Abstract
Mesenchymal stem cells (MSCs) have considerable therapeutic abilities in various disorders, including hepatic fibrosis. They may be affected with different culture conditions. This study investigated, on molecular basics, the effect of pretreatment with eugenol on the characteristics of adipose tissue-derived MSCs (ASCs) in vitro and the implication of eugenol preconditioning on the in vivo therapeutic abilities of ASCs against CCl4-induced hepatic fibrosis in rats. The effect of eugenol on ASCs was assessed using viability, scratch migration and sphere formation assays. Expressions of genes and proteins were estimated by immunofluorescence or qRT-PCR. For the in vivo investigations, rats were divided into four groups: the normal control group, fibrotic (CCl4) group, CCl4+ASCs group and CCl4 + eugenol-preconditioned ASCs (CCl4+E-ASCs) group. Eugenol affected the viability of ASCs in a concentration- and time-dependent manner. Eugenol improved their self-renewal, proliferation and migration abilities and significantly increased their expression of c-Met, reduced expression 1 (Rex1), octamer-binding transcription factor 4 (Oct4) and nanog genes. Furthermore, E-ASCs showed more of a homing ability than ASCs and improved the serum levels of ALT, AST, albumin, total bilirubin and hyaluronic acid more efficient than ASCs in treating CCl4-induced hepatic fibrosis, which was confirmed with histopathology. More interestingly, compared to the CCl4+ASCs group, CCl4+E-ASCs group showed a lower expression of inducible nitric oxide synthase (iNOS), monocyte chemoattractant protein-1 (MCP-1), cluster of differentiation 163 (CD163) and tumor necrosis factor-α (TNF-α) genes and higher expression of matrix metalloproteinase (MMP)-9 and MMP-13 genes. This study, for the first time, revealed that eugenol significantly improved the self-renewal, migration and proliferation characteristics of ASCs, in vitro. In addition, we demonstrated that eugenol-preconditioning significantly enhanced the therapeutic abilities of the injected ASCs against CCl4-induced hepatic fibrosis.
Highlights
New era for the treatment of many disorders have been presented by mesenchymal stem cells (MSCs) and natural compounds
Our study revealed that octamer-binding transcription factor 4 (Oct4), Nanog and reduced expression 1 (Rex1) were expressed in adipose tissue-derived MSCs (ASCs) and significantly up-regulated by eugenol treatment suggesting that eugenol may improve the proliferation and self-renewal characteristics of
As extension for our in vitro results, we, in vivo, investigated the effect of eugenol preconditioning on the therapeutic potential of ASCs against hepatic fibrosis induced by CCl4 in rats
Summary
New era for the treatment of many disorders have been presented by mesenchymal stem cells (MSCs) and natural compounds. MSCs have considerable therapeutic abilities in various disorders, including hepatic fibrosis [1,2,3] Their accessible characteristics and their self-renewal potential make them a promising candidate in regenerative medicine [4,5,6,7]. They have obvious immune-modulatory and migratory capabilities, which are controlled by different factors regulating their maintenance and self-renewal. The MSCs homing molecular mechanism is not clearly understood They may be affected with their tissue microenvironment and culture conditions that could affect their characteristics and self-renewal abilities, which in sequence limit their beneficial therapeutic outcomes [12,13,14]. New strategies in order to enhance these conditions are necessary to present valuable therapeutic outcomes
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