Rejuvenate aged adaptive immunity with bioengineered thymus organoids

用生物工程胸腺类器官恢复衰老的适应性免疫力

• 批准号: 9307727
• 负责人: YONG FAN
• 金额: $ 18.95万
• 依托单位: ALLEGHENY-SINGER RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9307727
• 关键词: 3-Dimensional; Adaptive Immune System; Age; Age-Years; Aging; Allogenic; Antigens; Architecture; Atrophic; Autoimmune Diseases; Biomedical Engineering; Birth; Cell Compartmentation; Cell Differentiation process; Cells; Cellularity; Chronic Disease; Complement; Cues; Cultured Cells; Data; Defect; Developed Countries; Developing Countries; Development; Elderly; Embryo; Environmental Risk Factor; Epithelial; Epithelium; Explosion; Extracellular Matrix; Fibroblasts; Generations; Goals; Healthcare; Homing; Human; Immune; Immune System Diseases; Immune System and Related Disorders; Immune response; Immune system; Immunization; In Vitro; Individual; Infection; Influenza; Laboratories; Life Expectancy; Lymphocyte; Malignant Neoplasms; Medical; Modern Medicine; Molecular; Mus; Natural regeneration; Nude Mice; Organ; Organoids; Output; Peripheral; Pharmacotherapy; Phenotype; Population; Predisposition; Property; Protocols documentation; Publishing; Quality of life; Refractory; Regenerative Medicine; Rejuvenation; Research Project Grants; Research Proposals; Signal Transduction; Skin graft; Source; Stem cells; T memory cell; T-Cell Development; T-Lymphocyte; Techniques; Technology; Therapeutic; Thymic epithelial cell; Thymus Gland; Tissues; Translating; Transplantation; Vaccination; adaptive immune response; adaptive immunity; age related; aged; aging population; base; cost; cytokine; embryonic stem cell; human embryonic stem cell; immune function; immunosenescence; improved; in vivo; innovation; irradiation; next generation sequencing; novel; pathogen; postnatal; pre-clinical research; progenitor; response; scaffold; skin allograft; stem cell differentiation; success; transdifferentiation; young adult

ABSTRACT One of the most prominent consequences of aging is the decline of immune function. Quite often, elderly individuals do not respond efficiently to novel or previously encountered antigens. This is exemplified by increased vulnerability of individuals 70 years of age and older to influenza and other infectious pathogens. The situation is exacerbated further by their refractory to protective vaccination. Thanks to the advances of modern medicine, life expectancy in developed countries has increased dramatically in the past century. Developing therapeutics to rejuvenate aged immune system will not only have tremendous impact on the quality of living of the fast growing aged population, but also help to stop the explosion of the age-related medical cost. Thymus involution, a condition manifested as progressive regression in thymic size and cellularity, is the one of the leading causes for age-associated immune dysfunction. While numerous efforts have been made to modulate/rejuvenate thymic function, manipulating the thymus, either in vitro or in vivo, proves to be difficult. The major challenge is to reproduce its unique extracellular matrix microenvironment that is critical for the survival and function of thymic epithelial cells (TECs), the predominant population within thymic stroma that are critical for both the success of T-cell development and maintaining the integrity of the thymus microenvironment. TECs cultured in traditional 2-D culture rapidly lose their molecular properties and fail to thrive. The preclinical research proposal proposes an innovative approach to rejuvenate the aged thymus. The project will take advantage of a novel thymus bioengineering technique, with which functional thymus organoids can be constructed de novo with isolated TECs. When transplanted into athymic mice, the bioengineered thymus organoids can support the development of a diverse, self-tolerant T-cell population in the hosts. The primary goal of the proposed project is to demonstrate the proof-of-concept that bioengineered thymus organoids constructed with TECs of younger donors can effectively rejuvenate adaptive immunity in aged mice (Aim 1). One foreseeable obstacle of the thymus bioengineering approach is the scarcity of TECs due to the rapid contraction of the postnatal TEC compartment, which occurs as early as 4-weeks after birth in mouse and 1 year in human. The proposal will explore the possibility of using human embryonic stem cells (hESCs) as an alternative source of TECs for therapeutics. The microenvironment of the bioengineered thymus scaffolds can provide both the extracellular matrix support and the signaling cues that might induce the differentiation of hESCs to TECs. Aim 2 of the proposal will demonstrate that the bioengineered thymus organoids constructed from TECs derived from hESCs can rejuvenate the adaptive immune system in aged mice. The long-term goal of the research project is to translate the thymus bioengineering technique to rejuvenate adaptive immunity in elders and to treat age-related immune dysfunction.

抽象的 衰老最显着的后果之一是免疫功能下降。很多时候， 老年人对新的或以前遇到的抗原不能有效地做出反应。举例来说 70 岁及以上的人更容易感染流感和其他传染性病原体。 由于他们难以接受保护性疫苗接种，这种情况进一​​步恶化。感谢以下人士的进步 现代医学显示，发达国家的预期寿命在过去的一个世纪里急剧增加。 开发使衰老的免疫系统恢复活力的疗法不仅会对 快速增长的老年人口的生活质量，也有助于阻止与年龄相关的人口爆炸 医疗费用。 胸腺退化是一种表现为胸腺大小和细胞结构逐渐退化的病症， 与年龄相关的免疫功能障碍的主要原因之一。尽管经过无数努力 旨在调节/恢复胸腺功能，在体外或体内操纵胸腺被证明是 难的。主要挑战是重现其独特的细胞外基质微环境，这对于 胸腺上皮细胞 (TEC) 的存活和功能，胸腺基质内的主要细胞群 对于 T 细胞发育的成功和维持胸腺的完整性至关重要 微环境。在传统二维培养中培养的 TEC 会迅速失去其分子特性，并且无法 蓬勃发展。临床前研究提案提出了一种使衰老胸腺恢复活力的创新方法。这 该项目将利用一种新颖的胸腺生物工程技术，利用该技术，功能性胸腺 可以用分离的 TEC 从头构建类器官。当移植到无胸腺小鼠体内时， 生物工程胸腺类器官可以支持多种、自我耐受的 T 细胞群的发育 主持人。拟议项目的主要目标是展示生物工程的概念验证 用年轻捐赠者的 TEC 构建的胸腺类器官可以有效恢复适应性免疫 老年小鼠（目标 1）。胸腺生物工程方法的一个可预见的障碍是 TEC 的稀缺 由于产后 TEC 室的快速收缩，最早在出生后 4 周就发生 小鼠和人类 1 年。该提案将探讨使用人类胚胎干细胞的可能性 （hESC）作为治疗用 TEC 的替代来源。生物工程的微环境 胸腺支架可以提供细胞外基质支持和可能诱导 hESC 向 TEC 的分化。该提案的目标 2 将证明生物工程胸腺 由 hESC 衍生的 TEC 构建的类器官可以恢复老年人的适应性免疫系统 老鼠。该研究项目的长期目标是将胸腺生物工程技术转化为 恢复老年人的适应性免疫并治疗与年龄相关的免疫功能障碍。