Liver Disease and Stem Cell Therapy at SIRM
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.
STEM CELL RESEARCH
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]
Bone Marrow Mesenchymal Stem Cells Reverse Liver Damage in a Carbon Tetrachloride-induced Mouse Model of Chronic Liver Injury.
Related Articles Bone Marrow Mesenchymal Stem Cells Reverse Liver Damage in a Carbon Tetrachloride-induced Mouse Model of Chronic Liver Injury. In Vivo. 2016 May-Jun;30(3):187-93 Authors: Wang M, Zhang X, Xiong XI, Yang Z, Li P, Wang J, Sun YU, Yang Z, Hoffman RM Abstract BACKGROUND/AIM: The aim of this study was to investigate the effect of bone-marrow mesenchymal stem cells (BMSCs) on repair of liver damage in a carbon tetrachloride (CCl4)-induced mouse model of chronic liver damage. MATERIALS AND METHODS: Green fluorescent protein (GFP)-expressing BMSCs, isolated from GFP transgenic mice, were transplanted into mice with chronic liver damage induced by CCl4 The GFP-expressing BMSCs in livers were detected by fluorescence microscopy. Serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were measured for assessment of liver function. Liver histopathology was performed to assess liver damage. mRNA and protein expression of liver-associated markers albumin (Alb) and alpha-fetoprotein (Afp) were detected to confirm the hepatic differentiation of BMSCs in the liver. Immunostaining for the expression of interleukin-10 (IL-10) and matrix metallopeptidase-9 (MMP-99), and enzyme-linked immunosorbent assay for the secretion of type III collagen and lamininin was carried out. RESULTS: After BMSC transplantation, GFP-expressing BMSCs were detected in the peri-portal and injured areas of the CCL4-injured liver. mRNA and protein expressions of Alb and Afp were significantly increased in BMSC-transplanted liver. Mice treated with BMSCs displayed reduced serum levels of ALT and AST, and CCl4-induced histopathological changes in livers were repaired. BMSC transplantation increased the production of IL-10 and inhibited the expression of MMP-9, as well as the secretion of type III collagen and lamininin. CONCLUSION: BMSCs transplanted into mice can migrate into damaged liver, differentiate into hepatocytes and promote recovery from chemically-induced liver damage. Promotion of IL-10 and inhibition of MMP-9 by transplanted BMSCs may be involved in the anti-inflammatory and anti-fibrotic action of BMSCs. PMID: 27107074 [PubMed - indexed for MEDLINE]Read more...
Related Articles Nanofiber-expanded stem cells mitigate liver fibrosis: Experimental study. Tissue Cell. 2016 Oct;48(5):544-51 Authors: Salem NA, Ahmed HH, Aglan HA, ElShebiney SA Abstract OBJECTIVES: This study examines a pretreatment strategy to strengthen the hepatic lineage divergence of mesenchymal stem cells (MSCs). DESIGN AND METHODS: BMSCs were expanded in the presence or absence of nanofiber (NF) and treated with growth factors (GF) prior to transplantation. Thioacetamide (TA) was used for liver fibrosis induction and transplantation of NF-expanded BMSCs was compared biochemically and histologically to the cells expanded without NF scaffold. RESULTS: The ultraweb NF caused better proliferation and characterization of MSCs. MSCs transplantation significantly improved liver functions, increased hepatic HGF and Bcl-2 levels, whereas decreased serum fibronectin, hepatic TNF-α and TGF-β1 levels. Hepatic HNF4α, FOXa2, CYP7a1 genes expression were enhanced while β-5-Tub and AFP genes expression were depressed. Histological study documented these results. Differentiated NF-MSCs showed pronounced enhancement of the aforementioned parameters as compared to differentiated MSCs in the absence of NF. CONCLUSION: pretreatment with growth factors in the presence of NF augment homing, repopulation and hepatic differentiation abilities of MSCs and proves to be a promising approach for the treatment of liver fibrosis. PMID: 27481213 [PubMed - indexed for MEDLINE]Read more...
Hyaluronan coating improves liver engraftment of transplanted human biliary tree stem/progenitor cells.
Related Articles Hyaluronan coating improves liver engraftment of transplanted human biliary tree stem/progenitor cells. Stem Cell Res Ther. 2017 Mar 20;8(1):68 Authors: Nevi L, Carpino G, Costantini D, Cardinale V, Riccioni O, Di Matteo S, Melandro F, Berloco PB, Reid L, Gaudio E, Alvaro D Abstract BACKGROUND: Cell therapy of liver diseases with human biliary tree stem cells (hBTSCs) is biased by low engraftment efficiency. Coating the hBTSCs with hyaluronans (HAs), the primary constituents of all stem cell niches, could facilitate cell survival, proliferation, and, specifically, liver engraftment given that HAs are cleared selectively by the liver. METHODS: We developed a fast and easy method to coat hBTSCs with HA and assessed the effects of HA-coating on cell properties in vitro and in vivo. RESULTS: The HA coating markedly improved the viability, colony formation, and population doubling of hBTSCs in primary cultures, and resulted in a higher expression of integrins that mediate cell attachment to matrix components. When HA-coated hBTSCs were transplanted via the spleen into the liver of immunocompromised mice, the engraftment efficiency increased to 11% with respect to 3% of uncoated cells. Notably, HA-coated hBTSC transplantation in mice resulted in a 10-fold increase of human albumin gene expression in the liver and in a 2-fold increase of human albumin serum levels with respect to uncoated cells. Studies in distant organs showed minimal ectopic cell distribution without differences between HA-coated and uncoated hBTSCs and, specifically, cell seeding in the kidney was excluded. CONCLUSIONS: A ready and economical procedure of HA cell coating greatly enhanced the liver engraftment of transplanted hBTSCs and improved their differentiation toward mature hepatocytes. HA coating could improve outcomes of stem cell therapies of liver diseases and could be immediately translated into the clinic given that GMP-grade HAs are already available for clinical use. PMID: 28320463 [PubMed - in process]Read more...
