已知的炎症、血管生成和吻合机制为指导，我们将系统地测试 这些创新技术在肌肉下植入物中使用特定抑制剂和基因工程小鼠 模型。通过提供可行的解决方案，预期成果将显着推动该领域向前发展 组织工程面临的主要障碍 - 快速血管化和植入细胞的存活 和纸巾。