Systemic amyloidosis represents a class of disorders in which misfolded proteins are secreted by effector organs and deposited as proteotoxic aggregates at downstream target tissues. Despite being well-described clinically, the contribution of effector organs such as the liver to the pathogenesis of these diseases is poorly understood. Here, we utilize a patient-specific induced pluripotent stem cell (iPSC)-based model of hereditary transthyretin (TTR) amyloid disease (ATTR amyloidosis) in order to define the contributions of hepatic cells to the distal proteotoxicity of secreted TTR. To this end, we employ a gene correction strategy to generate isogenic, ATTR amyloidosis patient-specific iPSCs expressing either amyloidogenic or wild-type TTR. We further utilize this gene editing strategy in combination with single cell RNAseq to identify multiple hepatic proteostasis factors, including many components of adaptive unfolded protein response (UPR) signaling pathways, whose expression correlates with the production of destabilized TTR variants in iPSC-derived hepatic cells. We further demonstrate that enhancing ER proteostasis within ATTR amyloidosis iPSC-derived hepatic lineages via stress-independent activation of aforementioned adaptive UPR signaling preferentially reduces the secretion of destabilized amyloidogenic TTR. Together, these results suggest the potential of the liver to chaperone-at-a-distance and impact pathogenesis at downstream target cells in the context of systemic amyloid disease, and further highlight the promise of UPR modulating therapeutics for the treatment of TTR-mediated and other amyloid diseases.*   A1AT    :   alpha-1 antitrypsin    Aß    :   amyloid ß    AD    :   Alzheimer’s disease    AFP    :   alpha fetoprotein    ALB    :   albumin    ATTR amyloidosis    :   transthyretin amyloidosis    DLT    :   domino liver transplant    FDR    :   false discovery rate    GSEA    :   gene set enrichment analysis    HLC    :   hepatocyte-like cell    iPSC    :   induced pluripotent stem cell    LC/MS    :   liquid chromatography/mass spectrometry    PCA    :   principle component analysis    PSC    :   pluripotent stem cell    scRNAseq    :   single cell RNA sequencing    TALEN    :   transcription activator-like effector nuclease    TF    :   transferrin    TMT    :   tandem mass tag    TTR    :   transthyretin    UPR    :   unfolded protein response

Amyloidogenic Proteins Drive Hepatic Proteostasis Remodeling in an Induced Pluripotent Stem Cell Model of Systemic Amyloid Disease