Liver Cell Transplantation Research Articles

Incidence of skin cancer development in pancreatic islet cell transplant patients: A retrospective study

To the Editor: Long-term survivors of solid organ transplants are at an increased risk of malignancies, most commonly skin cancer.1 While the risks of heart, lung, kidney, kidney-pancreas, liver, and hematopoietic cell transplant recipients are established, there are limited data on pancreatic islet cell transplant (ICT) recipients.2 ICT is an effective beta-cell replacement therapy performed to normalize glycemic control in patients with type 1 diabetes mellitus3 and/or as a treatment for patients with chronic pancreatitis.

Brucellosis in transplant recipients: A systematic review.

Brucellosis is a bacterial disease caused by Brucella species. The purpose of this study was to evaluate brucellosis in all types of transplant patients. All the cases of brucellosis in transplant patients with no time and language limitations were searched and retrieved on May 20, 2020, using the following search keywords: (Brucella OR Brucellosis) AND (Transplant OR Transplantation) through the following medical databases: Web of Sciences, Google Scholar, Scopus, PubMed, and regional databases, for example, SID. All clinical features, including the time of transmission (before, during, and after transplantation), treatment protocols and medications, and patients' outcomes were investigated. A total of 14 cases reported in 14 studies (out of 777 studies) were retrieved. Kidney (50%), liver (28.5%), and hematopoietic stem cell transplantation (14.2%) were the most reported types of transplantation. The presentation of brucellosis in 42.8% of the patients occurred in the early post-transplantation period, whereas 57.1% of the cases presented with late onset disease. Brucellosis in transplant recipients seems to be uncommon even in the endemic regions. However, rare cases could be transmitted through bone marrow transplantation and transfusion. Precise screening and meticulous supervision during and after transplantation might lead to a reduction in the frequency of brucellosis.

Generation of reconstituted hemato-lymphoid murine embryos by placental transplantation into embryos lacking HSCs

In order to increase the contribution of donor HSC cells, irradiation and DNA alkylating agents have been commonly used as experimental methods to eliminate HSCs for adult mice. But a technique of HSC deletion for mouse embryo for increase contribution of donor cells has not been published. Here, we established for the first time a procedure for placental HSC transplantation into E11.5 Runx1-deficient mice mated with G1-HRD-Runx1 transgenic mice (Runx1-/-::Tg mice) that have no HSCs in the fetal liver. Following the transplantation of fetal liver cells from mice (allogeneic) or rats (xenogeneic), high donor cell chimerism was observed in Runx1-/-::Tg embryos. Furthermore, chimerism analysis and colony assay data showed that donor fetal liver hematopoietic cells contributed to both white blood cells and red blood cells. Moreover, secondary transplantation into adult recipient mice indicated that the HSCs in rescued Runx1-/-::Tg embryos had normal abilities. These results suggest that mice lacking fetal liver HSCs are a powerful tool for hematopoiesis reconstruction during the embryonic stage and can potentially be used in basic research on HSCs or xenograft models.

Population pharmacokinetics of mycophenolic acid in paediatric patients.

Mycophenolic acid (MPA) is widely used in paediatric kidney transplant patients and sometimes prescribed for additional indications. Population pharmacokinetic or pharmacodynamic modelling has been frequently used to characterize the fixed, random and covariate effects of MPA in adult patients. However, MPA population pharmacokinetic data in the paediatric population have not been systematically summarized. The objective of this narrative review was to provide an up-to-date critique of currently available paediatric MPA population pharmacokinetic models, with emphases on modelling techniques, pharmacological findings and clinical relevance. PubMed and EMBASE were searched from inception of database to May 2020, where a total of 11 studies have been identified representing kidney transplant (n = 4), liver transplant (n = 1), haematopoietic stem cell transplant (n = 1), idiopathic nephrotic syndrome (n = 2), systemic lupus erythematosus (n = 2), and a combined population consisted of kidney, liver and haematopoietic stem cell transplant patients (n = 1). Critical analyses were provided in the context of MPA absorption, distribution, metabolism, excretion and bioavailability in this paediatric database. Comparisons to adult patients were also provided. With respect to clinical utility, Bayesian estimation models (n = 6) with acceptable accuracy and precision for MPA exposure determination have also been identified and systematically evaluated. Overall, our analyses have identified unique features of MPA clinical pharmacology in the paediatric population, while recognizing several gaps that still warrant further investigations. This review can be used by pharmacologists and clinicians for improving MPA pharmacokinetic-pharmacodynamic modelling and patient care.

