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.

Bioengineering in organ transplantation: targeting the liver.

About 27,000 deaths are registered annually in the United States due to liver disease. At this time, the only definitive treatment of hepatic failure is orthotopic transplantation. However, there is a critical shortage of organs with the total waiting list for all organs currently at 100,000 requests. The number is increasing by 5% every year. Given that only organs in pristine condition are transplantable and that the hidden demand for organs as an anti-aging solution will be many times the current figures, orthotopic transplantation will always remain a limited pool. The increasing donor organ shortage requires consideration of alternative emerging technologies. Regenerative medicine may offer novel strategies to treat patients with end-stage organ failure. The ultimate aim of cell transplantation, tissue engineering, and stem cells is to regenerate tissues and organs. With the development of whole organ decellularization methods, the equation of organ shortage may dramatically change in the near future. Decellularized organs provide the ideal transplantable scaffold with all the necessary microstructure and extracellular cues for cell attachment, differentiation, vascularization, and function. New techniques to re-engineer organs may have major implications for the fields of drug discovery, regeneration biology, and ultimately organ transplantation. In this review we have provided an overview of complementary approaches to study and enhance the success of organ repopulation strategies creating new grafts/organs for transplantation.

Diluted blood reperfusion as a model for transplantation of ischemic rat livers: alanine aminotransferase is a direct indicator of viability.

Donors after cardiac death present a significant pool of untapped organs for transplantation, and use of machine perfusion strategies has been an active focus area in experimental transplantation. However, despite 2 decades of research, a gold standard has yet to emerge for machine perfusion systems and protocols. Whole blood reperfusion has been used as a surrogate for organ transplantation, especially as a model for the short-term response posttransplantation, and for optimization of perfusion systems. Although it is known that there is a strong correlation between liver function in whole-blood reperfusion and survival, the exact nature of these correlations, and to what extent they can be considered as an indicator of viability for transplantation/recipient survival, remain unclear. In this work, we demonstrate that diluted whole-blood reperfusion can be used as a direct model for transplantation of ischemic rat liver grafts. Specifically, we show that recipient survival can be predicted based simply on the value of alanine aminotransferase during perfusion, providing quantitative criteria of viability for use in this animal model. These results indicate that in the rat model graft survival is highly correlated with hepatocellular damage.