Allogeneic transplant procurement in the times of COVID-19: Quality report from the central European cryopreservation site.

BACKGROUND: Because of limitations of transportation imposed by the COVID-19 pandemic, current recommendation calls for cryopreservation of allogeneic stem cell transplants before patient conditioning. A single cell therapy laboratory was selected to function as the central cryopreservation hub for all European registry donor transplants intended for the Australian-Pacific region. We examined properties of these transplants to ascertain how quality is maintained. METHODS: We analyzed 100 pandemic-related allogeneic mobilized blood-derived stem cell apheresis products generated at 30 collection sites throughout Europe, shipped to and cryopreserved at our center between April and November of 2020. Products were shipped in the cool, subsequently frozen with DMSO as cryoprotectant. Irrespective of origin, all products were frozen within the prescribed shelf-life of 72 h. RESULTS: Prior to cryopreservation, viable stem cell and leukocyte count according to the collection site and our reference laboratory were highly concordant (r2 = 0.96 and 0.93, respectively) and viability was > 90% in all instances. Median nominal post-thaw recovery of viable CD34+ cells was 42%. Weakly associated with poorer CD34+ cell recovery was higher leukocyte concentration, but not time lag between apheresis or addition of cryopreservant, respectively, and start of freezing. The correlation between pre- and post-thaw CD34+ cell dose was high (r2 = 0.85), hence predictable. Neutrophil and platelet engraftment were prompt with no evidence of dose dependency within the range of administered cell doses (1.31-15.56 × 106 CD34+ cells/kg). CONCLUSIONS: General cryopreservation of allogeneic stem cell transplants is feasible. While more than half of the CD34+ cell content is lost, the remaining stem cells ensure timely engraftment.

A Review of Donor Acute Kidney Injury and Posttransplant Outcomes.

Although over 90 000 people are on the kidney transplant waitlist in the United States, some kidneys that are viable for transplantation are discarded. Transplant surgeons are more likely to discard deceased donors with acute kidney injury (AKI) versus without AKI (30% versus 18%). AKI is defined using changes in creatinine from baseline. Transplant surgeons can use DonorNet data, including admission, peak, and terminal serum creatinine, and biopsy data when available to differentiate kidneys with AKI from those with chronic injury. Although chronic kidney disease is associated with reduced graft survival, an abundance of literature has demonstrated similar graft survival for deceased donors with AKI versus donors without AKI. Donors with AKI are more likely to undergo delayed graft function but have similar long-term outcomes as donors without AKI. The mechanism for similar graft survival is unclear. Some hypothesized mechanisms include (1) ischemic preconditioning; (2) posttransplant and host factors playing a greater role in long-term survival than donor factors; and (3) selection bias of transplanting only relatively healthy donor kidneys with AKI. Existing literature suggests transplanting more donor kidneys with stage 1 and 2 AKI, and cautious utilization of stage 3 AKI donors, may increase the pool of viable kidneys. Doing so can reduce the number of people who die on the waitlist by over 500 every year.

Minimizing Risks of Liver Transplantation With Steatotic Donor Livers by Preferred Recipient Matching.

BACKGROUND: Donor livers with ≥30% macrosteatosis (steatotic livers) represent a possible expansion to the donor pool, but are frequently discarded as they are associated with an increased risk of mortality and graft loss. We hypothesized that there are certain recipient phenotypes that would tolerate donor steatosis well, and are therefore best suited to receive these grafts. METHODS: Using national registry data from the Scientific Registry of Transplant Recipients between 2006 and 2017, we compared 2048 liver transplant recipients of steatotic livers with 69 394 recipients of nonsteatotic (<30%) livers. We identified recipient factors that amplified the impact of donor steatosis on mortality and graft loss using interaction analysis, classifying recipients without these factors as preferred recipients. We compared mortality and graft loss with steatotic versus nonsteatotic livers in preferred and nonpreferred recipients using Cox regression. RESULTS: Preferred recipients of steatotic livers were determined to be first-time recipients with a model for end-stage liver disease 15-34, without primary biliary cirrhosis, and not on life support before transplant. Preferred recipients had no increased mortality risk (hazard ratio [HR]: 0.921.041.16; P = 0.5) or graft loss (HR: 0.931.031.15; P = 0.5) with steatotic versus nonsteatotic livers. Conversely, nonpreferred recipients had a 41% increased mortality risk (HR: 1.171.411.70; P < 0.001) and 39% increased risk of graft loss (HR: 1.161.391.66; P < 0.001) with steatotic versus nonsteatotic livers. CONCLUSIONS: The risks of liver transplantation with steatotic donor livers could be minimized by appropriate recipient matching.