Mesenchymal stem cells increase expression of heme oxygenase-1 leading to anti-inflammatory activity in treatment of acute liver failure.
Related Articles Mesenchymal stem cells increase expression of heme oxygenase-1 leading to anti-inflammatory activity in treatment of acute liver failure. Stem Cell Res Ther. 2017 Mar 20;8(1):70 Authors: Zhang ZH, Zhu W, Ren HZ, Zhao X, Wang S, Ma HC, Shi XL Abstract BACKGROUND: Mesenchymal stem cells (MSCs) have been studied for the treatment of acute liver failure (ALF) for several years. MSCs may exert their effect via complex paracrine mechanisms. Heme oxygenase (HO) 1, a rate-limiting enzyme in heme metabolism, exerts a wide range of anti-inflammatory, anti-apoptotic and immunoregulatory effects in a variety of diseases. However, the relationship between MSCs and HO-1 in the treatment of ALF is still unclear. We investigated the preventive and therapeutic potential of intravenously administered BMSCs. METHODS: Bone marrow-derived mesenchymal stem cells (BMSCs) obtained from Sprague-Dawley rats were isolated and cultured. We employed BMSCs, hemin (a HO-1 inducer) and zinc protoporphyrin (ZnPP, the HO-1 activity inhibitor) in D-galactosamine (D-Gal)/lipopolysaccharides (LPS)-induced ALF rats. Rats were sacrificed at days 1, 3, 5, and 7 post-transfusion, respectively. Blood samples and liver tissues were collected. Hepatic injury, HO-1 activity, chemokines, inflammatory cytokines, the number and oxidative activity of neutrophils, ki67, and TUNEL-positive cells were evaluated. RESULTS: HO-1 induction or BMSCs transplantation attenuated D-galactosamine/lipopolysaccharide-induced increases in alanine aminotransferase, aspartate aminotransferase, total bilirubin (TBIL), ammonia, and inflammatory cytokines. Treatment with hemin or BMSCs also inhibited neutrophil infiltration, oxidative activity, and hepatocyte apoptosis. The protective effect of BMSCs was partially neutralized by ZnPP, suggesting the key role of HO-1 in the process. CONCLUSIONS: These findings may correlate with inhibition of nuclear factor-κ B activation. BMSCs ameliorated ALF by increasing the HO-1 expression, which reduced PMN infiltration and function, and played an important anti-inflammatory and anti-apoptotic role. Proposed mechanism by which BMSCs reduce inflammation, neutrophil activation, and hepatocyte apoptosis and promote hepatocyte proliferation via HO-1. BMSCs increase HO-1 expression in liver via Nrf2. HO-1 protects against LPS/D-Gal-induced ALF by inhibiting neutrophil infiltration and inflammatory burst, and hepatocyte apoptosis and necrosis. HO-1 also promotes hepatocyte proliferation. PMID: 28320485 [PubMed - in process]Read more...
Paracrine Effects of Bone Marrow Mononuclear Cells in Survival and Cytokine Expression after 90% Partial Hepatectomy.
Related Articles Paracrine Effects of Bone Marrow Mononuclear Cells in Survival and Cytokine Expression after 90% Partial Hepatectomy. Stem Cells Int. 2017;2017:5270527 Authors: Kieling CO, Uribe-Cruz C, López ML, Osvaldt AB, da Silveira TR, Matte U Abstract Acute liver failure is a complex and fatal disease. Cell-based therapies are a promising alternative therapeutic approach for liver failure due to relatively simple technique and lower cost. The use of semipermeable microcapsules has become an interesting tool for evaluating paracrine effects in vivo. In this study, we aimed to assess the paracrine effects of bone marrow mononuclear cells (BMMC) encapsulated in sodium alginate to treat acute liver failure in an animal model of 90% partial hepatectomy (90% PH). Encapsulated BMMC were able to increase 10-day survival without enhancing liver regeneration markers. Gene expression of Il-6 and Il-10 in the remnant liver was markedly reduced at 6 h after 90% PH in animals receiving encapsulated BMMC compared to controls. This difference, however, was neither reflected by changes in the number of CD68+ cells nor by serum levels of IL6. On the other hand, treated animals presented increased caspase activity and gene expression in the liver. Taken together, these results suggest that BMMC regulate immune response and promote apoptosis in the liver after 90% PH by paracrine factors. These changes ultimately may be related to the higher survival observed in treated animals, suggesting that BMMC may be a promising alternative to treat acute liver failure. PMID: 28326105 [PubMed - in process]Read more...