Introduction
Mesenchymal stem cells (MSC) in liver injury
The MSC secretome
Functional effects of the MSC secretome
Immunomodulatory activities
Amelioration of liver injury
Source | Injury model | Effect(s) | Mechanism(s) | References | |
---|---|---|---|---|---|
Human liver | IP injection of MSC-CM at the time of injury | Partial hepatectomy | Increased hepatocyte proliferation | Upregulated TNF-α, HGF, TGF-β, IL-1RA, and IL-10 | [2] |
Umbilical cord | IP injection of undifferentiated or hepatocyte-like MSC secretome | CCl4- and TAA-induced liver fibrosis | Reduced number of activated α-SMA+ HSC Reduced collagen deposition | Decreased TGF-β signaling | [21] |
Human bone marrow | IV injection of MSC-CM | D-Gal-induced liver failure | Decreased hepatocyte apoptosis Reduced serum AST and ALT levels | Increased circulating IL-10 reduced serum TNF- α, IL-6, IL-1ra and attenuated CD45+ leukocyte infiltration | [38] |
Murine bone marrow | IV injection of MSC-CM | α-GalCer-induced acute liver failure | Reduced serum AST & ALT levels Expanded CD4+CD25+ T cell infiltration and reduced NKT cell-mediated hepatotoxicity | Suppressed Teff cell proliferation | [24] |
Human umbilical cord | MSC- CM | In vitro H2O2-induced hepatocyte injury | Increased hepatocyte viability | Modulated Bax and Bcl-2 expression | [34] |
Murine compact bone | IV injection of MSC-CM | TAA-induced acute liver failure and CCl4-induced chronic liver fibrosis | Reduced collagen deposition and α-SMA+ cells induced apoptosis of activated HSC in the livers of CCl4-injured mice Reduced hepatocyte apoptosis Increased cell proliferation | Reduced hepatic leukocyte infiltration decreased CD11b+F4/80+ macrophage and Th-17 Induced the expansion of spleen-derived CD4+ CD25+ Tregs in CCl4-injured mice | [28] |
Human adipose tissue | MSC- CM (normoxia or hypoxia pre-conditioned) | None | Increased hepatocyte viability (H-CM) Enhanced glycogen and ICG uptake by hepatocytes | [47] | |
Human umbilical cord | MSC Co-culture | CCl4-injured murine hepatocytes | Increased hepatocyte viability Increased albumin production Increased number of proliferating hepatocytes | [37] | |
Human adipose tissue | IV injection of ASC-CM (Untreated and LPS-primed) | Partial hepatectomy | Increased number of proliferating cells Accelerated liver regeneration Reduced serum transaminase levels | Decreased serum TNF-α and IL-6 levels Increased hepatic expression of p-STAT3 and PCNA | [29] |
Source | Injury model | Effect(s) | Mechanism(s) | References | |
---|---|---|---|---|---|
Human liver | IV injection of HLSC-MV | Partial hepatectomy | Increased hepatocyte proliferation Reduced apoptosis | Upregulated hepatic expression of cyclin A1 | [3] |
Human umbilical cord | Intrahepatic injection of MSC-Ex | CCl4-induced acute liver injury | Inhibited hepatocyte apoptosis Reduced collagen-1 and -3 expression Reduced the serum levels of HA | Suppressed TGF-β signaling and inhibited EMT | [36] |
Human umbilical cord | IV injection of MSC-Ex | CCl4-induced liver failure | Increased cell viability | Reduced levels of ROS Upregulated Bcl2 expression | [22] |
Human and murine bone marrow | IP and IV injection of MSC-EV | D-gal/TNF-α-induced lethal hepatic failure | Reduced apoptosis Increased survival | Attenuated inflammation Increased macrophages Transfer of Y-RNA-1 within EV | [23] |
Murine bone marrow | IV injection of MSC-EV | Hepatic ischemia–reperfusion injury | Reduced apoptosis | Increased Nlrp12 and CXCL1 Increased number of macrophages Altered NFkβ activity and decreased cytokine and growth factors Reduced ROS | [33] |
Human huE59.E1- | Intrasplenic injection of MSC-EV | CCl4-induced acute liver injury In vitro APAP- and H2O2-induced hepatocyte injury | Decreased apoptosis Increased cell viability | Upregulated cyclin D, NFkβ and cyclin E expression reduced caspase 3 activity, restored Bcl-xL expression and increased the amount of activated STAT3 Increased expression of immune mediators: TNF-α, IL-6, iNOS, COX-2 and MIP-2 | [30] |
Rat bone marrow | Intrahepatic injection of MSC-exosome-enriched fraction | In vitro H2O2- and APAP-induced HepG2 injury CCL4-induced acute liver injury and IRI | Increased hepatic regeneration Reduced serum AST, ALT, and bilirubin levels Protected HepG2 cells from toxin-induced death Promoted hepatocyte proliferation | Significantly reduced ROS levels and LDH activity in toxin-injured HepG2 cells Reduced the number of 8-OHdG+ hepatocytes in CCL4-injured animals | [35] |
Adipose tissue | IV injection of MSC secretome (1%, 5%, 10%, and 21% pO2) | In vitro IRI Partial hepatectomy | Reduced serum IL-6 and TNF-α levels Reduced serum transaminases Accelerated liver regeneration Increased the hepatocyte proliferation | Increased p-STAT3 and PCNA expression Decreased hepatic expression of SOCS3 and increased SIRT1 Increase in survival genes (e.g., Bcl-xL and Mcl-1) | [41] |