(E-162) Donor-matched Multiorgan Microphysiological Systems for the Studies of Immunometabolic Diseases

Introduction::
Some of our time's most significant biomedical urgencies come from metabolic and autoimmune disorders. Even though their clinical manifestation can often be associated predominantly with one particular region of the body, they involve the interaction of an intricate network of different cell types, organ systems, and a disruption thereof. A notable example can be found in the gut-liver axis, where the two organ systems, and the environment, in the form of the microbiome, are intimately interconnected. Patients who suffer from inflammatory bowel disease (IBD) are more likely to develop certain inflammatory diseases of the liver and vice-versa. Significant correlations exist between ulcerative colitis (UC) or Crohn’s disease (CD) and autoimmune hepatitis and primary sclerosing cholangitis (PSC). While interorgan crosstalk is most often discussed in the context of the cellular secretome and humoral communication, tissue-resident and migratory T cells are essential in orchestrating signaling between various tissues. An urgent need exists to understand the basic biology of how the mucosal T cell environment shapes systemic immunity in the context of autoinflammatory diseases and the role migratory T cells play in the multiorgan manifestation of these diseases.




Materials and Methods::
Human multiorgan microphysiological systems (MOMPS) are engineered environments whose purpose is to mimic native cellular surroundings. This is accomplished with the use of tissue-specific biomaterials, machined or printed 3D architecture and perfusion. We have recently established a donor-matched MOMPS model of the gut-liver axis, which allows us to study TCR-dependent and independent activation of T cells across multiple organs and circulation of the same patient. We have streamlined the procurement of donor-matched liver, gut, and blood tissue and optimized the isolation of individual cell types of interest. These cells are being reconstructed on our multiorgan platforms at various levels of complexity and challenged via TCR-dependent and bystander activation.




Results, Conclusions, and Discussions::
We show that tissue-level interaction between and within the tissues led to increased tissue maturation and increased in vivo-like functionality. Further, using single-cell RNA sequencing, we have identified distinct clonally related T-cell subsets found in all three tissues with high effector and migratory capacity. Gene signatures of these subsets are closely related to both gut and liver inflammation as revealed by GWAS. Functional challenges of the gut-liver MOMPS with TLR3 and 4 ligands LPS and Poly I:C revealed distinct roles of individual tissue-resident T cells in both tissue inflammation and repair. Studies of their interplay with reconstructed intestinal and liver tissue further highlight how TCR-dependent and bystander T cell activation contributes to the perpetuation of inflammation in the gut-liver axis.


The controlled interaction of individual human tissues and the scalability of biological complexity in MOMPS, supported by advances in systems biology, might hold the key to identifying novel relationships between interorgan crosstalk, metabolism, and immunity. Here we show a granular view into the complex interplay of tissue inflammation, resident immunity and interorgan crosstalk as contributors to the inflammation of the gut-liver axis.






Acknowledgements (Optional): : This work is supported by the NIH NIGMS R35GM146900 MIRA Grant.

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