Acetaminophen (APAP) is the major cause of drug-induced liver injury, with limited treatment options. APAP overdose invokes excessive oxidative stress that triggers mitochondria-to-nucleus retrograde pathways, contributing to APAP-induced liver injury (AILI). Mesenchymal stem cell therapy is a promising tool for acute liver failure. Therefore, the purpose of this study was to investigate the beneficial effects of adipose-derived mesenchymal stem cell (AMSC) therapy on AILI and reveal the potential therapeutic mechanisms. C57BL/6 mice were used as the animal model and AML12 normal murine hepatocytes as the cellular model of APAP overdose. Immunohistochemical staining, Western blotting, immunofluorescence staining, and RNA sequencing assays were used for assessing the efficacy and validating mechanisms of AMSC therapy. We found AMSC therapy effectively ameliorated AILI, while delayed AMSC injection lost its efficacy related to the c-Jun N-terminal kinase (JNK)-mediated mitochondrial retrograde pathways. We further found that AMSC therapy inhibited JNK activation and mitochondrial translocation, reducing APAP-induced mitochondrial damage. The downregulation of activated ataxia telangiectasia-mutated (ATM) and DNA damage response proteins in AMSC-treated mouse liver indicated AMSCs blocked the JNK-ATM pathway. Overall, AMSCs may be an effective treatment for AILI by inhibiting the JNK-ATM mitochondrial retrograde pathway, which improves APAP-induced mitochondrial dysfunction and liver injury.
Keyphrases
- liver injury
- oxidative stress
- drug induced
- cell therapy
- signaling pathway
- dna damage response
- induced apoptosis
- mesenchymal stem cells
- liver failure
- diabetic rats
- dna damage
- cell death
- dna repair
- bone marrow
- stem cells
- hepatitis b virus
- umbilical cord
- single cell
- high glucose
- endoplasmic reticulum stress
- metabolic syndrome
- cell proliferation
- intensive care unit
- genome wide
- endothelial cells
- adipose tissue
- weight gain
- high throughput
- early onset
- adverse drug
- mechanical ventilation
- weight loss
- skeletal muscle
- electronic health record
- ultrasound guided
- combination therapy
- reactive oxygen species
- allogeneic hematopoietic stem cell transplantation
- flow cytometry