Immune system evasion of stem cell-derived cardiomyocytes

干细胞来源的心肌细胞的免疫系统逃避

• 批准号: 10427271
• 负责人: Jessica Garbern
• 金额: $ 1.6万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-14 至 2022-07-18
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10427271
• 关键词: Adult; Adverse effects; Allogenic; Autologous; Biocompatible Materials; Biology; Biomedical Engineering; CD47 gene; CRISPR/Cas technology; Cardiac Myocytes; Cell Line; Cell Surface Proteins; Cell Therapy; Cell Transplantation; Cell membrane; Cells; Cellular Membrane; Child; Childhood; Chronic; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Development; Eating; Engineering; Engraftment; Erythrocyte Membrane; Ethics; Excision; Exposure to; Flow Cytometry; Foundations; Genes; Goals; Graft Rejection; HLA Antigens; Heart; Heart Transplantation; Heart failure; Human; Immune; Immune Tolerance; Immune response; Immune system; Immunodeficient Mouse; Immunology; Immunosuppression; In Vitro; Infection; Infiltration; Injections; International; K-Series Research Career Programs; Lead; Macrophage Activation; Major Histocompatibility Complex; Malignant Neoplasms; Medicine; Membrane; Membrane Fusion; Membrane Proteins; Mentors; Mentorship; Methods; Modification; Molecular Biology; Mus; Myocardium; NK Cell Activation; Nanotechnology; Natural regeneration; Organ; Pathway interactions; Patients; Pharmaceutical Preparations; Physicians; Physiology; Population; Pregnancy; Proteins; RNA Interference; RNA delivery; Regenerative capacity; Research; Research Personnel; Risk; Scientist; Signal Transduction; Source; Structure; T-Cell Activation; T-Cell Proliferation; T-Lymphocyte; Tail; Technology; Testing; Tissue Engineering; Tissues; Training; Transplantation; United States; Universities; Veins; Work; cardiac regeneration; career; career development; congenital heart disorder; design; experience; experimental study; heart damage; human embryonic stem cell; humanized mouse; immune activation; immunocytochemistry; immunoregulation; in vivo; induced pluripotent stem cell; induced pluripotent stem cell derived cardiomyocytes; inherited cardiomyopathy; kidney dysfunction; macrophage; mouse model; nanoparticle; pediatric heart failure; prevent; professor; protein complex; regenerative biology; research and development; skills; small molecule; stem cell biology; stem cells; transcriptome sequencing; ventricular assist device

PROJECT SUMMARY/ABSTRACT This Mentored Clinical Scientist Research Career Development Award proposal describes a five-year research and career development training plan for Dr. Jessica Garbern to establish an independent research career in cardiac regeneration. Dr. Garbern aims to become a physician-scientist developing cellular therapies to regenerate and restore damaged cardiac tissue to treat pediatric heart failure and congenital heart disease. Dr. Garbern will be primarily mentored by Dr. Richard Lee, Professor in the Department of Stem Cell and Regenerative Biology at Harvard University, internationally recognized for his work studying heart regeneration, and co-mentored by Dr. David Mooney, Professor of Bioengineering at Harvard University, internationally recognized for his work in tissue engineering. Through the research plan, didactic experiences, and structured mentorship described in this proposal, Dr. Garbern will combine her prior background in biomaterials, molecular biology, and physiology with new skills in gene editing of induced pluripotent stem cells (iPSCs), immunology, and nanotechnology to test whether strategies to alter expression of human leukocyte antigens (HLA) will render iPSC-derived CMs hypoimmunogenic. The adult mammalian heart has a very limited ability to regenerate, and multiple strategies have been proposed to develop cell-based therapies for heart failure. To be clinically viable, such strategies must overcome barriers produced by the immune system to promote regeneration and prevent rejection of transplanted cells while avoiding the complications of chronic immunosuppression seen following heart transplant. Allogeneic CMs derived from iPSCs capable of evading the host immune system could potentially eliminate the need for immunosuppression while also be available for immediate use. Human leukocyte antigens (HLA) are cell surface proteins that allow the body to recognize foreign cells. Removal of selected HLA proteins on iPSCs that are then differentiated into CMs may prevent immune rejection of transplanted cells. In Specific Aim 1, Dr. Garbern will test the hypothesis that CMs derived from HLA-deficient iPSCs avoid T cell activation and immune rejection in vitro and in vivo. Removal of selected HLA proteins from iPSCs will be performed using CRISPR gene editing technology. Alternatively, immunomodulatory biomaterials designed to suppress the host immune response might minimize the need for immunosuppression after cell transplantation. In Specific Aim 2, Dr. Garbern will test the hypothesis that bioengineered nanoparticles capable of delivery of RNA interference to selected HLA genes will inhibit T cell activation in vitro. Through the career development activities described in this proposal, Dr. Garbern will build upon her foundations in engineering, biology and medicine to become a leader in overcoming immune barriers to transplantation of iPSC-derived CMs.