Outcomes After Declining a Steatotic Donor Liver for Liver Transplant Candidates in the United States.

BACKGROUND: Steatotic donor livers (SDLs, ≥30% macrosteatosis on biopsy) are often declined, as they are associated with a higher risk of graft loss, even though candidates may wait an indefinite time for a subsequent organ offer. We sought to quantify outcomes for transplant candidates who declined or accepted an SDL offer. METHODS: We used Scientific Registry of Transplant Recipients offer data from 2009 to 2015 to compare outcomes of 759 candidates who accepted an SDL to 13 362 matched controls who declined and followed candidates from the date of decision (decline or accept) until death or end of study period. We used a competing risk framework to understand the natural history of candidates who declined and Cox regression to compare postdecision survival after declining versus accepting (ie, what could have happened if candidates who declined had instead accepted). RESULTS: Among those who declined an SDL, only 53.1% of candidates were subsequently transplanted, 23.8% died, and 19.4% were removed from the waitlist. Candidates who accepted had a brief perioperative risk period within the first month posttransplant (adjusted hazard ratio [aHR]: 2.493.494.89, P < 0.001), but a 62% lower mortality risk (aHR: 0.310.380.46, P < 0.001) beyond this. Although the long-term survival benefit of acceptance did not vary by candidate model for end-stage liver disease (MELD), the short-term risk period did. MELD 6-21 candidates who accepted an SDL had a 7.88-fold higher mortality risk (aHR: 4.807.8812.93, P < 0.001) in the first month posttransplant, whereas MELD 35-40 candidates had a 68% lower mortality risk (aHR: 0.110.320.90, P = 0.03). CONCLUSIONS: Appropriately selected SDLs can decrease wait time and provide substantial long-term survival benefit for liver transplant candidates.

Living Donor Versus Deceased Donor Liver Transplantation for HCC.

INTRODUCTION: Liver transplantation is the definitive treatment modality of the patients having an end-stage liver disease with hepatocellular carcinoma. DISCUSSION: The number of living donor liver transplantations has been increased because of the deceased donor organ shortage, especially in Asian countries. CONCLUSION: Reports of different clinics about the postoperative course and tumor recurrence rates comparing living donor versus deceased donor liver transplantations, besides patient selection criteria, are reviewed along with our clinic's experiences.

What Are the Immune Obstacles to Liver Xenotransplantation Which Is Promising for Patients with Hepatocellular Carcinoma?

PURPOSE: Liver transplantation is the most important achievement in the twentieth and twenty-first century. It is the gold standard treatment for hepatocellular carcinoma. However, it provides the best results when performed under strict selection criteria. Nevertheless, organ supply is overwhelmed by the number of patients on the waiting list. There are certain strategies to expand the donor pool such as split liver transplantation, use of extended criteria donors, and living donor liver transplantation. Xenotransplantation can also be a strategy in decreasing the organ shortage. We reviewed the current status of xenotransplantation. METHODS: We evaluated the historical attempts of xenotransplantation to humans and also made a summary of the preclinical studies in the field. RESULTS: Molecular biology and genetic engineering are developing with an incredible speed. There are great achievements made in cell therapy, 3D bioprinting of the organs, and ultimately xenotransplantation. There is a vast amount of problems to be handled before evaluating the efficacy of xenotransplantation in the treatment of hepatocellular carcinoma. Major problems include antibody-mediated rejection to antigens such as galactose ⍺1-3 galactose, N- glycolylneuraminic acid, ß1,4-N-acetylgalactosaminyltransferase, lethal thrombocytopenia, and erythrocyte sequestration. Antibody mediated rejection to these specific antigens are addressed using gene editing technology including CRISPR Cas9, TALEN and other recombination methods. Although hyperacute rejection is reduced, long-term survival could not be achieved in experimental models. CONCLUSION: The future is yet to come, there are developments made in the field of genetic editing, immunosuppressive medication, and pretransplant desensitization techniques. Therefore, we believe that xenotransplantation will be in clinical practice, at least for treatment of critically ill patients.

Liver Transplantation with "Hors Tour" Allocated Versus Standard MELD Allocated Grafts: Single-Center Audit and Impact on the Liver Pool in France.

