UNS: Collaborative Research: Stem Cell-inspired Nanotherapeutics for Regenerative Repair of Elastic Matrix

UNS：合作研究：干细胞启发的弹性基质再生修复纳米疗法

• 批准号: 1509377
• 负责人: Raj Rao
• 金额: $ 30万
• 依托单位: Virginia Commonwealth University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2016-10-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1509377&HistoricalAwards=false
• 关键词: UNS; Collaborative; Research; Stem; Cell

PI: Ramamurthi, Anand/ Rao, Raj R Proposal Number: 1508642 / 1509377 Restoring structurally damaged soft, elastic tissues to a healthy state is difficult since adult cells are poorly capable of building new elastic fibers, which allow tissues to stretch and recoil. In this project, the investigators propose identification and characterization of factors derived from stem cells towards regenerating and repairing elastic fiber assembly and structure. Further, the studies aim to deliver factors in a sustained manner using degradable polymeric particles which are themselves chemically modified to stimulate new elastic fiber formation and prevent its breakdown. The investigators will then test the effectiveness of the particles in treating abdominal aortic aneurysms, a disorder characterized by breakdown of the structure of the major elastic blood vessel (aorta). In the future, this platform technology can be extended to treat other non-vascular elastic tissue types (e.g., lung tissue) in need of structural repair. This proposal aims to develop innovative, new approaches to enable in situ, biomimetic elastic matrix regenerative repair in soft, elastic tissues structurally compromised by proteolytic injury. The proposed approach seeks to overcome intrinsically-poor auto-regenerative repair of disrupted elastic matrix by stable adult cell types. The investigators have recently shown bone marrow mesenchymal stem cell (BM-MSC)-derived smooth muscle cells (BM-SMCs), but not undifferentiated BM-MSCs, to be significantly more elastogenic than adult vascular SMCs (healthy, diseased), and their secretions to stimulate elastic matrix regenerative repair by SMCs of a diseased, matrix assembly-impaired phenotype. As physical delivery of stem cells faces several challenges, this project proposes to design and test a stem cell-inspired, but cell-free regenerative approach to in situ ECM regenerative repair. The approach is based on sustained, local delivery of BM-SMC secretome components identified to be necessary and sufficient for pro-elastin regenerative stimulus from novel polymer nanocarriers that themselves exhibit pro-elastogenic and anti-proteolytic properties. Through experiments designed to address three specific aims, the investigators will test hypotheses that a) human BM-MSCs (hBM-MSCs) can be efficiently differentiated into SMCs (hBM-SMCs) exhibiting distinct, elastogenicity-determining phenotypic states; b) pro-elastogenic effects of hBM-SMCs on abdominal aortic aneurysm SMCs are mediated by their secreted trophic factors (secretome); c) key components of hBM-SMC secretome individually or in combination are necessary and sufficient for pro-elastogenic and anti-proteolytic effect; and d) integrating sustained delivery of key hBM-SMC secretome factor(s) with nanocarriers will augment quantity & quality of regenerative elastic matrix repair in an ECM-disrupted, 3-D tissue space. The broad research impact of this project is based on its potential that a novel nanotherapeutic approach may enable regenerative elastic matrix repair that recapitulates regenerative effects of SC secretions. Through this project, the investigators will a) develop educational modules for students at several educational levels to better understand stem cell- and tissue engineering, and b) provide unique inter-institutional collaborative training opportunities for students at Cleveland Clinic and Virginia Commonwealth University. By working through well-established summer internship and outreach programs at these institutions, the investigators will develop educational modules that will benefit high school students, undergraduate students and the general public. This proposal is co-funded by the Biomedical Engineering Program in the Chemical, Bioengineering, Environmental and Transport Systems Division, and by the Biomaterials Program in the Division of Materials Research.

PI：Ramamurthi、Anand/ Rao、Raj R 提案编号：1508642 / 1509377 将结构受损的软弹性组织恢复到健康状态很困难，因为成体细胞很难构建新的弹性纤维，从而使组织能够拉伸和回缩。在该项目中，研究人员提出鉴定和表征源自干细胞的因子，以再生和修复弹性纤维组件和结构。此外，这些研究的目的是使用可降解聚合物颗粒以持续的方式传递因子，这些颗粒本身经过化学修饰，以刺激新弹性纤维的形成并防止其分解。然后，研究人员将测试这些颗粒治疗腹主动脉瘤的有效性，腹主动脉瘤是一种以主要弹性血管（主动脉）结构破坏为特征的疾病。未来，该平台技术可以扩展到治疗需要结构修复的其他非血管弹性组织类型（例如肺组织）。该提案旨在开发创新的新方法，以在结构上因蛋白水解损伤而受损的软弹性组织中实现原位仿生弹性基质再生修复。所提出的方法旨在克服稳定的成体细胞类型对破坏的弹性基质的本质上较差的自动再生修复。研究人员最近发现，骨髓间充质干细胞 (BM-MSC) 衍生的平滑肌细胞 (BM-SMC)（而非未分化的 BM-MSC）比成人血管 SMC（健康、患病）的弹性显着增强，并且它们的分泌物可刺激患病、基质组装受损表型的 SMC 进行弹性基质再生修复。由于干细胞的物理递送面临若干挑战，该项目建议设计和测试一种受干细胞启发的无细胞再生方法，以进行原位 ECM 再生修复。该方法基于持续、局部递送 BM-SMC 分泌组成分，这些成分被认为对于新型聚合物纳米载体的促弹性蛋白再生刺激是必要和充分的，这些纳米载体本身表现出促弹性和抗蛋白水解特性。通过旨在实现三个特定目标的实验，研究人员将测试以下假设：a) 人类 BM-MSC (hBM-MSC) 可以有效分化为 SMC (hBM-SMC)，表现出不同的、决定弹性的表型状态； b) hBM-SMC 对腹主动脉瘤的促弹性作用 SMC 由其分泌的营养因子（分泌组）介导； c) hBM-SMC分泌组的关键成分单独或组合对于促弹性和抗蛋白水解作用是必要和充分的； d) 将关键 hBM-SMC 分泌因子与纳米载体的持续递送相结合，将增加 E​​CM 破坏的 3D 组织空间中再生弹性基质修复的数量和质量。该项目的广泛研究影响是基于其潜力，即一种新颖的纳米治疗方法可以实现再生弹性基质修复，从而重现 SC 分泌物的再生效应。通过这个项目，研究人员将a）为多个教育水平的学生开发教育模块，以更好地了解干细胞和组织工程，b）为克利夫兰诊所和弗吉尼亚联邦大学的学生提供独特的机构间协作培训机会。通过在这些机构开展完善的暑期实习和外展项目，研究人员将开发有利于高中生、本科生和公众的教育模块。该提案由化学、生物工程、环境和运输系统部门的生物医学工程项目以及材料研究部门的生物材料项目共同资助。