Waitlisted Transplant Candidates’ Attitudes and Concerns Toward Transplantation During COVID-19

BackgroundIn solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) recipients, coronavirus disease 2019 (COVID-19) can contribute to a severe clinical course and an increased risk of death. Thus, patients awaiting a SOT or HSCT face the dilemma of choosing between a life-saving treatment that presents a significant threat of COVID-19 and the risk of waitlist dropout, progression of disease, or mortality. The lack of established literature on COVID-19 complicates the issue as patients, particularly those with inadequate health literacy, may not have the resources needed to navigate these decisions.Material/MethodsWe conducted a standardized phone survey of patients awaiting SOT or HSCT to assess the prevalence of inadequate health literacy and attitudes toward transplant during the COVID-19 pandemic.ResultsSeventy-one patients completed the survey, with a response rate of 84.5%. Regardless of health literacy, most waitlisted candidates recognized that the current pandemic is a serious situation affecting their care and that COVID-19 poses a significant risk to their health. Despite the increased risks, most patients reported they would choose immediate transplantation if there was no foreseeable end to the pandemic, and especially if the medical urgency did not permit further delay. There were no differences in responses across the patient waitlist groups for heart, kidney, liver, and stem cell transplant.ConclusionsThese findings can help transplant centers decide how transplantation services should proceed during this pandemic and can be used to educate patients and guide discussions about informed consent for transplant during the COVID-19 pandemic.

PRO56 The Epidemiology of Transthyretin Amyloid Cardiomyopathy in Sweden

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a rare and fatal disease caused by deposition of transthyretin amyloid fibrils in the heart. The prevalence of ATTR-CM is largely unknown due to fragmented knowledge of the disease, underdiagnosing and limitations of current diagnostic methods. This study aims to estimate the age and sex specific prevalence and study the epidemiology of ATTR-CM in Sweden. This was a retrospective, observational study which utilized data extracted from nation-wide Swedish administrative health registers covering the years 1998 to 2018. ATTR-CM patients were identified between 2008 and 2018 using diagnosis of amyloidosis in combination with either heart failure or cardiomyopathy. The years 1998 -2008 were used as look-back period. Patients with light chain amyloidosis (AL), Multiple Myeloma (MM) and previous heart, liver or stem cell transplants were excluded. In the process of patient identification, 497 patients were excluded due to AL, MM or transplants. A remaining total of 994 diagnosed ATTR-CM patients were identified over the study period. Between 2008-2013, an average of 79 patients were identified per year, between 2014-2018 this number rose to 104 patients per year. The average age at identification increased from 70 to 76 years between 2008 and 2018. During the study period the estimated prevalence of ATTR-CM cases increased from 1.04/100,000 in 2008 to 4.99/100,000 in 2018. In 2018, the majority of diagnosed ATTR-CM patients was male (75%) and above age 75 (52%). This is the first Nordic Study estimating the prevalence of ATTR-CM using a national dataset over a period of 11 years. The prevalence and average age over time likely reflect increased awareness and the adaption of non- invasive imaging modalities in recent years. The estimated prevalence in 2018 is still well below the threshold of 50/100,000 used by the European Medicines Agency for orphan designation.

Recommended parameters for hepatocyte isolation-a review

<p>There is an increasing demand for primary human hepatocytes for toxico-pharmacological studies and for exploring their role in liver cell transplantation. During the whole process of isolation, culture and cryopreservation hepatocytes are subjected to various stress. All these factors will lead to the impairment in the metabolic capability of the hepatocytes post isolation. Hepatocyte isolation is an expensive and resource driven procedure. Thus, it is important to consider all the factors before we subject the specimen for isolation of cells. By considering the factors that influence hepatocyte isolation, hepatocytes of good quality can be obtained. With recommendations on the ideal parameters for isolation being made the researcher shall have a knowledge on what critical factors need to be taken care of during hepatocyte isolation. There will be an opportunity to modify critical factors if possible, during the procurement of specimen by working in tandem with the clinicians. The specimen which shall be deemed un fit when two or more factors have exceeded the critical limits can be rejected.</p>

Induced pluripotent stem cells for the treatment of liver diseases: challenges and perspectives from a clinical viewpoint.

