CAREER: Mechanistic Investigations to Enable Rationally Designed Biomanufacturing of Mesenchymal Stem Cell Exosomes

使用患者自身细胞的疗法在治疗包括癌症在内的各种疾病方面显示出巨大的前景。可靠地制造治疗性细胞是一个重大挑战。该项目将定义设计和控制参数，以使这一点成为可能。最初的重点是生产一种基于细胞的伤口愈合疗法。如果成功，开发的技术可能会在其他威胁生命的疾病的治疗方面取得突破。一项教育计划将促进高中至研究生阶段的机会和培训。每年影响数百名学生的高中水平的进步计划将增加对研究机会的接触，并促进STEM职业道路上的留住。还将支持社区外展计划，并将整合研究成果以加强这些计划。为治疗性间充质干细胞/基质细胞(MSC)外体的生物制造方法的合理设计建立新的标准是该项目的重点。外切体具有治疗生物活性，包括血管形成。许多与基于细胞的治疗相关的治疗效果现在被归因于蛋白质、核酸和/或来自外体和由植入细胞分泌的其他细胞外小泡的脂肪转移。一般的假设是，MSC外切体的产生和治疗生物活性是由细胞培养微环境和产生MSCs的状态决定的。研究的目标是：1)研究血管生物活性的机制；2)研究细胞密度对生产的影响机制；3)开发定量预测标准，以实现外切体生产的质量控制。如果成功，这项技术将通过为伤口修复、缺血和其他疾病提供新的治疗选择来影响患者。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Therapies that use a patient's own cells show great promise in the treatment of a variety of diseases, including cancer. Manufacturing therapeutic cells reliably is a major challenge. This project will define design and control parameters to make this possible. The initial focus is on producing a cell-based therapy for wound healing. If successful, the technology that is developed could lead to breakthroughs in treatments for other life-threatening diseases. An education plan will promote opportunities and training at the high school through post-graduate levels. A progressive program at the high school level that impacts hundreds of students per year will increase exposure to research opportunities and promote retention in STEM career paths. Community outreach programs will also be supported, and research findings will be integrated to enhance these programs.Establishing new criteria for rational design of biomanufacturing approaches for therapeutic mesenchymal stem/stromal cell (MSC) exosomes is the focus of this project. Exosomes have therapeutic bioactivity, including vascularization. Many of the therapeutic effects associated with cell-based therapies are now being ascribed to protein, nucleic acid, and/or lipid transfer from exosomes and other extracellular vesicles secreted by implanted cells. The general hypothesis is that MSC exosome production and therapeutic bioactivity are defined by the cell culture microenvironment and the status of producer MSCs. The research objectives are to: 1) investigate the mechanism of vascularization bioactivity; 2) investigate the mechanism of cell density effects on production; and 3) develop quantitative predictive criteria to enable quality control of exosome production. If successful, this technology will impact patients by enabling new therapeutic options for wound repair, and ischemic and other diseases.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.