BACKGROUND: The French transplant governing system defined "Rescue" (the so-called "Hors Tour") livers as those livers which were declined for the five top-listed patients. This study compares the outcomes following liver transplantation (LT) in patients who received a donor liver through a rescue allocation (RA) procedure or according to MELD score priority (standard allocation, SA) and evaluates the impact on the graft pool of a proactive policy to accept RA grafts. METHODS: Data from all consecutive patients who underwent LT with SA or RA grafts from 2011 to 2015 were compared in terms of short- and long-term outcomes. RESULTS: The 249 elective first LTs were performed with 64 (25.7%) RA and 185 (74.3%) SA grafts. RA grafts were obtained from older donors and were associated with a longer cold ischemia time. Recipients of RA livers were older and had lower MELD scores. The rates of delayed graft function, primary nonfunction, retransplantation, complications, and mortality were similar between the RA and SA groups. At 1 and 3 and 5 years, graft and patient survival rates were similar between the groups. These results were maintained after matching on recipient characteristics. Our proactive policy to accept RA grafts increased the liver pool for elective first transplantation by 25%. CONCLUSIONS: RA livers can be safely transplanted into selected recipients and significantly expand the liver pool.

ABO-incompatible pediatric kidney transplantation without antibody removal.

BACKGROUND: Because of the severe shortage of suitable deceased donors, ABO-incompatible living donor kidney transplantation (ABOi LDKT) is performed even in pediatric recipients in Japan. We performed pediatric ABOi LDKT using rituximab without anti-A/B antibody removal. METHODS: Thirteen pediatric recipients (mean age 7.4, range 3.4-15.7, four females) whose baseline anti-A/B IgG titers were ≤ × 64 underwent ABOi LDKT without antibody removal and splenectomy between July 2013 and April 2017 at Toho University. Mycophenolate mofetil (MMF) was initiated on day - 10. Rituximab (100 mg) was administered twice. Basiliximab and triple maintenance immunosuppression (calcineurin inhibitor, MMF, and steroids) were administered. Protocol biopsy was performed at 3 months and 1 year after transplantation. We retrospectively compared the clinical outcomes between these recipients and 37 children (mean age 9.0, range 2.6-18.9, 15 female) who underwent ABO-compatible (ABOc) LDKT during the same period. RESULTS: The mean follow-up periods of ABOi and ABOc groups were 31.9 ± 13.5 and 28.8 ± 14.4 months, respectively. In the ABOi group, no clinical acute rejection (AR) was noted and subclinical AR was observed in four patients without evidence of acute antibody-mediated rejection. In the ABOc group, clinical and subclinical AR developed in 3 and 10 patients, respectively. No significant difference was identified for the mean eGFR between the ABOi and ABOc groups (98.3 ± 48.8 vs. 86.9 ± 39.4, P = 0.452 at 3 months; 78.2 ± 21.2 vs. 79.7 ± 21.3, at 1 year, P = 0.830). Death-censored graft survival at follow-up was 100% in the ABOi group and 94.6% in the ABOc group. Patient survival during the follow-up period in both the groups was 100%. Late-onset neutropenia (LON) requiring granulocyte colony-stimulating factor occurred more frequently in the ABOi group than in the ABOc group (4 vs. 0 patients) (P < 0.001). CONCLUSIONS: Pre- and post-transplantation antibody removal is not a prerequisite for successful pediatric ABOi LDKT, at least in patients with a low anti-A/B IgG antibody titer. However, LON caused by rituximab should be monitored.

Progenitor-derived human endothelial cells evade alloimmunity by CRISPR/Cas9-mediated complete ablation of MHC expression.

Tissue engineering may address organ shortages currently limiting clinical transplantation. Off-the-shelf engineered vascularized organs will likely use allogeneic endothelial cells (ECs) to construct microvessels required for graft perfusion. Vasculogenic ECs can be differentiated from committed progenitors (human endothelial colony-forming cells or HECFCs) without risk of mutation or teratoma formation associated with reprogrammed stem cells. Like other ECs, these cells can express both class I and class II major histocompatibility complex (MHC) molecules, bind donor-specific antibody (DSA), activate alloreactive T effector memory cells, and initiate rejection in the absence of donor leukocytes. CRISPR/Cas9-mediated dual ablation of ß2-microglobulin and class II transactivator (CIITA) in HECFC-derived ECs eliminates both class I and II MHC expression while retaining EC functions and vasculogenic potential. Importantly, dually ablated ECs no longer bind human DSA or activate allogeneic CD4+ effector memory T cells and are resistant to killing by CD8+ alloreactive cytotoxic T lymphocytes in vitro and in vivo. Despite absent class I MHC molecules, these ECs do not activate or elicit cytotoxic activity from allogeneic natural killer cells. These data suggest that HECFC-derived ECs lacking MHC molecule expression can be utilized for engineering vascularized grafts that evade allorejection.