The only curative treatment for severe end-stage liver disease (ESLD) is liver transplantation (LT) but it is limited by the shortage of organ donors. The increase of the incidence of liver disease has led to develop new therapeutic approaches such as liver cell transplantation. Current challenges that limit a wider application of this therapy include a limited cell source and the poor engraftment in the host liver of cryopreserved hepatocytes after thawing. Induced pluripotent stem cells (iPSCs) that can be differentiated into hepatocyte-like cells (HLCs) are being widely explored as an alternative to human hepatocytes because of their unlimited proliferation capacity and their potential ability to avoid the immune system. Their large-scale production could provide a new tool to produce enough HLCs for treating patients with metabolic diseases, acute liver failure (ALF), those with ESLD or patients not considered for organ transplantation. In this review we discuss current challenges for generating differentiated cells compatible with human application as well as in-depth safety evaluation. This analysis highlights the uncertainties and deficiencies that should be addressed before their clinical use but also points out the potential benefits that will produce a great impact in the field of hepatology.

Long-Term Survival of Transplanted Autologous Canine Liver Organoids in a COMMD1-Deficient Dog Model of Metabolic Liver Disease.

The shortage of liver organ donors is increasing and the need for viable alternatives is urgent. Liver cell (hepatocyte) transplantation may be a less invasive treatment compared with liver transplantation. Unfortunately, hepatocytes cannot be expanded in vitro, and allogenic cell transplantation requires long-term immunosuppression. Organoid-derived adult liver stem cells can be cultured indefinitely to create sufficient cell numbers for transplantation, and they are amenable to gene correction. This study provides preclinical proof of concept of the potential of cell transplantation in a large animal model of inherited copper toxicosis, such as Wilson’s disease, a Mendelian disorder that causes toxic copper accumulation in the liver. Hepatic progenitors from five COMMD1-deficient dogs were isolated and cultured using the 3D organoid culture system. After genetic restoration of COMMD1 expression, the organoid-derived hepatocyte-like cells were safely delivered as repeated autologous transplantations via the portal vein. Although engraftment and repopulation percentages were low, the cells survived in the liver for up to two years post-transplantation. The low engraftment was in line with a lack of functional recovery regarding copper excretion. This preclinical study confirms the survival of genetically corrected autologous organoid-derived hepatocyte-like cells in vivo and warrants further optimization of organoid engraftment and functional recovery in a large animal model of human liver disease.

Alginate microencapsulated human hepatocytes for the treatment of acute liver failure in children

Liver transplantation (LT) is the most effective treatment for patients with acute liver failure (ALF), but is limited by surgical risks and the need for life-long immunosuppression. Transplantation of microencapsulated human hepatocytes in alginate is an attractive option over whole liver replacement. The safety and efficacy of hepatocyte microbead transplantation have been shown in animal models. We report our experience of this therapy in children with ALF treated on a named-patient basis. Clinical grade human hepatocyte microbeads (HMBs) and empty microbeads were tested in immunocompetent healthy rats. Subsequently, 8 children with ALF, who were awaiting a suitable allograft for LT, received intraperitoneal transplantation of HMBs. We monitored complications of the procedure, assessing the host immune response and residual function of the retrieved HMBs, either after spontaneous native liver regeneration or at the time of LT. Intraperitoneal transplantation of HMBs in healthy rats was safe and preserved synthetic and detoxification functions, without the need for immunosuppression. Subsequently, 8 children with ALF received HMBs (4 neonatal haemochromatosis, 2 viral infections and 2 children with unknown cause at time of infusion) at a median age of 14.5 days, range 1 day to 6 years. The procedure was well tolerated without complications. Of the 8 children, 4 avoided LT while 3 were successfully bridged to LT following the intervention. HMBs retrieved after infusions (at the time of LT) were structurally intact, free of host cell adherence and contained viable hepatocytes with preserved functions. The results demonstrate the feasibility and safety of an HMB infusion in children with ALF. Acute liver failure in children is a rare but devastating condition. Liver transplantation is the most effective treatment, but it has several important limitations. Liver cell (hepatocyte) transplantation is an attractive option, as many patients only require short-term liver support while their own liver recovers. Human hepatocytes encapsulated in alginate beads can perform the functions of the liver while alginate coating protects the cells from immune attack. Herein, we demonstrated that transplantation of these beads was safe and feasible in children with acute liver failure.

