Using microgravity to model inflammaging in complex organ chip models of heart, gut, and brain - PROJECT SUMMARY/ABSTRACT Cellular aging, characterized by the accumulation of damaged proteins and senescent cells, leads to functional decline in the heart, brain, and intestine, increasing susceptibility to age-related diseases. Monocytes and macrophages play crucial roles in tissue development and repair, but their function can decline with age, contributing to chronic inflammation known as inflammaging. Recent studies indicate that spaceflight can also alter monocyte and macrophage functionality, simulating aspects of aging and inflammation. Microphysiological systems (MPS) represent an innovative approach to replicate complex human tissue environments, augmenting traditional 2D cultures, and will be employed in this study to assess aging phenotypes in microgravity. This proposal seeks to explore the impact of spaceflight-induced aging and inflammaging on various tissue types using multi-lineage (MPS). The research will be conducted in two phases: the UG3 phase will establish MPS-based models for accelerated aging harboring human induced pluripotent stem cell (hiPSC)-derived tissues, whereas the UH3 phase will identify signatures of spaceflight- induced cell aging and attempt to reverse them using senolytic strategies. The hypothesis of this proposal is that multi-lineage MPS, also known as organ-on-chips, can serve as a platform for elucidating the mechanisms of spaceflight-induced accelerated aging and tissue degradation. This work builds upon the Principal Investigators’ (MPIs Sharma and Svendsen) existing studies utilizing MPS systems to model human disease and employing hiPSCs to explore human physiology and biomanufacturing in space. Aim 1 of this proposal is to develop hiPSC-derived, multi-lineage gut, brain, and heart MPS systems and integrate with hiPSC-derived macrophages (iMACS) to examine tissue maturation and stability. Aim 1 will utilize fluorescent reporter hiPSC lines, differentiation of hiPSCs into multiple lineages, in-space microscopy, analysis of MPS effluent, and custom spaceflight-compatible MPS from implementation partner BioServe Space Technologies. Aim 2 will examine the impact of spaceflight on altering aging-related biomarkers in heart, brain, intestinal MPS models with or without iMACS. The MPS will be subjected to microgravity in space and their integrity, functionality, and transcriptomic/metabolomic profiles will be examined to determine the impact of spaceflight on accelerated tissue and immune cell aging and degradation. Aim 3 will repeat the spaceflight experiment proposed in Aim 2, and will also identify senescence-specific biomarkers in space-flown iMACS and MPS and test senolytic compounds aiming to reverse microgravity-induced aging phenotypes. Collaborations with experts in immune aging and spaceflight experience will bolster this project's impact. Ultimately, findings will aim to translate insights gained in microgravity to improve human health on Earth, via comprehensive in-flight and post-flight analyses in multi-lineage, hiPSC-derived MPS systems.
