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

• 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
• 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

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.

访问随时可用的小直径（2-4毫米）血管移植物表现出对随后的患者的需求 周围动脉损伤或周围动脉动脉粥样硬化。尽管假肢或自体移植可能是 用于此目的，假肢移植物中感染或血栓形成的潜在风险和有限 由疾病，先前利用或大小不匹配引起的一部分患者的自体血管可用性 受伤的船只限制了其应用。细胞组织工程的血管移植物（TEVG） 人类诱导的多能干细胞（HIPSC）为自体或合成移植物提供了有希望的替代方法。 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，以前已证明具有与天然相当的机械性能 临床旁路手术中使用的血管。 HIPSC-TEVGS比其他血管移植物具有多个优点， 值得注意的是，HIPSC自我更新和分化为体内的每种细胞类型的能力都可以 可复制的来源从中得出VSMC来可重复创建TEVG。至关重要的是，hipsc-tevgs可以 可用于满足周围动脉的容易获得的小直径血管移植的需求 通过脱细胞化损伤或动脉粥样硬化，然后进行TEVG内皮化。而acelular TEVG可以直接实施，因为较大直径的血管移植物，小直径移植需要 内皮以防止血栓形成血栓形成。这一事实进一步增加了HIPSC技术的价值 由于成功地推导了为此目的的“通用” EC。低免疫原性 HIPSC是通过调节人白细胞抗原（HLA）的表达而创建的，以避免 宿主免疫系统破坏，同时为小直径移植物提供健康的内皮。创建 并研究机械鲁棒性，低免疫原性的生物材料和细胞相互作用 内皮化HIPSC-TEVGS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扩张性，产品对产品的实际影响 病人的民众。为了追求这一点，将对低肿瘤生成的广泛验证和表征进行 通用EC差异化以在功能和机械上为移植工程生产强大的EC。 还将产生脱细胞的，低免疫原性的内皮化hipsc-tevgs，并生物相容性的生物相容性 将评估血小板和全血表面相互作用。此外，体内免疫相容性和 通用HIPSC-TEVG的治疗效率将在人源化的大鼠主动脉介入移植物中进行评估 模型。从该提案中收集的信息将证明普遍的多样性和实用性 HIPSC-TEVG技术，为未来的非人类灵长类动物铺平了道路，并最终临床利用 这些移植物适用于周围动脉损伤或动脉粥样硬化的患者。