Development of HLA engineered universal vascular grafts from human iPSCs

利用人类 iPSC 开发 HLA 工程通用血管移植物

基本信息

批准号：
10685550
负责人：
Yibing Qyang
金额：
$ 41.88万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10685550
关键词：
Accidents Acute Address Adsorption Aging Aorta Arterial Injury Atherosclerosis Autologous Autologous Transplantation Biocompatible Materials Bioreactors Blood Blood Platelets Blood Vessel Prosthesis Blood Vessels Blood coagulation Bypass CD47 gene CRISPR/Cas technology Cell Differentiation process Cell Line Cells Chronic Clinic Clinical Collaborations Collagen Complement Derivation procedure Development Diabetes Mellitus Diameter Disease Eating Economics Endothelial Cells Endothelium Engineering Extracellular Matrix Female Fibrinogen Future Genes Glean Glycocalyx Goals HLA Antigens Hemodialysis Heparin Histocompatibility Antigens Class I Histologic Human Human body Immune system Immunologic Deficiency Syndromes Immunology Implant In Situ In Vitro Infection Injury Intervention Investigation Jordan Ligation Mechanics Modeling Nature Operative Surgical Procedures Patients Performance Peripheral Peripheral Blood Mononuclear Cell Persons Physiologic pulse Polyglycolic Acid Population Property Prosthesis Rattus Reproducibility Risk Rodent Model Signal Transduction Smooth Muscle Myocytes Somatic Cell Source Stenosis Surface Technology Testing Thrombosis Thrombus Tissue Engineering Transplantation Treatment Efficacy Ultrasonography Validation Vascular Diseases Vascular Graft Vascular Smooth Muscle Wait Time Whole Blood biomaterial compatibility cell type combat efficacious treatment experimental study follow-up immunogenicity immunoreactivity implantation in vitro Assay in vivo in vivo Model induced pluripotent stem cell induced pluripotent stem cell technology infection risk injured male mechanical properties nonhuman primate novel overexpression patient subsets pluripotency prevent scaffold self-renewal stem cell biology stem cells success tissue stem cells transcription activator-like effector nucleases vascular injury vascular tissue engineering virtual

项目摘要

Access to readily available small diameter (2-4 mm) vascular grafts presents an unmet need to patients following peripheral arterial injury or peripheral arterial atherosclerosis. Although prosthetic or autologous grafts could be utilized for this purpose, the potential risk of infection or thrombus formation in prosthetic grafts and the limited autologous vessel availability in a subset of patients arising from disease, prior utilization, or size mismatch to the injured vessel restricts their application. Acellular tissue engineered vascular grafts (TEVGs) derived from human induced pluripotent stem cells (hiPSCs) provide a promising alternative to autologous or synthetic grafts. These hiPSC-TEVGs can be constructed from vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) derived from hiPSCs and have previously been shown to have mechanical properties comparable to native vessels used in clinical bypass surgeries. hiPSC-TEVGs offer several advantages over other vascular grafts, notably the ability for hiPSCs to self-renew and differentiate into almost every cell type in the body allows for a replenishable source from which to derive VSMCs to reproducibly create TEVGs. Critically, hiPSC-TEVGs could be utilized to address the unmet needs of readily available small diameter vascular grafts for peripheral arterial injury or atherosclerosis through decellularization followed by endothelialization of the TEVG. Whereas acellular TEVGs could directly be implemented as larger diameter vascular grafts, small diameter grafts require an endothelium to prevent thrombosis in the vessel. This fact further increases the value of the hiPSC technology due to the successful derivation of hypoimmunogenic, “universal” ECs for this purpose. Hypoimmunogenic hiPSCs are created through modulating the expression of human leukocyte antigens (HLAs) so as to avoid destruction by the host immune system, while providing a healthy endothelium to small diameter grafts. Creation and investigation of the biomaterial and cellular interactions of mechanically robust, hypoimmunogenic, endothelialized hiPSC-TEVGs forms the basis of this proposal, and success here will increase the economic and practical impact of the product through enhancing short term storage capability and reaching an expansive patient populace. In pursuit of this, expansive validation and characterization will be done on hypoimmunogenic, universal EC differentiation to produce functionally and mechanically robust ECs for graft engineering. Decellularized, hypoimmunogenic endothelialized hiPSC-TEVGs will also be generated and biocompatibility of platelet- and whole blood-luminal surface interactions will be assessed. Further, in vivo immunocompatibility and therapeutic efficacy of universal hiPSC-TEVGs will be evaluated in a humanized rat aortic interposition graft model. Information gleaned from this proposal will demonstrate the diversity and practicality of the universal hiPSC-TEVG technology, and pave the way for future non-human primate, and ultimately clinical utilization of these grafts for patients with peripheral arterial injury or atherosclerosis.

对于以下患者来说，获得现成的小直径（2-4 毫米）血管移植物是一个未得到满足的需求外周动脉损伤或外周动脉粥样硬化虽然可以使用假体或自体移植物。用于此目的，假体移植物中感染或血栓形成的潜在风险以及有限的由于疾病、先前使用或尺寸不匹配而导致的一部分患者的自体血管可用性受损的血管限制了其应用。人类诱导多能干细胞（hiPSC）为自体或合成移植物提供了一种有前途的替代品。这些 hiPSC-TEVG 可以由血管平滑肌细胞 (VSMC) 和内皮细胞构建 (EC) 源自 hiPSC，之前已被证明具有与天然细胞相当的机械性能临床搭桥手术中使用的血管与其他血管移植物相比具有多种优势，值得注意的是，hiPSC 具有自我更新和分化为体内几乎所有细胞类型的能力，这使得重要的是，hiPSC-TEVG 可以从中获得 VSMC 以重复地创建 TEVG。用于解决外周动脉现成的小直径血管移植物的未满足需求 TEVG 脱细胞后内皮化导致损伤或动脉粥样硬化。 TEVG可以直接作为较大直径的血管移植物实施，小直径的移植物需要这一事实进一步增加了 hiPSC 技术的价值。由于为此目的成功衍生出低免疫原性的“通用”EC。 hiPSC 是通过调节人类白细胞抗原 (HLA) 的表达来产生的，以避免宿主免疫系统的破坏，同时为小直径移植物提供健康的内皮。以及机械坚固、低免疫原性的生物材料和细胞相互作用的研究，内皮化 hiPSC-TEVG 构成了该提案的基础，这里的成功将增加经济和通过增强短期存储能力并达到广泛的应用范围来发挥产品的实际影响为了实现这一目标，将对低免疫原性、通用 EC 分化，为移植工程生产功能和机械稳健的 EC。还将生成脱细胞、低免疫原性内皮化 hiPSC-TEVG，并且具有生物相容性此外，还将评估血小板和全血-管腔表面相互作用。通用 hiPSC-TEVG 的治疗效果将在人源化大鼠主动脉介入移植物中进行评估从该提案中收集的信息将证明通用性的多样性和实用性。 hiPSC-TEVG技术，为未来非人灵长类动物最终临床应用铺平道路这些移植物适用于患有外周动脉损伤或动脉粥样硬化的患者。