Human umbilical cord mesenchymal stem cells ameliorate acute liver failure by inhibiting apoptosis, inflammation and pyroptosis

Abstract

Background: Human umbilical cord mesenchymal stem cells (UC-MSCs) are multipotent progenitor cells representing an attractive therapeutic tool for tissue damage and inflammation owing to their unique immunomodulatory properties. This study was designed to determine the protective effects and underlying mechanisms of UC-MSCs on acute liver failure (ALF). Methods: ALF was induced in mice by intraperitoneal injection of D-galactosamine (D-GalN) and lipopolysaccharide (LPS). Mice were intravenously injected with 1×10 6 UC-MSCs one hour before or six hours after D-GalN/LPS injection. Liver function was valued by serum biochemical parameters and hematoxylin-eosin staining. Inflammatory cytokine and chemokine levels were measured by real-time PCR, and inflammatory cells infiltration was observed by immunofluorescence staining. Hepatocyte apoptosis and pyroptosis related proteins were detected by western blot. Murine macrophage Raw264.7 in the presentation of LPS was treated with the UC-MSCs condition medium (UC-MSCs-CM), and then the levels of inflammatory cytokines and NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome in Raw264.7 were measured. Results: UC-MSCs significantly reduced the mortality, decreased serum alanine aminotransferase and aspartate aminotransferase levels, and improved the pathological damage. Moreover, UC-MSCs inhibited inflammatory cytokine and chemokine levels, especially TNF-α, interleukins-6 (IL-6), IL-1β, monocyte chemoattractant protein (MCP-1), CC-chemokines ligand 2 (CCL2), C-X-C motif ligand 2 (CXCL2), and reduced macrophage, neutrophil and T lymphocyte infiltration into the liver tissue. UC-MSCs also attenuated hepatocyte apoptosis, as evidenced by decreased TUNEL positive cells, increased Bcl-xl/Bax protein ratio and downregulated cleaved caspase 3 levels. NLRP3 inflammasome activation, IL-1β maturation and cleaved caspase1 were suppressed by UC-MSC administration. Furthermore, the UC-MSCs-CM reduced the levels of inflammatory cytokines and the activation of NLRP3 inflammasome in Raw264.7. Conclusions: Our results demonstrated that UC-MSCs exerted therapeutic effects on ALF by inhibiting apoptosis, inflammation, and pyroptosis.

Hepatic TGFβr1 Deficiency Attenuates Lipopolysaccharide/D-Galactosamine–Induced Acute Liver Failure Through Inhibiting GSK3β–Nrf2–Mediated Hepatocyte Apoptosis and Ferroptosis

“…23 , 35 , 36 Previous research has shown that inflammatory responses, oxidative stress, endoplasmic reticulum (ER) stress, and apoptosis mainly contributed to LPS/D-GalN-induced ALF. 30 , 37 , 38 , 39 , 40 However, Liu et al 41 and Yang et al 42 found that pyroptosis occurred in LPS/D-GalN-induced ALF through activating caspase 1 and inflammasome NLR family pyrin domain containing 3 (NLRP3). Studies also showed that ferroptosis took place in LPS/D-GalN-induced ALF by increasing lipid peroxidation with cyclooxygenase (COX) and lysyl oxidase (LOX) pathway up-regulation and inhibiting GSH synthesis.…”

Mesenchymal stem cells: Emerging concepts and recent advances in their roles in organismal homeostasis and therapy

“…Osteoporosis, the skeletal degenerative disease, is characterized by loss of bone mass with increased marrow adiposity. It has been well documented that BMMSCs suffer from reduced proliferation with a differentiation shift from osteogenesis to adipogenesis in osteopenias of diverse pathologies ( Liu et al, 2016 ; Sui et al, 2016a ; Li et al, 2017 ). These functional impairments of BMMSCs could be attributed to the detrimental effects of diseased microenvironmental factors, such as estrogen deficiency and inflammation status ( Chen et al, 2015 ; Shao et al, 2015 ).…”

Mesenchymal Stem Cells and Their Small Extracellular Vesicles as Crucial Immunological Efficacy for Hepatic Diseases

“…Acute liver failure (ALF) is a life-threatening clinical syndrome characterized by sudden massive hepatocellular necrosis and coagulopathy (98). Both human adipose-derived MSCs (hADSCs) (13) and hucMSCs ( 14) are effective against ALF, relieving hepatotoxicity, promoting hepatocyte regeneration (15), and alleviating inflammation. PGE2 secreted by BMSCs blocks MF activation by inhibiting TGF-b-activated kinase 1 (TAK1) signaling and the NLRP3 inflammasome and induces M2 MF by activating STAT6 and rapamycin (mTOR) signaling (19).…”