Donation approval among obese living kidney donor candidates: The impact of metabolic syndrome.

BACKGROUND: The scarcity of organs available for transplantation has increased attempts to augment transplantation by utilizing obese living kidney donors. The literature has suggested that these donors have increased risks postdonation. Not surprising, the threshold for living kidney donor approval among obese persons is typically higher and the process more costly. Therefore, a screening tool to predict the likelihood of approval among obese living kidney donor candidates was created. METHODS: A single-center retrospective study was performed among obese (body mass index ≥ 30 kg/m2) living kidney donor candidates evaluated in clinic (January 1, 2012, to December 31, 2017). Approved candidates were compared with those not approved using multivariable logistic regression, and a prediction tool was generated. RESULTS: Among 389 obese living kidney donor candidates, there were no significant differences in sex or race and ethnicity by approval status. However, nonapproved candidates had a higher prevalence of metabolic syndrome. In the prediction model, glucose impairment and hypertension were most predictive of nonapproval. CONCLUSION: Among obese living kidney donor candidates, several metabolic syndrome components were associated with decreased odds of approval. This tool may serve as a useful initial screening for obese living kidney donor candidates, permitting more cost-effective evaluation processes. The tool could also be used to promote expeditious interventions in the preclinical setting, including weight management programs, to improve the likelihood of donation and postdonation outcomes.

Utilizing increased risk for disease transmission (IRD) kidneys for pediatric renal transplant recipients.

BACKGROUND: Strategies to expand numbers of deceased donor kidneys suitable for pediatric recipients are urgently needed to prevent long-term dialysis-associated morbidity and mortality. Donors designated as increased risk of disease transmission (IRD) are infrequently used in pediatric recipients. We examined outcomes of these kidneys in pediatric patients and the potential to increase the donor pool. METHODS: The United Network for Organ Sharing (UNOS) database records presence of IRD in all deceased donors since 2004. All pediatric kidney transplant recipients from 2004 to 2017 were identified and stratified by IRD status, and outcomes were examined. RESULTS: Four hundred seventy-three pediatric kidney transplant recipients received an IRD allograft. IRD donors had lower kidney donor profile index (KDPI); were more likely to be younger, male, and Caucasian; and were more likely to have used drugs. IRD kidneys were more likely to have been biopsied and placed on pulsatile perfusion. Other than an older recipient age, demographic data were not different between groups. Allograft and patient survivals were similar, as were rejection and delayed graft function rates. Compared with adult recipients and adult IRD recipients, pediatric recipients were more likely to have a younger donor, receive a kidney with a lower creatinine, and were less likely to have delayed graft function (p < 0.05). There were no recorded disease transmissions in IRD group. CONCLUSIONS: Patient and allograft survivals are similar in IRD and non-IRD kidneys. High-quality IRD organs used in adults represent a large number of donors with excellent outcomes. IRD allografts have a potential to increase transplant volume and should be considered for pediatric patients.

Liver transplantation for hepatocellular carcinoma: Where do we stand?

Hepatocellular carcinoma represents an important cause of morbidity and mortality worldwide. It is the sixth most common cancer and the fourth leading cause of cancer death. Liver transplantation is a key tool for the treatment of this disease in human therefore hepatocellular carcinoma is increasing as primary indication for grafting. Although liver transplantation represents an outstanding therapy for hepatocellular carcinoma, due to organ shortage, the careful selection and management of patients who may have a major survival benefit after grafting remains a fundamental question. In fact, only some stages of the disease seem amenable of this therapeutic option, stimulating the debate on the appropriate criteria to select candidates. In this review we focused on current criteria to select patients with hepatocellular carcinoma for liver transplantation as well as on the strategies (bridging) to avoid disease progression and exclusion from grafting during the stay on wait list. The treatments used to bring patients within acceptable criteria (down-staging), when their tumor burden exceeds the standard criteria for transplant, are also reported. Finally, we examined tumor reappearance following liver transplantation. This occurrence is estimated to be approximately 8%-20% in different studies. The possible approaches to prevent this outcome after transplant are reported with the corresponding results.

