Molecular Pathways Modulated by Mesenchymal Stromal Cells and Their Extracellular Vesicles in Experimental Models of Liver Fibrosis

Abstract

End-stage liver fibrosis is common to all chronic liver diseases. Since liver transplantation has several limitations, including lack of donors, immunological rejection, and high medical costs, therapeutic alternatives are needed. The administration of mesenchymal stromal cells (MSCs) has been proven effective in tissue regeneration after damage. However, the risk of uncontrolled side effects, such as cellular rejection and tumorigenesis, should be taken into consideration. A safer alternative to MSC transplantation is represented by the MSC secretome, which retains the same beneficial effect of the cell of origin, without showing any considerable side effect. The paracrine effect of MSCs is mainly carried out by secreted particles in the nanometer range, known as extracellular vesicles (EVs) that play a fundamental role in intercellular communication. In this review, we discuss the current literature on MSCs and MSC-EVs, focusing on their potential therapeutic action in liver fibrosis and on their molecular content (proteins and RNA), which contributes in reverting fibrosis and prompting tissue regeneration.

In Vitro Evaluation of Cytotoxicity and Proliferative Effects of Lyophilized Porcine Liver Tissue on HepG2 Hepatoma Cells and Adipose-Tissue-Derived Mesenchymal Stromal Cells

“…Our results indicate that a porcine liver lyophilized powder derived from the whole organ without any chemical treatment is safe and maintains an in vitro stimulatory effect on HepG2 and At-MSC, although a different response was observed for the two cell types. Interestingly, the LLP stimulates proliferation in At-MSCs, in agreement with other results indicating a reciprocal cross-talk between liver cells and MSCs [21,38]. The work has some weak points that need to be addressed in the future.…”

“…Therefore, the EVs of MSCs represent a powerful tool capable of maintaining or renewing tissue homeostasis and interacting directly with the immune system, regulating its activity [18,19]. Interestingly, secreted factors prepared from MSCs derived from liver and human liver stem cells (HLSC) have been proposed as an effective stimulus to promote liver regeneration [20][21][22] supporting the hypothesis that the organ can contribute to its own homeostasis [22,23]. These findings suggest that liver-derived biological preparations can play an important role to study liver biology and regeneration in vitro, but also represent a potential tool to control the progression of chronic liver injuries in vivo.…”

Human Liver Stem Cell-Derived Extracellular Vesicles Target Hepatic Stellate Cells and Attenuate Their Pro-fibrotic Phenotype

“…Several studies have investigated the effect of MSC-EVs of different origin in liver fibrosis, both in vivo and in vitro ( Chiabotto et al, 2020 ). In vivo , EVs derived from MSCs of embryonic origin (amnion, umbilical cord, embryonic stem cells) reduced the expression of fibrotic genes in liver fibrosis induced by carbon tetrachloride (CCl 4 ) ( Li T. et al, 2013 ; Ohara et al, 2018 ), NASH ( Ohara et al, 2018 ), thioacetamide ( Mardpour et al, 2018 , 2019 ; Fiore et al, 2020 ), and schistosomiasis ( Dong et al, 2020 ).…”

The Agonists of Peroxisome Proliferator-Activated Receptor-γ for Liver Fibrosis

“…Oxidative stress and inflammation play an important role in the pathogenesis of the initiation and progression of many liver diseases. 34 , 35 ROS promotes the expression of IL-6 and IL-1β by stimulating intracellular signal cascades, such as NF-κB. In contrast, inflammatory cells, such as monocytes and lymphocytes, also produce additional ROS after activation.…”