Adult Hepatocytes Are Generated by Self-Duplication Rather than Stem Cell Differentiation

Abstract

SUMMARY The liver is thought to utilize facultative stem cells, also known as “oval cells” or “atypical ductal cells” (ADCs), for regeneration following various types of injury. However, this notion has been based largely on in vitro studies and transplantation models; where lineage tracing has been used, results have been conflicting and effect sizes have been small. Here, we used genetic and nucleoside analog-based tools to mark and track the origin and contribution of various cell populations to liver regeneration in vivo following several ADC-inducing insults. We report that, contrary to prevailing stem-cell-based models of regeneration, virtually all new hepatocytes come from preexisting hepatocytes.

Rescue Effects and Underlying Mechanisms of IntraglandShhGene Delivery on Irradiation-Induced Hyposalivation

“…27 Similar mechanisms have been reported for the growth and maintenance of other glands in the digestive tract including liver and pancreas. [37][38][39] Our data from the lineage-tracing assay of cells expressing Bmi1, a putative marker of salivary gland stem/progenitor cells and a direct target of Hh/Gli signaling, are consistent with the acinar cell self-duplication model, and suggest that transient activation of Hh/Gli signaling rescues IR-induced hyposalivation mainly in a non-cell-autonomous manner.…”

Lineage fate of ductular reactions in liver injury and carcinogenesis

“…In line with this concept of DRCs physiologically acting as bipotential progenitors, cells isolated from DRs can self-renew, give rise to biliary cells and hepatocytes in vitro, and regenerate hepatocytes with variable success when transplanted into Fah -/-mice, a mouse model of hereditary tyrosinemia type 1 (13)(14)(15)(16)). Yet, recent attempts to address the capacity of DRCs to act as physiological progenitors to regenerate hepatocytes after short-term liver injury using genetic lineage-tracing methods have revealed conflicting results (14,(17)(18)(19)(20)(21)(22)(23). Beyond liver repair, LPCs have also come into focus as a likely candidate cellular compartment susceptive to malignant transformation and that can give rise to hepatocellular carcinoma (HCC) or cholangiocarcinoma (24,25); however, evidence from compartment-specific lineage-tracing in vivo models that supports the view that HCCs originate from an adult LPC compartment does not exist.…”

“…Notably, tdTom/HNF4α costaining did not reveal significant neogenesis of hepatocytes from DRCs in our injury models, with the exception of the 2-week CDE model, in which a very small fraction (0.04% ± 0.019%) of tdTom + / HNF4α + hepatocytes was observed ( Figure 2, B and C). The DDC and CDE models are considered prototypical mouse "oval cell models" that produce bipotential LPCs; however, their potential and quantitative contribution to reparative hepatocyte neogenesis remains controversial (10,14,(17)(18)(19)(20)(21)(22)(23). Neither introducing a 2-week recovery period (DDC diet for 2 weeks plus 2 weeks recovery) nor prolonging DDC feeding (DDC diet for 4 weeks) carcinogenesis and close important knowledge gaps within this controversial field.…”

Cellular and Molecular Cascades during Liver Regeneration

“…25 In mice it takes one week for the liver to return to 75% of its original size. The regenerative response involves constitution of hepatocytes first followed by biliary epithelial cells and then non-parenchymal cells.…”