Rejuvenate aged adaptive immunity with bioengineered thymus organoids

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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.