Anephrogenic phenotype induced by SALL1 gene knockout in pigs.

To combat organ shortage in transplantation medicine, a novel strategy has been proposed to generate human organs from exogenous pluripotent stem cells utilizing the developmental mechanisms of pig embryos/foetuses. Genetically modified pigs missing specific organs are key elements in this strategy. In this study, we demonstrate the feasibility of using a genome-editing approach to generate anephrogenic foetuses in a genetically engineered pig model. SALL1 knockout (KO) was successfully induced by injecting genome-editing molecules into the cytoplasm of pig zygotes, which generated the anephrogenic phenotype. Extinguished SALL1 expression and marked dysgenesis of nephron structures were observed in the rudimentary kidney tissue of SALL1-KO foetuses. Biallelic KO mutations of the target gene induced nephrogenic defects; however, biallelic mutations involving small in-frame deletions did not induce the anephrogenic phenotype. Through production of F1 progeny from mutant founder pigs, we identified mutations that could reliably induce the anephrogenic phenotype and hence established a line of fertile SALL1-mutant pigs. Our study lays important technical groundwork for the realization of human kidney regeneration through the use of an empty developmental niche in pig foetuses.

Liver Transplantation in France.

In France, the main indications for liver transplantation are hepatocellular carcinoma (HCC) and alcoholic cirrhosis. The number of candidates for decompensated hepatitis C virus-related cirrhosis has markedly decreased since the advent of direct-acting antiviral agents. Nonalcoholic steatohepatitis represents a lower proportion of candidates as compared with the United States. The main source of donors is donation after brain death, but the program of transplantation using donation after circulatory death is growing with excellent results. The deceased donation rate was 28.8 per million people in 2017, which has increased over the last few years. Adult-to-adult living donor liver transplantation has been almost completely abandoned. Donors are allocated on a national basis, and there is no longer local or regional priority. In patients with decompensated cirrhosis, prioritization is based on the Model for End-Stage Liver Disease (MELD) score. The distance between the donor and the recipient is taken into account according to an original gravity model. In patients with HCC, prioritization depends on the alfa-fetoprotein (AFP) score, the MELD score, and waiting time. Only patients with HCC tumor-node-metastasis ≥2 and AFP score ≤2 are eligible for the HCC score. A list of MELD exceptions, consisting of uncommon complications where mortality risk is not adequately predicted by the MELD score and conditions other than cirrhosis, has been established. MELD exceptions must be individually validated by a college of experts mandated by the French Regulatory Agency of Transplantation (Agence de la Biomédecine). The most common MELD exception is refractory ascites with a low MELD score. A major challenge is to reduce the rate of refusal of donation through information campaigns.

Patient outcomes from time of listing for lung transplantation in the UK: are there disease-specific differences?

BACKGROUND: The demand for lung transplantation vastly exceeds the availability of donor organs. This translates into long waiting times and high waiting list mortality. We set out to examine factors influencing patient outcomes from the time of listing for lung transplantation in the UK, examining for differences by patient characteristics, lung disease category and transplant centre. METHODS: Data were obtained from the UK Transplant Registry held by NHS Blood and Transplant for adult lung-only registrations between 1January 2004 and 31 March 2014. Pretransplant and post-transplant outcomes were evaluated against lung disease category, blood group and height. RESULTS: Of the 2213 patient registrations, COPD comprised 28.4%, pulmonary fibrosis (PF) 26.2%, cystic fibrosis (CF) 25.4% and other lung pathologies 20.1%. The chance of transplantation after listing differed by the combined effect of disease category and centre (p<0.001). At 3 years postregistration, 78% of patients with COPD were transplanted followed by 61% of patients with CF, 59% of other lung pathology patients and 48% of patients with PF, who also had the highest waiting list mortality (37%). The chance of transplantation also differed by height with taller patients having a greater chance of transplant (HR: 1.03, 95% CI: 1.02 to 1.04, p<0.001). Patients with blood group O had the highest waiting mortality at 3 years postregistration compared with all other blood groups (27% vs 20%, p<0.001). CONCLUSIONS: The way donor lungs were allocated in the UK resulted in discrepancies between the risk profile and probability of lung transplantation. A new donor lung allocation scheme was introduced in 2017 to try to address these shortcomings.

Expansion of the Liver Donor Supply Through Greater Use of Split-Liver Transplantation: Identifying Optimal Recipients.

