Human umbilical cord mesenchymal stem cells protect against ferroptosis in acute liver failure through the IGF1-hepcidin-FPN1 axis and inhibiting iron loading

Abstract

Acute liver failure (ALF) is a significant global issue with elevated morbidity and mortality rates. There is an urgent and pressing need for secure and effective treatments. Ferroptosis, a novel iron-dependent regulation of cell death, plays a significant role in multiple pathological processes associated with liver diseases, including ALF. Several studies have demonstrated that mesenchymal stem cells (MSCs) have promising therapeutic potential in the treatment of ALF. This study aims to investigate the positive effects of MSCs against ferroptosis in an ALF model and explore the underlying molecular mechanisms of their therapeutic function. Our results show that intravenously injected MSCs protect against ferroptosis in ALF mouse models. MSCs decrease iron deposition in the liver of ALF mice by downregulating hepcidin level and upregulating FPN1 level. MSCs labelled with Dil are mainly observed in the hepatic sinusoid and exhibit colocalization with the macrophage marker CD11b fluorescence. ELISA demonstrates a high level of IGF1 in the CCL4+MSC group. Suppressing the IGF1 effect by the PPP blocks the therapeutic effect of MSCs against ferroptosis in ALF mice. Furthermore, disruption of IGF1 function results in iron deposition in the liver tissue due to impaired inhibitory effects of MSCs on hepcidin level. Our findings suggest that MSCs alleviate ferroptosis induced by disorders of iron metabolism in ALF mice by elevating IGF1 level. Moreover, MSCs are identified as a promising cell source for ferroptosis treatment in ALF mice.

1. Introduction

Acute liver failure (ALF) represents a potentially life-threatening condition characterized by sudden onset, rapid deterioration, numerous complications, and alarmingly high mortality rates [1]. ALF worldwide is estimated to affect approximately 1 to 6 individuals per million annually [2]. While liver transplantation remains the most effective treatment for ALF, its accessibility is hindered by the severity and rapid progression of patients’ illnesses, coupled with the scarcity of available donor organs. Furthermore, even after successful liver transplantation, the disease mortality rate can still reach up to 30% [3]. Regrettably, recent years have witnessed minimal progress in improving the survival rates of ALF patients [4,5]. Therefore, there is an imperative need to explore high-efficiency nonsurgical treatment to improve the overall prognosis of patients.

Ferroptosis is a recently discovered iron-dependent nonapoptotic programmed cell death mechanism [6]. Recent studies have shown that the characteristics of ferroptosis are found in different stages of liver diseases, encompassing iron metabolism disorder, imbalance of the antioxidant system and lipid peroxide accumulation [7]. Brent R. Stockwell identified metabolism, ROS, and iron biology as pivotal regulators of ferroptosis [8]. Moreover, a plethora of studies have also demonstrated that intracellular iron-loading status is necessary for intracellular ferroptosis [9,10]. Furthermore, it has been discovered that intracellular iron overload, which is mediated by hepcidin and ferroportin (FPN1), is the key link to the occurrence of ferroptosis [8,11]. Hepcidin, a circulating hormone primarily produced by the liver, strictly regulates systemic iron metabolism in mammals [12]. FPN1 is currently recognized as the exclusive iron export channel from cells into the plasma. The structure of hepcidin-bound FPN1 unveils iron homeostatic mechanisms, hepcidin binds to FPN1 in an outwards-open conformation to negatively regulate FPN1, and it completely occludes the iron efflux pathway by inhibiting iron transport [13–15]. A deficient hepcidin response to iron loading may result in systemic iron overload [16], whereas transgenic mice overexpressing hepcidin experience severe iron deficiency anemia [17]. In humans, juvenile hemochromatosis, caused by loss-of-function mutations in hepcidin, results in severe iron deposition and multiple organ damage, including afflictions of the liver, heart, and endocrine tissues [18]. In mice with subarachnoid hemorrhage treated with heparin (an inhibitor of hepcidin), downregulating the expression of hepcidin and increasing FPN1 level could exert protective effects against ferroptosis following subarachnoid hemorrhage [15]. Furthermore, several studies have indicated a negative association between FPN1 and ferroptosis.