Epigenetic remodelling licences adult cholangiocytes for organoid formation and liver regeneration

Aloia, Luigi; McKie, Mikel Alexander; Vernaz, Grégoire; Cordero-Espinoza, Lucía; Aleksieva, Niya; Ameele, Jelle van den; Antonica, Francesco; Font-Cunill, Berta; Raven, Alexander; Cigliano, Riccardo Aiese; Belenguer, Germán; Mort, Richard L.; Brand, Andrea H.; Zernicka‐Goetz, Magdalena; Forbes, Stuart J.; Miska, Eric A.; Huch, Meritxell

doi:10.1038/s41556-019-0402-6

Cited by 121 publications

(157 citation statements)

References 81 publications

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“…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 .…”

Section: The Molecular Mechanisms Of Lpc Activationmentioning

confidence: 93%

Liver progenitor cell-driven liver regeneration

Kim

Lee

et al. 2020

Exp Mol Med

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The liver is a highly regenerative organ, but its regenerative capacity is compromised in severe liver diseases. Hepatocyte-driven liver regeneration that involves the proliferation of preexisting hepatocytes is a primary regeneration mode. On the other hand, liver progenitor cell (LPC)-driven liver regeneration that involves dedifferentiation of biliary epithelial cells or hepatocytes into LPCs, LPC proliferation, and subsequent differentiation of LPCs into hepatocytes is a secondary mode. This secondary mode plays a significant role in liver regeneration when the primary mode does not effectively work, as observed in severe liver injury settings. Thus, promoting LPC-driven liver regeneration may be clinically beneficial to patients with severe liver diseases. In this review, we describe the current understanding of LPC-driven liver regeneration by exploring current knowledge on the activation, origin, and roles of LPCs during regeneration. We also describe animal models used to study LPC-driven liver regeneration, given their potential to further deepen our understanding of the regeneration process. This understanding will eventually contribute to developing strategies to promote LPC-driven liver regeneration in patients with severe liver diseases.

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Section: The Molecular Mechanisms Of Lpc Activationmentioning

confidence: 93%

Liver progenitor cell-driven liver regeneration

Kim

Lee

et al. 2020

Exp Mol Med

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“… [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.…”

Section: Liver Organoidsmentioning

confidence: 99%

Organoids to model liver disease

Nuciforo

Heim

2021

JHEP Reports

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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“…Under defined culture conditions, EpCAM pos HpSCs from adult liver can be expanded for months (>1 year) in culture, showing an exponential rate of proliferation and genetic stability ( 92 ). HpSCs can readily be expanded as bipotent stem cells into 3D organoids and differentiate into functional hepatocyte cells both in vitro and in vivo upon transplantation ( 93 , 94 ). Noteworthily, single isolated EpCAM pos cells develop into organoid with high colony forming efficiency, while EpCAM neg cells failed to create organoids ( 93 ).…”

Section: Perspectives and Applications Of Epcam Posmentioning

confidence: 99%

Distinct EpCAM-Positive Stem Cell Niches Are Engaged in Chronic and Neoplastic Liver Diseases

et al. 2020

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In normal human livers, EpCAM pos cells are mostly restricted in two distinct niches, which are (i) the bile ductules and (ii) the mucous glands present inside the wall of large intrahepatic bile ducts (the so-called peribiliary glands). These EpCAM pos cell niches have been proven to harbor stem/progenitor cells with great importance in liver and biliary tree regeneration and in the pathophysiology of human diseases. The EpCAM pos progenitor cells within bile ductules are engaged in driving regenerative processes in chronic diseases affecting hepatocytes or interlobular bile ducts. The EpCAM pos population within peribiliary glands is activated when regenerative needs are finalized to repair large intra- or extra-hepatic bile ducts affected by chronic pathologies, including primary sclerosing cholangitis and ischemia-induced cholangiopathies after orthotopic liver transplantation. Finally, the presence of distinct EpCAM pos cell populations may explain the histological and molecular heterogeneity characterizing cholangiocarcinoma, based on the concept of multiple candidate cells of origin. This review aimed to describe the precise anatomical distribution of EpCAM pos populations within the liver and the biliary tree and to discuss their contribution in the pathophysiology of human liver diseases, as well as their potential role in regenerative medicine of the liver.

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Epigenetic remodelling licences adult cholangiocytes for organoid formation and liver regeneration

Cited by 121 publications

References 81 publications

Liver progenitor cell-driven liver regeneration

Liver progenitor cell-driven liver regeneration

Organoids to model liver disease

Distinct EpCAM-Positive Stem Cell Niches Are Engaged in Chronic and Neoplastic Liver Diseases

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