Liver Progenitors and Adult Cell Plasticity in Hepatic Injury and Repair: Knowns and Unknowns

Abstract

The liver is a complex organ performing numerous vital physiological functions. For that reason, it possesses immense regenerative potential. The capacity for repair is largely attributable to the ability of its differentiated epithelial cells, hepatocytes and biliary epithelial cells, to proliferate after injury. However, in cases of extreme acute injury or prolonged chronic insult, the liver may fail to regenerate or do so suboptimally. This often results in life-threatening end-stage liver disease for which liver transplantation is the only effective treatment. In many forms of liver injury, bipotent liver progenitor cells are theorized to be activated as an additional tier of liver repair. However, the existence, origin, fate, activation, and contribution to regeneration of liver progenitor cells is hotly debated, especially since hepatocytes and biliary epithelial cells themselves may serve as facultative stem cells for one another during severe liver injury. Here, we discuss the evidence both supporting and refuting the existence of liver progenitor cells in a variety of experimental models. We also debate the validity of developing therapies harnessing the capabilities of these cells as potential treatments for patients with severe and chronic liver diseases.

NOTCH-YAP1/TEAD-DNMT1 axis regulates hepatocyte reprogramming into intrahepatic cholangiocarcinoma

“…There have been several studies demonstrating the critical roles for DNMT in liver cancer development and maintenance (31,(44)(45)(46); most of studies showed that pharmacologic DNMT inhibition leads to hypomethylation of the promoters of various tumor suppressors such as p16INK4a, FoxM1, TP53, PTEN, and others (47), which typically induces death of malignant cells. At the same time, like other epigenetic regulators (20,48,49), DNMT1 plays critical roles in various cell fate switches including HC-to-BEC conversion (29)(30)(31)(32)50). Likewise, we also found that DNMT1 inhibition impairs AN-mediated HC-to-BEC conversion, thereby completely abrogating HC-driven murine ICC development.…”

“…IHC confirmed the ICCs to be positive for biliary marker pan-cytokeratin (panCK), HA tag (AKT), MYC tag (NICD), and SOX9 where expected ( Fig.1F-H). Given the critical role for SOX9 downstream of Notch signaling in HC-to-BEC conversion in liver injury (18,20), we next generated AKT-SOX9 model by HDTVI of myr-Akt (HA tag) and Sox9. Interestingly, no tumors were observed at 5-weeks post-injection, either macroscopically or microscopically ( Transcriptome analysis of HC-derived ICC in AKT-NICD model reveals significant similarity to a subset of human ICCs.…”

“…Active cell fate transition between HC and BEC as well as activation of intermediate cell population (LPCs and ductular reaction) in diseased liver supports the concept that a subset of ICCs may be derived from HCs or LPCs. The plasticity of hepatic epithelial cells to reprogram into each other during hepatobiliary injury is now well recognized(20). While this is an important tier of repair, such reprogramming entails remodeling of chromatin structure and the epigenome, increasing temporal susceptibility to a stochastic event which may cumulatively lead to a higher risk of malignant transformation of a cell(38,39).…”

Differentiation of Cells Isolated from Afterbirth Tissues into Hepatocyte-Like Cells and Their Potential Clinical Application in Liver Regeneration

“…Several cell populations participate in this process. These are mainly hepatocytes, but also multiple multipotent and bipotent stem cell populations expressing endodermal or mesenchymal markers [15][16][17][18][19][20].…”

Alternative Cell Sources for Liver Parenchyma Repopulation: Where Do We Stand?

“…However, if hepatocytes are damaged too extensively to participate in the liver repair process, liver regeneration occurs via differentiation of (facultative) hepatocyte progenitor/stem cells. The origin of these progenitors remains not fully understood, and likely includes liver progenitor cells, cholangiocytes, and intermediary hepatocytes (recently reviewed in [1]). However, if liver damage persists, or gives rise to liver fibrosis and cirrhosis, none of the above mechanisms can repair lost hepatocytes, giving rise to liver failure.…”