Liver Disease Stem Cell Treatment

Liver Disease and Stem Cell Therapy at SIRM


Liver Disease and Stem Cell Treatment

Liver Disease and Stem Cell Treatment

What is Liver Disease?
The liver is under your ribs on the right hand side. The liver is the largest organ in the body and if the liver fails completely then untreated only 3-4 days to find a donor liver for a possible transplant.

Corrently there is no such thing as an artificial liver.

The liver not only produces many proteins it creates energy from our food. The liver removes waste products in our body and also removes unwanted drugs such as nicotine and alcohol.

The most common Liver conditions include infections such as hepatitis A, B, C, E, alcohol damage, fatty liver, cirrhosis, cancer, drug damage especially paracetamol (acetaminophen) and cancer drugs.


The liver does not have any pain nerves so liver disease can be unexpected.
Liver disease is commonly related to alcohol and diet problems.



Use of hepatocyte and stem cells for treatment of post-resectional liver failure: are we there yet?

Ezzat TM, Dhar DK, Newsome PN, Malagó M, Olde Damink SW.

2011 Jul;31(6):773-84. doi: 10.1111/j.1478-3231.2011.02530.x. Epub 2011 Apr 19.

HPB and Liver Transplantation Surgery, Royal Free Hospital, University College London, Pond Street, London, UK.

Post-operative liver failure following extensive resections for liver tumours is a rare but significant complication. The only effective treatment is liver transplantation (LT); however, there is a debate about its use given the high mortality compared with the outcomes of LT for chronic liver diseases.

Cell therapy has emerged as a possible alternative to LT especially as endogenous hepatocyte proliferation is likely inhibited in the setting of prior chemo/radiotherapy. Both hepatocyte and stem cell transplantations have shown promising results in the experimental setting; however, there are few reports on their clinical application.

This review identifies the potential stem cell sources in the body, and highlights the triggering factors that lead to their mobilization and integration in liver regeneration following major liver resections.

Therapeutic plasticity of stem cells and allograft tolerance.

Cytotherapy. 2011 May 10;

Authors: Sordi V, Piemonti L

Abstract Transplantation is the treatment of choice for many diseases that result in organ failure, but its success is limited by organ rejection. Stem cell therapy has emerged in the last years as a promising strategy for the induction of tolerance after organ transplantation. Here we discuss the ability of different stem cell types, in particular mesenchymal stromal cells, neuronal stem/progenitor cells, hematopoietic stem cells and embryonic stem cells, to modulate the immune response and induce peripheral or central tolerance.

These stem cells have been studied to explore tolerance induction to several transplanted organs, such as heart, liver and kidney. Different strategies, including approaches to generating tolerance in islet transplantation, are discussed here.

PMID: 21554176 [PubMed - as supplied by publisher]



Impaired function of bone marrow-derived endothelial progenitor cells in  murine liver fibrosis.

Biosci Trends. 2011 Apr;5(2):77-82

Authors: Shirakura K, Masuda H, Kwon SM, Obi S, Ito R, Shizuno T, Kurihara Y,  Mine T, Asahara T

Liver fibrosis (LF) caused by chronic liver damage has been considered as an  irreversible disease. As alternative therapy for liver transplantation, there  are high expectations for regenerative medicine of the liver.

Bone marrow (BM)-  or peripheral blood-derived stem cells, including endothelial progenitor cells  (EPCs), have recently been used to treat liver cirrhosis. We investigated the  biology of BM-derived EPC in a mouse model of LF. C57BL/6J mice were  subcutaneously injected with carbon tetrachloride (CCl4)  every 3 days for 90 days. Sacrificed 2 days after final injection, whole blood  (WB) was collected for isolation of mononuclear cells (MNCs) and biochemical  examination.

Assessments of EPC in the peripheral blood and BM were performed by  flow cytometry and EPC colonyforming assay, respectively, using purified MNCs  and BM c-KIT+, Sca-1+, and  Lin- (KSL) cells.

Liver tissues underwent histological  analysis with hematoxylin/eosin/Azan staining, and spleens were excised and  weighed. CCl4-treated mice exhibited histologically  bridging fibrosis, pseudolobular formation, and splenomegaly, indicating  successful induction of LF.

