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Liver diseases

A liver transplant is the most preferred solution when it comes to liver disease but donor organ shortage is the main reason why whole organ or hepatocyte transplants can’t be done very often. Therefore, the generation of hepatocyte-like cells from MSCs has become a real alternative to the isolation of primary hepatocytes. Under specific growth conditions, MSCs have been shown to adopt functional features of differentiated hepatocytes and successfully engrafted into mouse liver.

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In allylalcohol (AA) treated rat liver, xenografting of allogenic MSCs differentiated into hepatocytes-like cells which showed positive immunostaining for albumin, CK-19, CK-18, and asialoglycoprotein receptor.

Mesenchymal stem cells facilitate the recovery from chemically induced liver damage and also help in decreasing liver fibrosis in rat models. Similar results were observed in rat models of liver cirrhosis. Injected MSCs were diffusely engrafted in the liver parenchyma and showed CK-19 positive and albumin producing hepatocytess. Although the engraftment rate was low, MSCs showed therapeutic effects including the repair of damaged hepatocytes, intracellular glycogen restoration, and resolution of fibrosis. Similarly, bone marrow derived mesenchymal stem cells showed protection against experimental liver fibrosis in rat models. Both MSCs and MSCs derived hepatocytes, transplanted by either intrasplenic or intravenous route, engrafted in mice liver, differentiated into functional hepatocytes, and reduced liver failure.

In contradiction to this finding, Burra et al., suggested that systemic administration of umbilical cord MSCs accelerates the resolution of an acute liver injury without and differentiation and manipulation. Mesenchymal stem cell transplantation not only showed improvement in liver function caused by degenerative disease but also showed significant improvement in liver damage caused by Schistosoma japonicum. In combination with the conventional drug praziquantel, MSCs transplantation prolonged the survival time of infected mice by reducing egg granuloma diameter and decreasing the concentrations of serum TGF-β1 and hyaluronic acid.

The cytoprotective mechanism of MSCs is still very illusive. In a recent study it was suggested that the cytoprotective is due to the promotion of antioxidant response by bone marrow derived MSCs. Another recent study suggested that MSCs are recruited to injured liver in a beta1-integrin and CD44 dependent manner. In pre-clinical studies researchers observed that the mode of stem cell transplantation affects the outcome. In swine models of acute liver failure, transplantation by portal vein gave the best results and not only supported liver regeneration, but also prolonged the hosts survival. On the other hand, in rat liver fibrosis models, transplantation through intravenous injection has been shown to give the best results and protects the liver against fibrosis through IL-10 expression.

The potential of MSCs in liver repair is also being studied in humans. Phase I and Phase II clinical trials for liver cirrhosis has suggested that both differentiated and undifferentiated MSCs transplantation improved liver function. The follow up of patients at three and six months after transplant revealed partial improvement of the liver function tests with elevation of prothrombin concentration and serum albumin levels, decline of elevated bilirubin and Model for End-Stage Liver Disease score (MELD). In decompensated liver cirrhosis, umbilical cord MSCs transplantation showed a significant reduction in the volume of ascites. Umbilical cord MSC therapy also significantly improved liver function, as indicated by the increase of serum albumin levels, decrease in total serum bilirubin levels, and decrease in the MELD scores during one year follow up studies.

Another clinical observation for liver failure suggested that autologous bone marrow MSCs transplanted patients showed marked improvement in the level of alanine aminotransferase, albumin, total bilirubin, prothrombin time, and MELD from 2 to 3 weeks after transplantation but long-term follow up didn’t show any significant difference between the control and transplanted group.

Although pre-clinical and clinical studies have given promising results, thorough investigations are required to translate these studies into routine treatments. Scientists are also looking forward to improving the therapeutic effect of mesenchymal stem cells by applying pre-treatment with different chemicals and testing genetically modified MSCs.

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