Patient induced pluripotent stem cell-derived hepatostellate organoids establish a basis for liver pathologies in telomeropathies

Choi, Y.; Kim, M. S.; Rhoades, J. H.; Johnson, N. M.; Berry, C. T.; Root, S.; Chen, Q.; Tian, Y.; Fernandez, R. J.; Cramer, Z.; Adams-Tzivelekidis, S.; Li, N.; Johnson, F. B.; Lengner, C. J.

doi:10.1101/2021.11.19.469258

bioRxiv · 10.1101/2021.11.19.469258

Patient induced pluripotent stem cell-derived hepatostellate organoids establish a basis for liver pathologies in telomeropathies

Choi, Y.·Kim, M. S.·Rhoades, J. H.·Johnson, N. M.·Berry, C. T.·Root, S.·Chen, Q.·Tian, Y.·Fernandez, R. J.·Cramer, Z.·Adams-Tzivelekidis, S.·Li, N.·Johnson, F. B.·Lengner, C. J.

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Abstract

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, steatosis, inflammation, 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 followed by generation of genotype-admixed hepatostellate organoids revealed a dominant phenotype in the parenchyma, with DC hepatocytes eliciting a pathogenic hyperplastic response in stellate cells independent of stellate cell genotype. Pathogenic phenotypes could be rescued via suppression of AKT activity, a central regulator of MYC-driven hyperplasia downstream of DKC1 mutation. Thus, isogenic iPS-derived admixed hepatostellate organoids offer insight into the liver pathologies in telomeropathies and provide a framework for evaluating emerging therapies.

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Choi, Y., Kim, M. S., Rhoades, J. H., Johnson, N. M., Berry, C. T., Root, S., Chen, Q., Tian, Y., Fernandez, R. J., Cramer, Z., Adams-Tzivelekidis, S., Li, N., Johnson, F. B., Lengner, C. J.. 2021-11-20. Patient induced pluripotent stem cell-derived hepatostellate organoids establish a basis for liver pathologies in telomeropathies. https://doi.org/10.1101/2021.11.19.469258

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