The frequency of definitive EPC-colony-forming-units  (CFU) as well as total EPC-CFU at the equivalent cell number of 500 BM-KSL cells  decreased significantly (p < 0.0001) in LF mice compared with control mice;  no significant changes in primitive EPC-CFU occurred in LF mice.

The frequency  of WB-MNCs of definitive EPC-CFU decreased significantly (p < 0.01) in LF  mice compared with control mice. Together, these findings indicated the  existence of impaired EPC function and differentiation in BM-derived EPCs in LF  mice and might be related to clinical LF.

PMID: 21572251 [PubMed - in process]

Related Articles Sox9 regulates self-renewal and tumorigenicity by promoting symmetrical cell division of cancer stem cells in hepatocellular carcinoma. Hepatology. 2016 Jul;64(1):117-29 Authors: Liu C, Liu L, Chen X, Cheng J, Zhang H, Shen J, Shan J, Xu Y, Yang Z, Lai M, Qian C Abstract UNLABELLED: Hepatocellular carcinoma (HCC) is a highly aggressive liver tumor containing cancer stem cells (CSCs) that participate in tumor propagation, resistance to conventional therapy, and promotion of tumor recurrence, causing poor patient outcomes. The protein SRY (sex determining region Y)-box 9 (Sox9) is a transcription factor expressed in some solid tumors, including HCC. However, the molecular mechanisms underlying Sox9 function in liver CSCs remain unclear. Here, we show that Sox9 is highly expressed in liver CSCs and that high levels of Sox9 predict a decreased probability of survival in HCC patients. We demonstrate that Sox9 is required for maintaining proliferation, self-renewal, and tumorigenicity in liver CSCs. Overexpression of exogenous Sox9 in liver non-CSCs restored self-renewal capacity. Additionally, a reduction in the asymmetrical cell division of spheroid-cultured liver CSCs was observed when compared with differentiated cancer cells or liver CSCs with inhibited Notch signaling. Furthermore, we demonstrate that Sox9 is responsible for the asymmetrical-to-symmetrical cell division switch in liver CSCs. Sox9 also negatively regulates Numb expression, contributing to a feedback circuit that maintains Notch activity and directs symmetrical cell division. Clinical analyses revealed that the Sox9(High) Numb(Low) profile is associated with poor prognosis in human HCC patients. CONCLUSION: We demonstrate that Sox9 plays a critical role in self-renewal and tumor propagation of liver CSCs and identify the molecular mechanisms regulated by Sox9 that link tumor initiation and cell division. (Hepatology 2016;64:117-129). PMID: 26910875 [PubMed - indexed for MEDLINE]
Related Articles Assessing the therapeutic potential of lab-made hepatocytes. Hepatology. 2016 Jul;64(1):287-94 Authors: Rezvani M, Grimm AA, Willenbring H Abstract Hepatocyte transplantation has potential as a bridge or even alternative to whole-organ liver transplantation. Because donor livers are scarce, realizing this potential requires the development of alternative cell sources. To be therapeutically effective, surrogate hepatocytes must replicate the complex function and ability to proliferate of primary human hepatocytes. Ideally, they are also autologous to eliminate the need for immune suppression, which can have severe side effects and may not be sufficient to prevent rejection long term. In the past decade, several methods have been developed to generate hepatocytes from other readily and safely accessible somatic cells. These lab-made hepatocytes show promise in animal models of liver diseases, supporting the feasibility of autologous liver cell therapies. Here, we review recent preclinical studies exemplifying different types of lab-made hepatocytes that can potentially be used in autologous liver cell therapies. To define the therapeutic efficacy of current lab-made hepatocytes, we compare them to primary human hepatocytes, focusing on engraftment efficiency and posttransplant proliferation and function. In addition to summarizing published results, we discuss animal models and assays effective in assessing therapeutic efficacy. This analysis underscores the therapeutic potential of current lab-made hepatocytes, but also highlights deficiencies and uncertainties that need to be addressed in future studies aimed at developing liver cell therapies with lab-made hepatocytes. (Hepatology 2016;64:287-294). PMID: 27014802 [PubMed - indexed for MEDLINE]
