Human patient iPS cell-derived hepatostellate organoids establish a cellular and molecular basis for liver pathologies in telomeropathies

Patients with dyskeratosis congenita (DC) and related telomeropathies resulting from premature telomere dysfunction suffer from multi-organ failure. In the liver, DC patients present with nodular hyperplasia and cirrhosis. We model DC liver pathologies using isogenic human induced pluripotent stem (iPS) cells harboring a causal DC mutation in DKC1, or a clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9-corrected control allele. Differentiation of these iPS cells into hepatocytes or hepatic stellate cells reveals a dominant phenotype in the parenchyma. Generation of genotype admixed hepatostellate organoids indicates that DC hepatocytes elicit a pathogenic hyperplastic response in stellate cells independent of stellate cell genotype. Phenotypic rescue was achieved via suppression of AKT activity, a central regulator of mTORC1, MYC, and DC hepatocyte-driven hyperplasia. Thus, isogenic, iPS-derived admixed hepatostellate organoids offer insight into the liver pathologies in telomeropathies and provide a framework for evaluating emerging therapies. HB vs. HEP, Amino acid 353 Ala vs. Val