Adipose-derived mesenchymal stem cell therapy modulates mitochondrial function to attenuate acetaminophen-induced...

Acetaminophen (APAP) overdose is a leading cause of drug-induced liver injury, with limited treatment options. Mitochondrial dysfunction plays a central role in the pathogenesis of APAP-induced liver injury (AILI). Mitochondrial damage induces cell death, liver necrosis, and sever inflammation, leading to irreversible liver failure. Therefore, it is urgent to develop alternative treatments. Mesenchymal stem cell (MSC)-based cell therapy recently has received increasing attention for its role in regulating mitochondrial function.

This study aimed to investigate the regulation of mitochondrial function and the therapeutic potential of MSCs in treating AILI and underlying mechanisms.

AILI mouse model was established by injection of overdosed APAP. Mice were treated with adipose-derived MSCs (AMSCs) via the tail vein. The blood and liver tissues were collected for assessment of liver necrosis and mitochondrial function. To further verify the mechanism, hepatocyte-specific DNA damage-inducible transcript 4 (DDIT4) knockout (Ddit4^△Hep) mice were generated.

We showed that AMSCs treatment significantly reduced liver necrosis, oxidative stress, and mitochondrial dysfunction in AILI. DDIT4 expression in hepatocytes was identified as playing an important part in AMSCs treating AILI by using RNA-Seq and histological analysis. DDIT4 upregulation in liver samples of AILI patients characterized by snRNA-Seq and spatial transcriptomics analysis, which indicates DDIT4 plays a role in AILI. Ddit4^△Hep mice exhibited exacerbated mitochondrial dysfunction and liver damage to APAP overdose, and these changes could not be reversed by AMSCs treatment. Mechanistically, AMSCs induced mitochondrial biogenesis and mitophagy through DDIT4-mediated PGC-1α upregulation, consequently leading to the restoration of mitochondrial mass and function in AILI. Finally, inhibition of PGC-1α abolished the protective effects of AMSCs against APAP-induced mitochondrial damage.

In summary, this study indicates the potential role of stem cell therapy in modulating mitochondrial function and highlights the role of activation the DDIT4/PGC-1α pathway in protecting hepatic mitochondria to alleviate AILI. This study provides a new mechanistic perspective for stem cell therapy in the treatment of AILI and potential targets for clinical drug development.