Prognostication of inflammatory cells in liver transplantation: Is the waitlist neutrophil-to-lymphocyte ratio really predictive of tumor biology?

The objective of this retrospective study was to characterize the neutrophil to lymphocyte ratio (NLR) on the waitlist and determine its prognostic utility in liver transplantation (LT) for hepatocellular carcinoma (HCC) with special focus on longitudinal data. Biomarkers such as pre-operative NLR have been suggested to predict poor oncological outcomes for patients with HCC seeking LT. NLR's utility is thought to be related to tumor biology. However, recent studies have demonstrated that a high NLR conveys worse outcomes in non-HCC cirrhotics. This study investigated the relationship between NLR, liver function, tumor factors and patient prognosis. Patients with HCC undergoing LT were identified between 2002 and 2014 (n=422). Variables of interest were collected longitudinally from time of listing until LT. The prognostic utility of NLR was assessed using Kaplan-Meier and Cox Proportional Hazard regression. Associations between NLR and MELD-Na, AFP, and tumor morphology were also assessed. NLR demonstrated a positive correlation with MELD-Na at LT (R2=0.125, P<0.001) and had parallel trends over time. The lowest NLR quartile had a median MELD-Na of 9 while the highest had a median MELD-Na of 19. There were minimal differences in AFP, tumor morphology, and rates of vascular invasion between quartiles. NLR was a statistically significant predictor of OS (HR=1.64, P=0.017) and recurrence (HR=1.59, P=0.016) even after controlling for important tumor factors. However, NLR lost its statistical significance when MELD-Na was added to the Cox regression model (OS: HR=1.46, P=0.098) (recurrence: HR=1.40, P=0.115). NLR is a highly volatile marker on the waitlist that demonstrates a significant correlation and collinearity with MELD-Na temporally and at the time of LT. These characteristics of NLR bring into question its utility as a predictive marker in HCC patients.

A murine model demonstrating reversal of structural and functional correlates of cirrhosis with progenitor cell transplantation

Development of cell transplantation for treating liver cirrhosis hinges critically on the availability of animal models for studying human stem cell transplantation. We report an immune-permissive murine model of liver cirrhosis with full clinical correlates of decompensated liver disease, and allows testing efficacy of stem cell transplantation. Liver cirrhosis was induced in Nod-scid gamma(NSG) mice with oral thioacetamide(TA) and compared to controls over 12 months. 4 month TA treated cirrhotic mice were then transplanted intrasplenically with 2million human fetal liver progenitor cells(HFH) and compared with cirrhotic controls 2 months after transplantation. NSG-TA mice developed shrunken and nodular livers with histological evidence of fibrosis as compared to controls. This was associated with evidence of worsening decompensated liver disease, with jaundice, hypoalbuminemia, coagulopathy, and encephalopathy in NSG-TA mice. Transplantation of HFH resulted in improvement in both fibrosis and markers of decompensated liver disease. We have demonstrated that NSG-TA mice can recapitulate the full clinical picture of structural and functional cirrhosis, both of which can be improved by transplantation of human fetal liver cells. This model serves as a valuable tool for validation of in vivo liver stem cell transplantation and opens up opportunities for studying the mechanism how stem cells reverse fibrosis.

Translation, adaptation, and reliability of the Stanford Integrated Psychosocial Assessment for Transplantation in the Spanish population.

