Mesenchymal stem cells and their secreted molecules predominantly ameliorate fulminant hepatic failure and chronic liver fibrosis in mice respectively

Abstract

BackgroundOrthotopic liver transplantation is the only effective treatment for liver failure but limited with shortage of available donor organs. Recent studies show promising results of mesenchymal stem cells (MSCs)-based therapies.MethodsWe systematically investigate the therapeutic effects of MSCs or MSC-conditioned medium (MSC-CM) in ameliorating fulminant hepatic failure (FHF) and chronic liver fibrosis in mice. In addition, extensive flow cytometry analysis of spleens from vehicle and MSC- and MSC-CM-treated mice was applied to reveal the alteration of inflammatory state.ResultsIn FHF model, MSCs treatment reduced remarkably the death incidents; the analysis of gross histopathology showed that control livers were soft and shrunken with extensive extravasated blood, which was gradually reduced at later time points, while MSC–treated livers showed gross pathological changes, even 24 h after MSC infusion, and hematoxylin and eosin staining revealed dramatical hepatocellular death with cytoplasmic vacuolization suppressed by MSCs treatment; flow cytometry analysis of total lymphocytes showed that macrophages (F4/80) infiltrated into control livers more than MSC-treated livers; by contrast, MSC-CM partially ameliorates FHF. In chronic liver injury model, MSC and MSC-CM both suppressed fibrogenesis and necroinflammatory, and the later was better; activation of hepatic stellate cells (α-SMA) was inhibited; glycogen synthesis and storage (indicated by periodic acid-Schiff -staining) was improved; liver regeneration (Ki67) was promoted while liver apoptosis (TUNEL) was reduced. In the in vitro, MSCs promote macrophage line RAW264.7 apoptosis and MSC-CM promotes apoptosis and inhibits proliferation of HSC line LX-2. We also found that MSCs and MSC-CM could improve spleen; MSC-CM increased levels of Th2 and Treg cells, and reduced levels of Th17 cells, whereas levels of Th1 cells were unchanged; comparatively, MSC treatment did not affect Th17 and Treg cells and only slightly alters inflammatory state; MSC and MSC-CM treatment both substantially down-regulated macrophages in the spleens.ConclusionBoth MSCs and MSC-CM exert therapeutic effects by acting on various key cells during the pathogenesis of FHF and chronic fibrosis, stimulating hepatocyte proliferation and suppressing apoptosis, down-regulating infiltrating macrophages, converting CD4+ T lymphocyte system into an anti-inflammatory state, and facilitating hepatic stellate cell death.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-0792-1) contains supplementary material, which is available to authorized users.

Mesenchymal stem cell-derived exosomes as a new therapeutic strategy for liver diseases

“…58 Similar results were obtained when MSC-conditioned media (MSC-CM) were applied instead, 58, 59 which suggests that MSCs might achieve a therapeutic effect in vivo via their secreted EVs, such as exosomes.…”

Comparative therapeutic effects of mesenchymal stem cells versus their conditioned media in alleviation of CCL4-induced liver fibrosis in rats : Histological and biochemical study

“…They also observed marked reduction in mononuclear leukocytic infiltration, prevention of hepatocyte apoptosis and inhibition of bile duct duplication after MSC-CM treatment. Huang et al [65] also found that MSC and MSC-CM infusion similarly stimulated liver regeneration and suppressed hepatocelluar death in mice with acute and chronic liver failure.…”

“…Strong positive α-SMA immune-reaction was observed in the wall of the central vein and in-between the hepatocytes in CCL4 treated group. Cheung et al [47] mentioned that, α -SMA is a marker for the activity of hepatic stellate cells (HpSCs), which are the primary cell type that mediate fibrogenesis. In response to inflammation, HpSCs are activated into myofibroblasts and proliferated by the action of TGFb and PDGF, respectively, secreted by macrophages [44,45] .…”

A Novel Hepatic Anti-Fibrotic Strategy Utilizing the Secretome Released from Etanercept-Synthesizing Adipose-Derived Stem Cells

“…Although statistically insignificant, secretome treatment also reduced the cell viability of HSCs, suggestive of anti-fibrogenic effects of secretome itself. Indeed, several studies have reported the antifibrogenic effects of mesenchymal stem cells or their secretome in the model of liver fibrosis [37][38][39][40][41][42]. Since liver fibrosis process is initiated by inflammation, it appears that secretome reduces the viability of HSCs through anti-inflammatory activities.…”