Liver regeneration: Alternative epithelial pathways

Michalopoulos, George K.

doi:10.1016/j.biocel.2009.09.014

Cited by 113 publications

(96 citation statements)

References 72 publications

(81 reference statements)

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“…Nor does the model define the ultimate source of HSCs. It is fully consistent with the possibility that adult HSCs derive from putative precursors in either the adult biliary tree (33,61,62) or vestigial mesothelium (48,63). There is also room for MFs derived from cells other than HSCs in the new model.…”

Section: Methodssupporting

confidence: 76%

Smoothened is a master regulator of adult liver repair

Michelotti

Xie²,

Swiderska³

et al. 2013

J. Clin. Invest.

156

249

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Section: Methodssupporting

confidence: 76%

Smoothened is a master regulator of adult liver repair

Michelotti

Xie²,

Swiderska³

et al. 2013

J. Clin. Invest.

156

249

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“…In accordance with this view, the ability of the liver to rapidly regenerate after tissue injury or loss rests on the stem cell-like proliferative potential of all residual parenchymal cells and not on that of an elite subpopulation (1)(2)(3)(4)(5)(6)(7)(8). However, if hepatocytes or biliary epithelial cells lose the ability to proliferate, such as in chronic injury states, liver progenitor cells are activated.…”

Section: Introductionmentioning

confidence: 92%

Fate tracing of mature hepatocytes in mouse liver homeostasis and regeneration

Malato

Naqvi²,

Schürmann³

et al. 2011

J. Clin. Invest.

392

371

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Recent evidence has contradicted the prevailing view that homeostasis and regeneration of the adult liver are mediated by self duplication of lineage-restricted hepatocytes and biliary epithelial cells. These new data suggest that liver progenitor cells do not function solely as a backup system in chronic liver injury; rather, they also produce hepatocytes after acute injury and are in fact the main source of new hepatocytes during normal hepatocyte turnover. In addition, other evidence suggests that hepatocytes are capable of lineage conversion, acting as precursors of biliary epithelial cells during biliary injury. To test these concepts, we generated a hepatocyte fate-tracing model based on timed and specific Cre recombinase expression and marker gene activation in all hepatocytes of adult Rosa26 reporter mice with an adenoassociated viral vector. We found that newly formed hepatocytes derived from preexisting hepatocytes in the normal liver and that liver progenitor cells contributed minimally to acute hepatocyte regeneration. Further, we found no evidence that biliary injury induced conversion of hepatocytes into biliary epithelial cells. These results therefore restore the previously prevailing paradigms of liver homeostasis and regeneration. In addition, our new vector system will be a valuable tool for timed, efficient, and specific loop out of floxed sequences in hepatocytes.

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“…In contrast, after severe chronic liver injury, the duplication ability of the epithelial cells may be exhausted and stem or progenitor cells may be activated to supply hepatocytes and cholangiocytes (Espanol-Suner et al, 2012). In addition to the self-duplication and stem/progenitor cell systems, lineage conversion should be taken into consideration (Michalopoulos, 2011). It has been shown that mature hepatocytes (MHs) have the potential to transdifferentiate into cholangiocyte-like cells (Nishikawa et al, 2005;Zong et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Hepatic biliary epithelial cells acquire epithelial integrity but lose plasticity to differentiate into hepatocytes in vitro during development

Tanimizu

Nakamura

Ichinohe

et al. 2013

Journal of Cell Science

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SummaryIn developing organs, epithelial tissue structures are mostly developed by the perinatal period. However, it is unknown whether epithelial cells are already functionally mature and whether they are fixed in their lineage. Here we show that epithelial cells alter their plasticity during postnatal development by examining the differentiation potential of epithelial cell adhesion molecule (EpCAM) + cholangiocytes (biliary epithelial cells) isolated from neonatal and adult mouse livers. We found that neonatal cholangiocytes isolated from 1-week-old liver converted into functional hepatocytes in the presence of oncostatin M and MatrigelH. In contrast, neither morphological changes nor expression of hepatocyte markers were induced in adult cholangiocytes. The transcription factors hepatocyte nuclear factor 4a and CCAAT/enhancer binding protein a (C/EBPa), which are necessary for hepatocytic differentiation, were induced in neonatal cholangiocytes but not in adult cells, whereas grainyhead-like 2 (Grhl2) and hairy-enhance of slit 1 (Hes1), which are implicated in cholangiocyte differentiation, were continuously expressed in adult cells. Overexpression of C/EBPa and Grhl2 promoted and inhibited hepatocytic differentiation, respectively. Furthermore, adult cholangiocytes formed a monolayer with higher barrier function than neonatal ones did, suggesting that cholangiocytes are still in the process of epithelial maturation even after forming tubular structures during the neonatal period. Taken together, these results suggest that cholangiocytes lose plasticity to convert into hepatocytes during epithelial maturation. They lose competency to upregulate hepatocytic transcription factors and downregulate cholagiocytic ones under conditions inducing hepatocytic differentiation. Our results suggest that a molecular machinery augmenting epithelial integrity limits lineage plasticity of epithelial cells.

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Liver regeneration: Alternative epithelial pathways

Cited by 113 publications

References 72 publications

Smoothened is a master regulator of adult liver repair

Smoothened is a master regulator of adult liver repair

Fate tracing of mature hepatocytes in mouse liver homeostasis and regeneration

Hepatic biliary epithelial cells acquire epithelial integrity but lose plasticity to differentiate into hepatocytes in vitro during development

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