Liver-Regenerative Transplantation: Regrow and Reset.

Liver transplantation, either a partial liver from a living or deceased donor or a whole liver from a deceased donor, is the only curative therapy for severe end-stage liver disease. Only one-third of those on the liver transplant waiting list will be transplanted, and the demand for livers is projected to increase 23% in the next 20 years. Consequently, organ availability is an absolute constraint on the number of liver transplants that can be performed. Regenerative therapies aim to enhance liver tissue repair and regeneration by any means available (cell repopulation, tissue engineering, biomaterials, proteins, small molecules, and genes). Recent experimental work suggests that liver repopulation and engineered liver tissue are best suited to the task if an unlimited availability of functional induced pluripotent stem (iPS)-derived liver cells can be achieved. The derivation of iPS cells by reprogramming cell fate has opened up new lines of investigation, for instance, the generation of iPS-derived xenogeneic organs or the possibility of simply inducing the liver to reprogram its own hepatocyte function after injury. We reviewed current knowledge about liver repopulation, generation of engineered livers and reprogramming of liver function. We also discussed the numerous barriers that have to be overcome for clinical implementation.

GH administration rescues fatty liver regeneration impairment by restoring GH/EGFR pathway deficiency.

GH pathway has been shown to play a major role in liver regeneration through the control of epidermal growth factor receptor (EGFR) activation. This pathway is down-regulated in nonalcoholic fatty liver disease. Because regeneration is known to be impaired in fatty livers, we wondered whether a deregulation of the GH/EGFR pathway could explain this deficiency. Hepatic EGFR expression and triglyceride levels were quantified in liver biopsies of 32 obese patients with different degrees of steatosis. We showed a significant inverse correlation between liver EGFR expression and the level of hepatic steatosis. GH/EGFR down-regulation was also demonstrated in 2 steatosis mouse models, a genetic (ob/ob) and a methionine and choline-deficient diet mouse model, in correlation with liver regeneration defect. ob/ob mice exhibited a more severe liver regeneration defect after partial hepatectomy (PH) than methionine and choline-deficient diet-fed mice, a difference that could be explained by a decrease in signal transducer and activator of transcription 3 phosphorylation 32 hours after PH. Having checked that GH deficiency accounted for the GH signaling pathway down-regulation in the liver of ob/ob mice, we showed that GH administration in these mice led to a partial rescue in hepatocyte proliferation after PH associated with a concomitant restoration of liver EGFR expression and signal transducer and activator of trnascription 3 activation. In conclusion, we propose that the GH/EGFR pathway down-regulation is a general mechanism responsible for liver regeneration deficiency associated with steatosis, which could be partially rescued by GH administration.

New insights into liver regeneration.

Even if the Greeks probably anticipated rather than discovered the extraordinary regenerative capacity of the liver with the Prometheus myth, this phenomenon still fascinates scientists nowadays with the same enthusiasm. There are good reasons to decipher this process other than to find an answer to our fantasy of immortality: it could indeed help patients needing large liver resections or living-donor liver transplantation, it could increase our understanding of liver pathology and finally it could enable novel cell-therapy approaches. For decades, most of our knowledge about the mechanisms involved in liver regeneration came from the classic two-thirds partial hepatectomy (PH) model. In this scenario, hepatocytes play the leading role, which raises the question of the simple existence of a stem cell population. Recently however, hepatic progenitor cells come again under the limelight, seeming to play a role in liver physiology and in various liver diseases such as steatosis or cirrhosis. Excellent reviews have recently addressed liver regeneration. Our goal is therefore to focus on recent improvements in the field, highlighting data mostly published in the last two years in order to draw a putative picture of what the future research axes on liver regeneration might look like.