Epigenetic remodelling licences adult cholangiocytes for organoid formation and liver regeneration

Abstract

MH designed and performed experiments and interpreted results.. L.A. designed and performed the in vitro experiments, M.A.M., designed and performed the in vivo experiments, L.C-E., the hydroxymethylation and EdU stainings, G.B, experiments with small molecule inhibitors. G.V. and E.A.M. prepared and analysed WGBS and RRHP libraries, analysed RNAseq and interpreted corresponding bionformatic analyses related. N.A., A.R. and S.J.F. performed experiments with β1 integrin model and interpreted results of the p21 models. J.v.d.A. and A.H.B. performed DamID-seq experiments. B.F-C helped on the in vivo analysis. R.A.C. helped on bioinformatics analyses. R.L.M. provided the R26Fucci2a line. F.A. and M.Z.G. performed the live imaging of ductal cells.

Liver progenitor cell-driven liver regeneration

“…YAP and mTORC1 signaling positively regulate the growth of BECderived organoids in vitro and the proliferation of BECs and LPCs in mice 24 . TET1-mediated epigenetic remodeling through YAP signaling was also recently reported to positively control LPC activation 33 .…”

Organoids to model liver disease

“… [30] , [31] , [32] A direct comparison of chol-orgs and hep-orgs revealed 2 critical features that differ significantly between the culture systems, clonogenicity and growth rate. 27 Nearly every third ductal cell is able to initiate chol-org formation in a process involving major epigenetic and transcriptional remodeling, 24 , 33 while only 1 in a 100 hepatocytes expands and forms hep-orgs. 27 Chol-orgs proliferate rapidly with doubling times of ∼60 hours for more than 20 passages, whereas hep-orgs proliferate much slower and double every 5–7 days, if derived from foetal livers, or are passaged 1–2 times every 50–75 days if derived from adult livers.…”

Epigenetic Research in Stem Cell Bioengineering—Anti-Cancer Therapy, Regenerative and Reconstructive Medicine in Human Clinical Trials

“…As an example, a combination of in silico genomic feature annotations with association analysis, including linkage disequilibrium, genetic association and enriched genomic features, known as a Bayesian approach, described more than 200 breast cancer-related signals [108]. The regenerative potential of transient, genome-wide epigenomic remodelling was recently described in the process of organoid formation and liver regeneration following tissue damage [109]. Epigenetic genome modifications are not only considered in studies concerning the regeneration of tissue and stem cell, but most importantly in studies concerning the prognosis and metastasis of various types of cancers, specifically in relation to tumour microenvironment, immune regulation, tissue-level physical forces and other cell-intrinsic mechanisms, including integration of transcriptomics and metabolomics [110].…”