Immunomodulatory Effects of Adipose Tissue-Derived Stem Cells on Concanavalin A-Induced Acute Liver Injury in Mice

Abstract

Cell therapy with adipose tissue-derived stem cells (ASCs) is expected to be a candidate for the treatment of fulminant hepatic failure (FHF), which is caused by excessive immune responses. In order to evaluate the therapeutic effects of ASCs on FHF, the in vitro and in vivo immunomodulatory effects of ASCs were examined in detail in the mouse model. The in vitro effects of ASCs were examined by assessing their influence on the proliferation of lymphomononuclear cells (LMCs) stimulated with three kinds of mitogens: phorbol 12-myristate 13-acetate (PMA) plus ionomycin, concanavalin A (ConA), and lipopolysaccharide (LPS). The proliferation of LMCs was efficiently suppressed in a dose-dependent manner by ASCs in the cases of PMA plus ionomycin stimulation and ConA stimulation, but not in the case of LPS stimulation. The in vivo effects of transplanted ASCs were examined in the murine FHF model induced by ConA administration. The ALT levels and histological inflammatory changes in the ConA-administered mice were apparently relieved by the transplantation of ASCs. The analysis of mRNA expression patterns in the livers indicated that the expressions of the cytokines such as , and the cell surface markers such as Cd3γ, Cd4, Cd8α, Cd11b, and Cd11c were downregulated in the ASC-transplanted mice. The immunomodulatory and therapeutic effects of ASCs were confirmed in the mouse model both in vitro and in vivo. These suggest that the cell therapy with ASCs is beneficial for the treatment of FHF.

Transplantation of mesenchymal stem cells and their derivatives effectively promotes liver regeneration to attenuate acetaminophen-induced liver injury

“…This indicated that ESCs exert protective effects on APAP-treated mice mainly through paracrine effects rather than direct differentiation [74]. In addition, MSCs significantly attenuated liver inflammation to improve the liver functions in ALF models by downregulating TNF-α, IFN-γ, IL-1β, IL-6, and IL-10 [75]. ALF models had preserved liver functions and liver metabolic balance after MSC transplantation.…”

Mesenchymal stromal cells promote liver regeneration through regulation of immune cells

“…Moreover, MSC-derived growth factors such as hepatocyte growth factor, fibroblast growth factor, interleukin (IL)-6, fibrinogen and transforming growth factor (TGF)-α also participate in liver regeneration by promoting hepatocyte proliferation [20]. They also decrease the expression of pro-inflammatory factors, including tumor necrosis factor-α (TNF)-α, interferon (IFN)-γ and IL-1β, and the expression of chemokines, including CXCL1 and CXCL2, in vivo to attenuate liver inflammation [21,22]. The paracrine mechanisms of MSCs in liver diseases are reviewed elsewhere [23].…”

Liver Bioengineering: Promise, Pitfalls, and Hurdles to Overcome

“…The limited availability and inability of in vitro expansion of primary hepatocytes have led the field to search for new cell sources. Mesenchymal stem cells (MSC) seem to be a valuable substitute of human primary hepatocytes because MSCs are widely available, can be easily cultured in vitro, and are less immunogenic compared to hepatocytes [51]. These cells can be harvested from bone marrow, cord blood, adipose tissue, and amniotic fluid [40].…”