No contribution of umbilical cord mesenchymal stromal cells to capillarization and venularization of hepatic sinusoids accompanied by hepatic differentiation in carbon tetrachloride-induced mouse liver fibrosis

Abstract

The acceleration of capillarization and venularization of hepatic sinusoids after cell therapy would not be beneficial to restoration after liver disease. The goal was to observe the effects of umbilical cord (UC)-derived mesenchymal stromal cells (MSC) on liver microcirculation and their therapeutic potential in liver fibrosis. Human UC MSC labeled with or without CM-DIL were transplanted into NOD/SCID mice with carbon tetrachloride (CCl4)-induced chronic liver fibrosis models. Because of the high autofluorescence on the injured liver sections, we used immunohistochemistry, Western blot and reverse transcriptase-polymerase chain reaction (RT-PCR), but not immunofluorescence, in order to avoid false images under a confocal fluorescence microscope. Human-specific alpha-fetoprotein and albumin mRNA and proteins were detected in CCl4-treated mouse livers receiving human UC MSC transplants. We only observed the gene expression of human-specific endothelial-like cells markers CD31 and KDR by RT-PCR, but not protein expression by immunohistochemistry, in UC MSC-transplanted mouse livers. Vascular endothelial growth factor (VEGF) expression in injured livers 4 weeks after UC MSC transplantation was higher than in normal livers. However, UC MSC injection did not increase significantly the vascular density labeled by CD31 and (vWF) in the injured livers of UC MSC-transplanted mice compared with non-transplanted mice after CCl4 treatment. In addition, liver function was partly improved after UC MSC transplantation. Human UC MSC can differentiate into hepatocyte-like cells but do not accelerate the capillarization and venularization of hepatic sinusoids, finally leading to the partial improvement of liver function in mice with CCl4-mediated chronic liver fibrosis.