Related Articles Long-term outcomes of 176 patients with X-linked hyper-IgM syndrome treated with or without hematopoietic cell transplantation. J Allergy Clin Immunol. 2017 Apr;139(4):1282-1292 Authors: de la Morena MT, Leonard D, Torgerson TR, Cabral-Marques O, Slatter M, Aghamohammadi A, Chandra S, Murguia-Favela L, Bonilla FA, Kanariou M, Damrongwatanasuk R, Kuo CY, Dvorak CC, Meyts I, Chen K, Kobrynski L, Kapoor N, Richter D, DiGiovanni D, Dhalla F, Farmaki E, Speckmann C, Español T, Shcherbina A, Hanson IC, Litzman J, Routes JM, Wong M, Fuleihan R, Seneviratne SL, Small TN, Janda A, Bezrodnik L, Seger R, Raccio AG, Edgar JD, Chou J, Abbott JK, van Montfrans J, González-Granado LI, Bunin N, Kutukculer N, Gray P, Seminario G, Pasic S, Aquino V, Wysocki C, Abolhassani H, Dorsey M, Cunningham-Rundles C, Knutsen AP, Sleasman J, Costa Carvalho BT, Condino-Neto A, Grunebaum E, Chapel H, Ochs HD, Filipovich A, Cowan M, Gennery A, Cant A, Notarangelo LD, Roifman CM Abstract BACKGROUND: X-linked hyper-IgM syndrome (XHIGM) is a primary immunodeficiency with high morbidity and mortality compared with those seen in healthy subjects. Hematopoietic cell transplantation (HCT) has been considered a curative therapy, but the procedure has inherent complications and might not be available for all patients. OBJECTIVES: We sought to collect data on the clinical presentation, treatment, and follow-up of a large sample of patients with XHIGM to (1) compare long-term overall survival and general well-being of patients treated with or without HCT along with clinical factors associated with mortality and (2) summarize clinical practice and risk factors in the subgroup of patients treated with HCT. METHODS: Physicians caring for patients with primary immunodeficiency diseases were identified through the Jeffrey Modell Foundation, United States Immunodeficiency Network, Latin American Society for Immunodeficiency, and Primary Immune Deficiency Treatment Consortium. Data were collected with a Research Electronic Data Capture Web application. Survival from time of diagnosis or transplantation was estimated by using the Kaplan-Meier method compared with log-rank tests and modeled by using proportional hazards regression. RESULTS: Twenty-eight clinical sites provided data on 189 patients given a diagnosis of XHIGM between 1964 and 2013; 176 had valid follow-up and vital status information. Sixty-seven (38%) patients received HCT. The average follow-up time was 8.5 ± 7.2 years (range, 0.1-36.2 years). No difference in overall survival was observed between patients treated with or without HCT (P = .671). However, risk associated with HCT decreased for diagnosis years 1987-1995; the hazard ratio was significantly less than 1 for diagnosis years 1995-1999. Liver disease was a significant predictor of overall survival (hazard ratio, 4.9; 95% confidence limits, 2.2-10.8; P < .001). Among survivors, those treated with HCT had higher median Karnofsky/Lansky scores than those treated without HCT (P < .001). Among patients receiving HCT, 27 (40%) had graft-versus-host disease, and most deaths occurred within 1 year of transplantation. CONCLUSION: No difference in survival was observed between patients treated with or without HCT across all diagnosis years (1964-2013). However, survivors treated with HCT experienced somewhat greater well-being, and hazards associated with HCT decreased, reaching levels of significantly less risk in the late 1990s. Among patients treated with HCT, treatment at an early age is associated with improved survival. Optimism remains guarded as additional evidence accumulates. PMID: 27697500 [PubMed - indexed for MEDLINE]
Related Articles MELK is an oncogenic kinase essential for early hepatocellular carcinoma recurrence. Cancer Lett. 2016 Dec 01;383(1):85-93 Authors: Xia H, Kong SN, Chen J, Shi M, Sekar K, Seshachalam VP, Rajasekaran M, Goh BK, Ooi LL, Hui KM Abstract Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. Many kinases have been found to be intimately involved in oncogenesis and the deregulation of kinase function has emerged as a major mechanism by which cancer cells evade normal physiological constraints on growth and survival. Previously, we have performed gene expression profile analysis on HCC samples and have identified a host of kinases that are remarkably overexpressed in HCC. Among these, the Maternal Embryonic Leucine Zipper Kinase (MELK) is highly overexpressed in HCC and its