Mesenchymal stromal cells ameliorate hyperammonemia via IGF1-IGF1R- GLS2 axis inhibiting glutaminolysis in acute hepatic failure

Abstract

Hyperammonemia is a pernicious and severe consequence of acute hepatic failure (AHF). While prior research suggested the potential of mesenchymal stromal cells (MSCs) in reducing blood ammonia levels, the underlying molecular mechanism remains unclear. This study utilized a AHF mouse model to investigate the impact of MSCs on hyperammonemia and its mechanism. The study showed that CCL4-induced ALF mice suffered from hyperammonemia. MSCs effectively reduce arterial ammonia levels by downregulating glutaminase2 (Gls2) and upregulating glutamine synthetase (GS), rather than through urea cycle. RFP-labeled MSCs were observed in hepatic sinusoid and co-localized with macrophages. Moreover, the MSC treatment group exhibited elevated expression of insulin-like growth factor 1 (IGF1) and its receptor (IGF1R) than the PBS treatment group. Furthermore, Inhibition of the IGF1-IGF1R axis attenuated the ammonia-lowing effect of MSCs. Notably, blocking IGF1-IGF1R axis could affect the MSCs’ inhibition effects on Gls2. The finding indicates that MSCs can mitigate hyperammonemia in AHF mice by suppressing glutaminolysis through IGF1-IGF1R axis, making them a promising resource for treating hyperammonemia in critical conditions.