Donor organ shortage is the main limitation to liver transplantation as a treatment for end-stage liver disease (ESLD) and acute liver failure (ALF). Liver regenerative medicine may in the future offer an alternative form of therapy for these diseases, be it through cell transplantation, bioartificial liver (BAL) devices, or bioengineered whole organ liver transplantation. All three strategies have shown promising results in the past decade. However, before they are incorporated into widespread clinical practice, the ideal cell type for each treatment modality must be found, and an adequate amount of metabolically active, functional cells must be able to be produced. Research is ongoing in hepatocyte expansion techniques, use of xenogeneic cells, and differentiation of stem cell-derived hepatocyte-like cells (HLCs). HLCs are a few steps away from clinical application, but may be very useful in individualized drug development and toxicity testing, as well as disease modeling. Finally, safety concerns including tumorigenicity and xenozoonosis must also be addressed before cell transplantation, BAL devices, and bioengineered livers occupy their clinical niche. This review aims to highlight the most recent advances and provide an updated view of the current state of affairs in the field of liver regenerative medicine.

The SRBAL improved survival, reduced ammonia, and accelerated liver regeneration in post-hepatectomy ALF. Improved survival was associated with a neuroprotective benefit of SRBAL therapy. These favorable results warrant further clinical testing of the SRBAL. This article is protected by copyright. All rights reserved.

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Filamins are actin binding proteins that contribute to cytoskeletal integrity and biochemical scaffolds during mechanochemical signal transductions. Structurally, human filamins are dimers composed of an actin-binding domain with 24 immunoglobulin (Ig)-like repeats. In this study, we focus on the recently solved high-resolution crystal structure of Ig-like repeats 19-21 of filamin-A (IgFLNa-R19-R21). IgFLNa-R19-21 is of marked importance because it contains the binding site for integrins and facilitates the dynamic ability of filamin-A to communicate with the extracellular environment. However, the structure of filamin-A shows an interesting domain arrangement where the integrin binding site on IgFLNa-R21 is hindered sterically by IgFLNa-R20. Thus, a number of hypotheses on the regulation of filamin-A exist. Using molecular dynamics simulations we evaluated the effects of two primary regulators of filamin-A, force and phosphorylation. We find that a tensile force of 40 pN is sufficient to initiate the partial removal of the autoinhibition on the integrin binding site of IgFLNa-R21. Force coupled to phosphorylation at Ser(2152), however, affords complete dissociation of autoinhibition with a decreased force requirement. Phosphorylation seems to decrease the threshold for removing the IgFLNa-R20 beta-strand inhibitor within 300 ps with 40 pN tensile force. Furthermore, the molecular dynamic trajectories illustrate phosphorylation of Ser(2152) without force is insufficient to remove autoinhibition. We believe the results of this study implicate filamin-A as a tunable mechanosensor, where its sensitivity can be modulated by the degree of phosphorylation.

Share 35 was implemented in 2013 to direct livers to the most urgent candidates by prioritizing Model for End-Stage Liver Disease (MELD) 35 patients. We aim to evaluate this policy's impact on costs and mortality. Our study includes 834 wait-listed patients and 338 patients who received deceased donor, solitary liver transplants at Mayo Clinic between January 2010 and December 2014. Of these patients, 101 (30%) underwent transplantation after Share 35. After Share 35, 29 (28.7%) MELD 35 patients received transplants, as opposed to 46 (19.4%) in the pre-Share 35 era (P 5 0.06). No significant difference in 90-day wait-list mortality (P 5 0.29) nor 365-day posttransplant mortality (P 5 0.68) was found between patients transplanted before or after Share 35. Mean costs were $3,049 (P 5 0.30), $5226 (P 5 0.18), and $10,826 (P 5 0.03) lower post-Share 35 for the 30-, 90-, and 365-day pretransplant periods, and mean costs were $5010 (P 5 0.41) and $5859 (P 5 0.57) higher, and $9145 (P 5 0.54) lower post-Share 35 for the 30-, 90-, and 365-day posttransplant periods. In conclusion, the added cost of transplanting more MELD 35 patients may be offset by pretransplant care cost reduction. Despite shifting organs to critically ill patients, Share 35 has not impacted mortality significantly.Liver Transplantation 23:11-18 2017 AASLD. SEE EDITORIAL ON PAGE 9The Share 35 policy was implemented by United Network for Organ Sharing (UNOS) in June 2013 with the intention of reducing geographic disparities in organ access for liver transplantation across the United States. (1) By prioritizing regional transplant candidates with a Model for End-Stage Liver Disease (MELD) score of 35 or higher over local candidates with MELD scores under 35, this measure was expected to prolong survival of patients wait-listed in underserved organ distribution areas. (2,3) At the same time, it was hypothesized that this policy could reduce global transplant costs in the interim by reducing pretransplant health care expenses. (4,5) Out of the more than 6000 liver transplants that are performed every year within the United States, (6) approximately 20% take place in patients with MELD scores of 35 or higher-a proportion that increased to 25% within the first 6 months of the Share 35 policy's implementation. (4) Postoperative costs in patients with MELD scores of 35 or above have been found to be significantly higher than in patients with lower MELD scores due to longer intensive care unit and hospital stays, as well as more frequent hospitalizations. (7) These higher postoperative expenses, in conjunction with the foreseeable increase in transportation costs linked to the new allocation system, (8) warrant a total cost analysis to gauge the direction of Share 35's effect on global transplant costs.