The increased use of split-liver transplantation (SLT) represents a strategy to increase the supply of organs. Although outcomes after SLT and whole liver transplantation (WLT) are similar on average among pediatric recipients, we hypothesized that the relationship between graft type and outcomes may vary depending on patient, donor, and surgical characteristics. We evaluated graft survival among pediatric (<18 years) deceased donor, liver-only transplant recipients from March 2002 until December 2015 using data from the Scientific Registry of Transplant Recipients. Graft survival was assessed in a Cox proportional hazards model, with and without effect modification between graft type and donor, recipient, and surgical characteristics, to identify conditions where the risk of graft loss for SLT and WLT were similar. In a traditional multivariable model, characteristics associated with graft loss included donor age >50 years, recipient weight <10 kg, acute hepatic necrosis, autoimmune diseases, tumor, public insurance, and cold ischemia time (CIT) >8 hours. In an analysis that explored whether these characteristics modified the relationship between graft type and graft loss, many characteristics associated with loss actually had similar outcomes regardless of graft type, including weight <10 kg, acute hepatic necrosis, autoimmune diseases, and tumor. In contrast, several subgroups had worse outcomes when SLT was used, including recipient weight 10-35 kg, non-biliary atresia cholestasis, and metabolic disease. Allocation score, share type, or CIT did not modify risk of graft type and graft failure. Although one might anticipate that individuals with higher rates of graft loss would be worse candidates for SLT, data suggest that these patients actually have similar rates of graft loss. These findings can guide surgical decision making and may support policy changes that promote the increased use of SLT for specific pediatric recipients.

Update on the supply and use of allografts in locomotor system pathologies in France.

Allografts are increasingly used in orthopedics. The main aim of the present study was to map the use of locomotor system allografts in France between 2012 and 2016. The study hypothesis was that there are great differences in the distribution and activity of tissue banks and graft preservation procedure quality, failing to meet national requirements. MATERIAL AND METHODS: Data from activity reports of the French Biomedicine Agency (ABM) were collected for the period 2012-2016. Existing viral inactivation procedures were described. Preliminary results from a study of allograft requirements by the French Society of Arthroscopy (SFA) were reported. RESULTS: Nineteen tissue banks were located. Four dealt exclusively with cryopreserved tissue, 3 exclusively with virus-inactivated bone, and 12 with both. Distribution analysis found wide disparities in geographic location and in type of activity. Viral inactivation is presently implemented only for femoral heads derived from hip replacement. Stocks of long bones, femoral heads and ligaments/tendons increased constantly over the study period, by 8.3%, 50.8% and 316.2% respectively. The SFA questionnaire confirmed a serious shortage of tissues, necessitating importation of allografts. DISCUSSION: Each tissue bank had its own specificities and specialization. They should probably be coalesced, so as to centralize both supply and demand and improve nationwide response to requirements. Locomotor system tissue harvesting also needs to be expanded to meet increasing demand.

Domino Hepatocyte Transplantation: A Therapeutic Alternative for the Treatment of Acute Liver Failure.

Background and Aims: Acute liver failure (ALF) is a severe syndrome with an elevated mortality rate, ranging from 40 to 80 %. Currently, liver transplantation is the only definitive treatment for these patients and new therapies aiming to treat ALF include artificial organs implant and stem cells therapy, for example. However, a major limitation of liver donors exists. Living donor liver transplantation (LDLT), split liver transplantation (SLT), and domino liver transplantation (DLT) are some of the available alternatives to treat ALF patients, but these do not reduce the number of patients on waiting lists. Herein, we discuss domino hepatocyte transplantation (DHT) using livers that would not meet transplantation criteria. Methods: We conducted a literature search on PubMed/Medline using acute liver failure, liver transplantation, hepatocyte transplantation, and domino liver transplantation as key words. Results: New sources of biochemically functional hepatocytes and therapeutic treatments, in parallel to organ transplantation, may improve liver injury recovery and decrease mortality rates. Moreover, the literature reports hepatocyte transplantation as a therapeutic alternative for organ shortage. However, a major challenge remains for a wide clinical application of hepatocytes therapy, i.e., the availability of sufficient amounts of cells for transplantation. Ideally, hepatocytes isolated from livers rejected for transplantation may be a promising alternative for this problem. Conclusion: Our review suggests that DHT may be an excellent strategy to increase cell supplies for hepatocyte transplantation.