ISS: Tissue Engineered Liver Immune Chips in Microgravity as a Novel Platform to Study the Effect of Aging

University Of California-San Francisco, San Francisco CA

Investigators

Abstract

Aging is associated with impairment of the body's immune response. Each part of the immune system is influenced to some extent by the aging process. However, adaptive immunity, the immunity that allows us to eliminate disease producing agents (pathogens) or prevent their growth, seems more extensively affected. As a result, there is increased susceptibility to infection, poor responses to vaccination, and increased incidence of autoreactivity (immune responses directed against the body's own tissues). It is not known exactly what causes these observed changes, but an understanding of the possible causes is now beginning to emerge. Many space-related physiological changes resemble those observed during aging. However, following microgravity exposure, such changes are more or less quickly restored after re-entry to Earth. This project aims to investigate the relationship between an individual's immune aging and healing outcomes, and to investigate the biology of aging from two directions--not only during its development in microgravity conditions but also during recovery. Designed to work like human organs, tissue chips mimic living human tissues and cells. The investigators will use a tissue chip design that enables them to explore the relationship between liver aging and regeneration and immune responses and to look for possible ways to slow the aging process and enhance the liver healing process. Each immune system chip includes two types of cells: a specific type of immune cell and liver cells, which interact with the immune cells. By sending the chips into space, the investigators will be able simulate the aging process of the immune system and understand how it affects our liver's ability to repair itself as we grow older. This research is expected to provide new insights into the molecular basis for many human conditions, which in this particular project relates to how microgravity induces aging of the immune system that may lead to the development of novel therapies here on Earth. In tandem with the scientific objectives, the project will work with the Space Sciences Laboratory at Berkley to summarize how cell chips are plated and document each step of the space experience: from launch, to storage on the International Space Station (ISS), until sample return. The results and the concept of cellular engineering will be disseminated to a broad audience through a suite of new online resources. The education goals include attracting students to the many STEM disciplines by engaging them with cutting-edge investigations on age-old, fascinating questions that include extending the human lifespan, and possible long-term human existence elsewhere beyond Earth and strengthening educators' and the public's support of this and other NSF-funded research by drawing in and connecting not only educators and students, but the general public to exciting medical research taking place aboard the ISS. The overarching goal of this research thrust is to gain a better understanding of the influence of immunosenescence, the dysregulation of the body's immune response, which is associated with aging. Adaptive immunity seems particularly affected by the increase in the frequency of terminally differentiated CD8+ effector memory T (TEMRA) cells, which is driven by chronic antigen exposure and correlates with aging. Many space-related physiological changes resemble those observed during aging but are restored after re-entry. The investigators have already demonstrated that simulated microgravity induces the differentiation of T cells into TEMRA cells that impact the repair capacity of mesenchymal stem cells and epithelial progenitor cells (EPCs) in wound healing and tube formation, respectively. The focus of this project is to gain a better understanding of the influence of immunosenescence on the regenerative capacity of liver-specific stem cells. All experiments will utilize liver tissue mimics (in vitro 3D-co-cultures of CD8+ T cells and Liver Progenitor Cells (LPCs)) on tissue chips. Ultimately, the chips will be placed in the ISS for up to a month, where microgravity will serve as the aging model. The Research Plan is organized under two objectives. The First Objective is to study the effect of aged CD8+ T cells for liver progenitor cells behavior, plasticity, and repair capacity in space and to assess the relationship between an individual's immune reactivity and healing. For these studies, after the month in space, the chips will be fixed/frozen for subsequent post-flight analysis. The Second Objective is to investigate post-flight recovery of tissue chips using functional analysis. For these studies, after the month in space, the chips will be returned live from space for post-flight analysis as the microgravity aged tissues recover. The combined objectives enable investigation of the biology of aging--not only its development but also its reversal. The data obtained are expected to provide important insights into the influence of T cell aging on liver stem cells and subsequent liver healing and regeneration that will lead to a new treatment paradigm for future use in patients with age-associated alteration in the liver. (Project integration and operation on the ISS will be provided by the Center for the Advancement of Science in Space (CASIS) implementation partner, BioServe.) This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.