项目摘要/摘要 这份指导临床科学家研究职业发展奖的提案描述了一项为期五年的研究 和Jessica Garbern博士的职业发展培训计划，以在 心脏再生。加本博士的目标是成为一名内科科学家，开发细胞疗法 再生和修复受损的心脏组织，以治疗儿童心力衰竭和先天性心脏病。Dr。 加本将主要由干细胞系教授理查德·李博士指导 哈佛大学再生生物学，因研究心脏而获得国际认可 由哈佛大学生物工程教授大卫·穆尼博士共同指导， 他在组织工程方面的工作享誉国际。通过研究计划，教化经验， 和本提案中描述的结构化指导，Garbern博士将结合她以前的背景在 生物材料、分子生物学和生理学在诱导多能干细胞基因编辑方面的新技术 (Ipscs)、免疫学和纳米技术，以测试改变人类白细胞表达的策略 抗原(HL A)将使IPSC来源的CMS免疫原性降低。成年哺乳动物的心脏有一个非常 再生能力有限，已提出多种策略来开发基于细胞的疗法 心力衰竭。为了在临床上可行，这种策略必须克服免疫系统产生的障碍。 促进细胞再生和防止移植细胞排斥反应，同时避免慢性 心脏移植后出现免疫抑制。IPSCs来源的同种异体CMS可逃避 宿主免疫系统可以潜在地消除对免疫抑制的需要，同时也是可用的 即刻使用。人类白细胞抗原(人类白细胞抗原)是一种细胞表面蛋白，使人体能够识别 外来细胞。去除IPSCs上选定的、然后分化为CMS的HLA蛋白可能会阻止 移植细胞的免疫排斥反应。在特定的目标1中，加伯恩博士将检验CMS推导出的假设 来自人类白细胞抗原缺陷的IPSCs在体内外避免了T细胞的激活和免疫排斥反应。删除所选内容 将使用CRISPR基因编辑技术从iPSCs中提取HL A蛋白。或者， 旨在抑制宿主免疫反应的免疫调节生物材料可能会将 细胞移植后的免疫抑制。在《特定目标2》中，加伯恩博士将检验这一假设 能够对选定的人类白细胞抗原基因进行RNA干扰的生物工程纳米颗粒将抑制T细胞 体外激活。通过这份提案中描述的职业发展活动，加伯恩博士将建立 凭借她在工程、生物和医学方面的基础，成为克服免疫障碍的领导者 用于IPSC来源的CMS的移植。

项目成果

Heart regeneration: 20 years of progress and renewed optimism.

• DOI: 10.1016/j.devcel.2022.01.012
• 发表时间: 2022-02-28
• 期刊: Developmental cell
• 影响因子: 11.8
• 作者: Garbern JC;Lee RT
• 通讯作者: Lee RT

Tissue-embedded stretchable nanoelectronics reveal endothelial cell-mediated electrical maturation of human 3D cardiac microtissues.

组织包裹的可拉伸纳米电子学揭示了内皮细胞介导的人类3D心脏微动物的电气成熟。

• DOI: 10.1126/sciadv.ade8513
• 发表时间: 2023-03-10
• 期刊: SCIENCE ADVANCES
• 影响因子: 13.6
• 作者: Lin, Zuwan;Garbern, Jessica C.;Liu, Ren;Li, Qiang;Juncosa, Estela Mancheno;Elwell, Hannah L. T.;Sokol, Morgan;Aoyama, Junya;Deumer, Undine-Sophie;Hsiao, Emma;Sheng, Hao;Lee, Richard T.;Liu, Jia
• 通讯作者: Liu, Jia

Mitochondria and metabolic transitions in cardiomyocytes: lessons from development for stem cell-derived cardiomyocytes.

• DOI: 10.1186/s13287-021-02252-6
• 发表时间: 2021-03-12
• 期刊: Stem cell research & therapy
• 影响因子: 7.5
• 作者: Garbern JC;Lee RT
• 通讯作者: Lee RT