Rejuvenate aged adaptive immunity with bioengineered thymus organoids

摘要 衰老最突出的后果之一就是免疫功能的下降。很多时候， 老年人对新的或以前遇到的抗原没有有效的反应。这方面的例证是 70岁及以上的人对流感和其他传染性病原体的脆弱性增加。 由于他们难以接种保护性疫苗，这种情况进一步恶化。多亏了先进的 在现代医学中，发达国家的预期寿命在过去的一个世纪里大幅增加。 开发治疗方法以恢复衰老的免疫系统不仅将对 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爆炸性增长 医疗费用。 胸腺退缩是一种表现为胸腺大小和细胞数进行性退缩的情况。 这是导致年龄相关免疫功能障碍的主要原因之一。虽然已经做出了大量的努力 为了调节/恢复胸腺功能，无论是在体外还是在体内，操纵胸腺被证明是 很难。主要的挑战是重现其独特的细胞外基质微环境，这对 胸腺上皮细胞(TECs)的生存和功能，胸腺基质中的主要群体 对于T细胞发育的成功和维持胸腺的完整性都是至关重要的 微环境。在传统的二维培养中培养的TEC会迅速失去其分子特性，并无法 茁壮成长。临床前研究提案提出了一种使衰老的胸腺恢复活力的创新方法。这个 该项目将利用一种新的胸腺生物工程技术，通过这种技术，具有功能的胸腺 有机化合物可以用分离的TEC从头构建。当移植到无瘤小鼠体内时， 生物工程胸腺有机化合物可以支持多种自我耐受的T细胞群体的发展 主办方。被提议的项目的主要目标是展示生物工程 用年轻供者的TECs构建的胸腺有机化合物能有效地恢复小鼠的获得性免疫 老龄小鼠(目标1)。胸腺生物工程方法的一个可预见的障碍是TECs的稀缺。 由于出生后TEC室的快速收缩，最早发生在出生后4周 小鼠1岁，人1岁。该提案将探索使用人类胚胎干细胞的可能性 (HESCs)作为治疗学TECs的替代来源。生物工程的微环境 胸腺支架既可以提供细胞外基质支持，也可以提供信号提示，可能诱导 HESCs向TECs的分化。该提案的目标2将证明生物工程胸腺 人胚胎干细胞来源的TECs构建的有机化合物可以恢复老年人的获得性免疫系统 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。

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.