Psychosocial risk factors influence the course of transplantation. Psychosocial evaluation is an important part of pre-transplantation evaluation processes, yet there are no standardized instruments in Spanish. To translate, adapt, and test the reliability of the Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT) in organ and cell transplantation patients in the Spanish context. A Spanish version was developed and adapted using WHO's guidelines. The first 30 candidates' SIPAT interviews were recorded and scored by four independent examiners to test the inter-rater reliability. The internal consistency of the SIPAT items was calculated with a sample of 150 heart, liver, and allogeneic haematopoietic stem cell transplant candidates. Evaluations were conducted by SIPAT-trained and transplantation-experienced clinical psychologists and psychiatrists. Stanford Integrated Psychosocial Assessment for Transplantation achieved excellent intra-class correlation reliability coefficients between investigators (ICC=0.93 for the general score and from 0.77 to 0.94 for domain scores). Good internal consistency was found with Cronbach's alpha of 0.84 (from 0.69-0.71 for domains). This study presents the translated and adapted version of SIPAT. It has been found to have strong inter-rater reliability and good internal consistency. Further research is needed to confirm reliability (eg, test-retest) and establish its validity (eg, concurrent, predictive).

Assessment of animal experimental models of toxic liver injury in the context of their potential application as preclinical models for cell therapy

Preclinical animal models allow to study development and progression of several diseases, including liver disorders. These studies, for ethical reasons and medical limits, are impossible to carry out in human patients. At the same time, such experimental models constitute an important source of knowledge on pathomechanisms for drug- and virus-induced hepatotoxicity, both acute and chronic. Carbon tetrachloride, D-Galactosamine, and retrorsine are xenobiotics that can be used in immunocompetent animal models of hepatotoxicity, where chemical-intoxicated livers present histological features representative of human viruses-related infection.A prolonged derangement into liver architecture and functions commonly lead to cirrhosis, eventually resulting in hepatocellular carcinoma. In human, orthotopic liver transplantation commonly resolve most the problems related to cirrhosis. However, the shortage of donors does not allow all the patients in the waiting list to receive an organ on time.A promising alternative treatment for acute and chronic liver disease has been advised in liver cell transplantation, but the limited availability of hepatocytes for clinical approaches, in addition to the immunosuppressant regiment required to sustain cellular long-term engraftment have been encouraging the use of alternative cell sources. A recent effective source of stem cells have been recently identified in the human amnion membrane. Human amnion epithelial cells (hAEC) have been preclinically tested and proven sufficient to rescue immunocompetent rodents lethally intoxicated with drugs. The adoption of therapeutic procedures based on hAEC transplant in immunocompetent recipients affected by liver diseases, as well as patients with immune-related disorders, may constitute a successful new alternative therapy in regenerative medicine.

Generation of human hepatic progenitor cells with regenerative and metabolic capacities from primary hepatocytes.

Hepatocytes are regarded as the only effective cell source for cell transplantation to treat liver diseases; however, their availability is limited due to a donor shortage. Thus, a novel cell source must be developed. We recently reported that mature rodent hepatocytes can be reprogrammed into progenitor-like cells with a repopulative capacity using small molecule inhibitors. Here, we demonstrate that hepatic progenitor cells can be obtained from human infant hepatocytes using the same strategy. These cells, named human chemically induced liver progenitors (hCLiPs), had a significant repopulative capacity in injured mouse livers following transplantation. hCLiPs redifferentiated into mature hepatocytes in vitro upon treatment with hepatic maturation-inducing factors. These redifferentiated cells exhibited cytochrome P450 (CYP) enzymatic activities in response to CYP-inducing molecules and these activities were comparable with those in primary human hepatocytes. These findings will facilitate liver cell transplantation therapy and drug discovery studies.

Multisite Injection of Bioengineered Hepatic Units from Collagen Hydrogel and Neonatal Liver Cells in Parenchyma Improves Liver Cirrhosis.

Intrahepatic transplantation of hepatocytes/progenitor cells remodels or repopulates livers resulting in improved hepatic function, which represents a promising treatment option for liver diseases, but poor engraftment of transplanted liver cells in livers has been the major obstacle for exerting therapeutic efficacy on liver diseases. We herein demonstrated great potential of multisite injection of bioengineered hepatic units generating from collagen hydrogel and neonatal liver cells (MSI) in promoting engraftment, survival of liver cells, and the therapeutic potential of liver diseases in livers. The MSI allowed transplantation of large number of liver cells into parenchyma in one time. Superiorly, the MSI promoted the engraftment and survival of liver cells, and generated large, dispersively distributed tissue masses whose sizes were positively correlated with the number of injection sites in livers. Consistently, the MSI improved liver cirrhosis as evidenced by the reduction of collagen matrix deposit, improved liver architecture, and hepatic function in the MSI group compared to that of the nontreated control. These data indicate that the MSI represents a novel, improved bioengineered strategy that can exert therapeutic efficacy on liver diseases.

