Published online Sep 26, 2023. doi: 10.4252/wjsc.v15.i9.876
Peer-review started: April 20, 2023
First decision: June 7, 2023
Revised: June 21, 2023
Accepted: July 18, 2023
Article in press: July 18, 2023
Published online: September 26, 2023
Ischemia-reperfusion injury (IRI) and immune rejection are two important factors that affect the prognosis of liver transplantation. Mesenchymal stem cells (MSCs) have been used in liver transplantation and showed certain beneficial effects.
Some studies have indicated that the effects of MSCs are not very significant. Therefore, there is an urgent to find a new way to make MSCs exert better therapeutic effect.
In this study, we attempted to enhance the therapeutic potential of human menstrual blood-derived stromal cells (MenSCs) in a mouse liver ischemia-reperfusion (I/R) model through interferon-γ (IFN-γ) priming strategies and explore the specific mechanisms.
After determining the appropriate priming strategies, we applied MenSCs and primed MenSCs in the short-term and long-term mouse liver I/R models, and compared their therapeutic effects. In order to further explore the specific mechanism, we performed a metabolomic analysis of mouse liver samples.
IFN-γ-primed MenSCs secreted higher levels of indoleamine 2,3-dioxygenase (IDO), attenuated liver injury, and increased regulatory T cell (Treg) numbers in the mouse spleens to greater degrees than untreated MenSCs. Metabolomics and autophagy analyses proved that primed MenSCs more strongly induced protective autophagy in the mouse livers. Further experiments proved that IDO enhanced the protective autophagy by inhibiting the mammalian target of rapamycin (mTOR) pathway and activating the AMPK pathway.
IFN-γ-primed MenSCs exerted better therapeutic effects in the liver I/R model through secreting higher IDO levels. IDO, on the one hand, increased Treg numbers in the spleen; on the other hand, activated the AMPK-mTOR-autophagy axis to reduce IRI.
Our study suggests that IFN-γ-primed MenSCs may be a novel and superior MSC product for liver transplantation in the future, and the specific mechanism of how MSCs or IDO enhance autophagy in recipient cells is still worth further study.