overexpression strongly correlates with early recurrence and poor patients' survival. Silencing MELK inhibited cell growth, invasion, stemness and tumorigenicity of HCC cells by inducing apoptosis and mitosis. We further showed that the overexpression of MELK in HCC samples strongly correlated with the cell cycle- and mitosis-related genes which are directly regulated as part of the forkhead transcription factor FoxM1-related cell division program. Together, our data establish MELK as an oncogenic kinase involved in the pathogenesis and recurrence of HCC and could provide a promising molecular target to develop therapeutic strategies for patients with advanced HCC. PMID: 27693640 [PubMed - indexed for MEDLINE]
Related Articles Albiflorin ameliorates obesity by inducing thermogenic genes via AMPK and PI3K/AKT in vivo and in vitro. Metabolism. 2017 Aug;73:85-99 Authors: Jeong MY, Park J, Youn DH, Jung Y, Kang J, Lim S, Kang MW, Kim HL, So HS, Park R, Hong SH, Um JY Abstract OBJECTIVE: Brown adipose tissue (BAT) activation has been identified as a possible target to treat obesity and to protect against metabolic diseases by increasing energy consumption. We explored whether albiflorin (AF), a natural compound, could contribute to lowering the high risk of obesity with BAT and primary brown preadipocytes in vivo and in vitro. MATERIALS/METHODS: Human adipose tissue-derived mesenchymal stem cells (hAMSCs) were cultured with adipogenic differentiation media with or without AF. Male C57BL/6J mice (n=5 per group) were fed a high-fat diet (HFD) for six weeks with or without AF. Brown preadipocytes from the interscapular BAT of mice were cultured with or without AF. RESULTS: In white adipogenic differentiation of hAMSCs, AF treatment significantly reduced the formation of lipid droplets and the expression of adipogenesis-related genes. In HFD-induced obese C57BL/6J mice, AF treatment significantly reduced body weight gain as well as the weights of the white adipose tissue, liver and spleen. Furthermore, AF induced the expression of genes involved in thermogenic function in BAT. In primary brown adipocytes, AF effectively stimulated the expressions of thermogenic genes and markedly up-regulated the AMP-activated protein kinase (AMPK) signaling pathway. Pretreatment with phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 nullified the induction of the thermogenic genes by AF in primary brown adipocytes. Moreover, AF activated beige cell marker genes induced by the pharmacological activation of peroxisome proliferator-activated receptor γ in hAMSCs. CONCLUSION: This study shows that AF prevents the development of obesity in hAMSCs and mice fed an HFD and that it is also capable of stimulating the differentiation of brown adipocytes through the modulation of thermogenic genes by AMPK and PI3K/AKT. PMID: 28732574 [PubMed - in process]
Related Articles Steroid-Mediated Decrease in Blood Mesenchymal Stem Cells in Liver Transplant could Impact Long-Term Recovery. Stem Cell Rev. 2017 Jul 21;: Authors: Walker ND, Mourad Y, Liu K, Buxhoeveden M, Schoenberg C, Eloy JD, Wilson DJ, Brown LG, Botea A, Chaudhry F, Greco SJ, Ponzio NM, Pyrsopoulos N, Koneru B, Gubenko Y, Rameshwar P Abstract Orthotopic liver transplant (OLT) remains the standard of care for end stage liver disease. To circumvent allo-rejection, OLT subjects receive gluococorticoids (GC). We investigated the effects of GC on endogenous mesenchymal stem (stromal) cells (MSCs) in OLT. This question is relevant because MSCs have regenerative potential and immune suppressor function. Phenotypic analyses of blood samples from 12 OLT recipients, at pre-anhepatic, anhepatic and post-transplant (2 h, Days 1 and 5) indicated a significant decrease in MSCs after GC injection. The MSCs showed better recovery in the blood from subjects who started with relatively low MSCs as compared to those with high levels at the prehepatic phase. This drop in MSCs appeared to be linked to GC since similar change was not observed in liver resection subjects. In order to understand the effects of GC on decrease MSC migration, in vitro studies were performed in transwell cultures. Untreated MSCs could not migrate towards the GC-exposed liver tissue, despite CXCR4 expression and the production of inflammatory cytokines from the liver cells. GC-treated MSCs were inefficient with respect to migration towards CXCL12, and this correlated with retracted cytoskeleton and motility. These dysfunctions were partly explained by decreases in the CXCL12/receptor axis. GC-associated decrease in MSCs in OLT recipients recovered post-transplant, despite poor migratory ability towards GC-exposed liver. In total, the study indicated that GC usage in transplant needs to be examined to determine if this could be reduced or avoided with adjuvant cell therapy. PMID: 28733800 [PubMed - as supplied by publisher]