Equally Interchangeable? How Sex and Gender Affect Transplantation.

Organ transplantation as an option to overcome end-stage diseases is common in countries with advanced healthcare systems and is increasingly provided in emerging and developing countries. A review of the literature points to sex- and gender-based inequity in the field with differences reported at each step of the transplant process, including access to a transplantation waiting list, access to transplantation once waitlisted, as well as outcome after transplantation. In this review, we summarize the data regarding sex- and gender-based disparity in adult and pediatric kidney, liver, lung, heart, and hematopoietic stem cell transplantation and argue that there are not only biological but also psychological and socioeconomic issues that contribute to disparity in the outcome, as well as an inequitable access to transplantation for women and girls. Because the demand for organs has always exceeded the supply, the transplant community has long recognized the need to ensure equity and efficiency of the organ allocation system. In the spirit of equity and equality, the authors call for recognition of these inequities and the development of policies that have the potential to ensure that girls and women have equitable access to transplantation.

ADMINISTRATION OF BONE MARROW DERIVED MESENCHYMAL STEM CELLS MODULATE TLR EXPRESSION DURING LIVER REGENERATION

Liver cell transplantation is a powerful alternative to orthotopic cell transplantation in the treatment of liver failures. Recently, considerable effort is being channeled to understand the nature and kinetics of directing stem cells to effectively accumulate at the regenerating liver site. Mesenchymal stem cells are one of the promising cell sources modulating liver regeneration process. Present was designed to study how mesenchymal stem cells might modulate liver immune behaviors by changing Toll-like receptor (TLR) expression and increase regenerative potential during liver regeneration in rats. Normal and partially hepatectomized rats were treated with mesenchymal stem cells isolated and expanded from rat bone marrows. Accumulation of mesenchymal stem cells was confirmed by Real Time-Polymerase Chain Reaction (RT-PCR), Fluorescence-Activated Cell Sorting (FACS), and Immunofluorescence Staining (IFS). Student's t-test analysis was used to evaluate the significance of differences between sham and partially hepatectomized rat groups. Our results showed that mesenchymal stem cells expressed several TLRs, and their accumulation during regeneration was depended on the timing of injury. Mesenchymal stem cells isolated from bone marrow of normal rats were observed at the injured liver 3 days after the injection. There were no labeled mesenchymal stem cells in the liver sections of the uninjured animals. Mesenchymal stem cell administration significantly altered the expression of TLR2, 3 and 9 while retaining their migration potential to regenerating liver. Our findings implicated that mesenchymal stem cell administration during liver regeneration modulate the immune response through changing the expression of the TLRs in the remaining liver parts into which the cells are recruited or infused. This alteration may contribute to the regeneration process following partial hepatectomy.

Combined liver and hematopoietic stem cell transplantation in patients with X-linked hyper-IgM syndrome

Combined liver and hematopoietic stem cell transplantation in patients with X-linked hyper-IgM syndrome

Volume-outcome relationship and minimum volume regulations in the German hospital sector \u2013 evidence from nationwide administrative hospital data for the years 2005\u20132007

BackgroundThis paper analyses the volume-outcome relationship and the effects of minimum volume regulations in the German hospital sector.MethodsWe use a full sample of administrative data from the unselected, complete German hospital population for the years 2005 to 2007. We apply regression methods to analyze the association between volume and hospital quality. We measure hospital quality with a binary variable, which indicates whether the patient has died in hospital. Using simulation techniques we examine the impact of the minimum volume regulations on the accessibility of hospital services.ResultsWe find a highly significant negative relationship between case volume and mortality for complex interventions at the pancreas and oesophagus as well as for knee replacement. For liver, kidney and stem cell transplantation as well as for CABG we could not find a strong association between volume and quality. Access to hospital care is only moderately affected by minimum volume regulations.ConclusionThe effectiveness of minimum volume regulations depends on the type of intervention. Depending on the type of intervention, quality gains can be expected at the cost of slightly decreased access to care.