Abstract
BackgroundHepatocytes and stem cells transplantation may be an alternative to liver transplantation in acute or chronic liver disease. We aimed to evaluate the therapeutic potential of mesenchymal stem cells from human umbilical cord (UCMSCs), a readily available source of mesenchymal stem cells, in the CCl4-induced acute liver injury model.MethodsMesenchymal stem cells profile was analyzed by flow cytometry. In order to evaluate the capability of our UCMSCs to differentiate in hepatocytes, cells were seeded on three different supports, untreated plastic support, MatrigelTM and human liver acellular matrix. Cells were analyzed by immunocitochemistry for alpha-fetoprotein and albumin expression, qPCR for hepatocyte markers gene expression, Periodic Acid-Schiff staining for glycogen storage, ELISA for albumin detection and colorimetric assay for urea secretion.To assess the effects of undifferentiated UCMSCs in hepatic regeneration after an acute liver injury, we transplanted them via tail vein in mice injected intraperitoneally with a single dose of CCl4. Livers were analyzed by histological evaluation for damage quantification, immunostaining for Kupffer and stellate cells/liver myofibroblasts activation and for UCMSCs homing. Pro- and anti-inflammatory cytokines gene expression was evaluated by qPCR analysis and antioxidant enzyme activity was measured by catalase quantification.Data were analyzed by Mann–Whitney U-test, Kruskal-Wallis test and Cuzick’s test followed by Bonferroni correction for multiple comparisons.ResultsWe have standardized the isolation procedure to obtain a cell population with hepatogenic properties prior to in vivo transplantation. When subjected to hepatogenic differentiation on untreated plastic support, UCMSCs differentiated in hepatocyte-like cells as demonstrated by their morphology, progressive up-regulation of mature hepatocyte markers, glycogen storage, albumin and urea secretion. However, cells seeded on 3D-supports showed a minor or negligible differentiation capacity.UCMSCs-transplanted mice showed a more rapid damage resolution, as shown by histological analysis, with a lower inflammation level and an increased catalase activity compared to CCl4-treated mice.ConclusionsOur findings show that UCMSCs can be reliably isolated, have hepatogenic properties and following systemic administration are able to accelerate the resolution of an acute liver injury without any differentiation and manipulation. These features make UCMSCs strong candidates for future application in regenerative medicine for human acute liver disease.
Highlights
Hepatocytes and stem cells transplantation may be an alternative to liver transplantation in acute or chronic liver disease
UCMSCs were able to differentiate toward adipogenic and osteogenic lineages. All these results demonstrated that the UCMSCs isolated were a novel mesenchymal stem cell population
For the first time, we unexpectedly demonstrated that undifferentiated UCMSCs constitutively expressed mRNA coding for microsomal trialcylglycerol transfer protein (MTP), a transfer protein localized in the endoplasmic reticulum of mature hepatocytes and enterocytes; this protein catalyses the transport of triglycerides, cholesteryl esters and phospholipids [33]
Summary
Hepatocytes and stem cells transplantation may be an alternative to liver transplantation in acute or chronic liver disease. Adult stem cells have been widely explored in recent years as a more acceptable source of cells, including the mesenchymal stem cells (MSCs), a population of multipotent progenitors capable of differentiating towards adipogenic, osteogenic [6], and hepatogenic lineages [7,8] with a low immunogenicity [9]. This cell population is considered to be a promising candidate for novel cellbased therapeutic strategies [10]
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