Related Articles Cholangiocytes: Cell transplantation. Biochim Biophys Acta. 2017 Jul 19;: Authors: Ridola L, Bragazzi MC, Cardinale V, Carpino G, Gaudio E, Alvaro D Abstract BACKGROUND: Due to significant limitations to the access to orthotropic liver transplantation, cell therapies for liver diseases have gained large interest worldwide. SCOPE OF REVIEW: To revise current literature dealing with cell therapy for liver diseases. We discussed the advantages and pitfalls of the different cell sources tested so far in clinical trials and the rationale underlying the potential benefits of transplantation of human biliary tree stem cells (hBTSCs). MAJOR CONCLUSIONS: Transplantation of adult hepatocytes showed transient benefits but requires immune-suppression that is a major pitfall in patients with advanced liver diseases. Mesenchymal stem cells and hematopoietic stem cells transplanted into patients with liver diseases are not able to replace resident hepatocytes but, rather they target autoimmune or inflammatory processes into the liver. Stem cells isolated from fetal or adult liver have been recently proposed as an alternative cell sources for advanced liver cirrhosis and metabolic liver disease. We demonstrated the presence of multipotent cells expressing a variety of endodermal stem cell markers in (peri)-biliary glands of bile ducts in fetal or adult human tissues, and in crypts of gallbladder epithelium. In the first cirrhotic patients treated in our center with biliary tree stem cell therapy we registered no adverse event but significant benefits. GENERAL SIGNIFICANCE: The biliary tree stem cell could represent the ideal cell source for the cell therapy of liver diseases. This article is part of a Special Issue entitled: Cholangiocytes in Health and Diseaseedited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen. PMID: 28735098 [PubMed - as supplied by publisher]
Biodistribution of Liver-Derived Mesenchymal Stem Cells After Peripheral Injection in a Hemophilia A Patient. Transplantation. 2017 Aug;101(8):1845-1851 Authors: Sokal EM, Lombard CA, Roelants V, Najimi M, Varma S, Sargiacomo C, Ravau J, Mazza G, Jamar F, Versavau J, Jacobs V, Jacquemin M, Eeckhoudt S, Lambert C, Stéphenne X, Smets F, Hermans C Abstract BACKGROUND: With the exception of liver transplantation, there is no cure for hemophilia, which is currently managed by preemptive replacement therapy. Liver-derived stem cells are in clinical development for inborn and acquired liver diseases and could represent a curative treatment for hemophilia A. The liver is a major factor VIII (FVIII) synthesis site, and mesenchymal stem cells have been shown to control joint bleeding in animal models of hemophilia. Adult-derived human liver stem cells (ADHLSCs) have mesenchymal characteristics and have been shown able to engraft in and repopulate both animal and human livers. Thus, the objectives were to evaluate the potency of ADHLSCs to control bleeding in a hemophilia A patient and assess the biodistribution of the cells after intravenous injection. METHODS: A patient suffering from hemophilia A was injected with repeated doses of ADHLSCs via a peripheral vein (35 million In-oxine-labeled cells, followed by 125 million cells the next day, and 3 infusions of 250 million cells every 2 weeks thereafter; total infusion period, 50 days). RESULTS: After cell therapy, we found a temporary (15 weeks) decrease in the patient's FVIII requirements and severe bleeding complications, despite a lack of increase in circulating FVIII. The cells were safely administered to the patient via a peripheral vein. Biodistribution analysis revealed an initial temporary entrapment of the cells in the lungs, followed by homing to the liver and to a joint afflicted with hemarthrosis. CONCLUSION: These results suggest the potential use of ADHLSCs in the treatment of hemophilia A. PMID: 28738402 [PubMed - in process]

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