Ferroptotic MSCs protect mice against sepsis via promoting macrophage efferocytosis

Abstract

The therapeutic effect of mesenchymal stem cells (MSCs) on sepsis has been well-known. However, a comprehensive understanding of the relationship between MSCs and macrophages remains elusive. Superparamagnetic iron oxide (SPIO) is one of the most commonly used tracers for MSCs. Our previous study has shown that SPIO enhanced the therapeutic effect of MSCs in a macrophage-dependent manner. However, the fate of SPIO-labeled MSCs (MSCSPIO) after infusion remains unknown and the direct interaction between MSCSPIO and macrophages remains unclear. Mice were injected intravenously with MSCSPIO at 2 h after Escherichia coli infection and sacrificed at different times to investigate their distribution and therapeutic effect. We found that MSCSPIO homed to lungs rapidly after infusion and then trapped in livers for more than 10 days. Only a few MSCSPIO homed to the spleen and there was no MSCSPIO detectable in the brain, heart, kidney, colon, and uterus. MSCSPIO tended to stay longer in injured organs compared with healthy organs and played a long-term protective role in sepsis. The mRNA expression profiles between MSCs and MSCSPIO were rather different, genes related to lipid metabolism, inflammation, and oxidative stress were changed. The levels of ROS and lipid peroxide were elevated in MSCSPIO, which confirmed that SPIO-induced ferroptosis in MSCSPIO. Ferroptosis of MSCSPIO induced by SPIO enhanced the efferocytosis of macrophages and thus enhanced the protective effect on septic mice, while the benefits were impaired after MSCSPIO were treated with Ferrostatin-1 (Fer-1) or Liproxtatin-1 (Lip-1), the inhibitors of ferroptosis. SPIO-induced ferroptosis in MSCs contributes to better therapeutic effects in sepsis by enhancing the efferocytosis of macrophages. Our data showed the efficacy and advantage of MSCSPIO as a therapeutic tool and the cell states exert different curative effects on sepsis.

Mechanisms of ferroptosis in nonalcoholic fatty liver disease and therapeutic effects of traditional Chinese medicine: a review

“…The primary organ for storing iron and metabolizing lipids is the liver. When the liver is impaired, the levels of iron and lipid ROS are significantly elevated ( 45 ). Patients with NAFLD often have increased serum ferritin levels, which are linked to intrahepatic iron accumulation;, iron levels are markedly elevated in the liver when the liver is dysfunctional.…”

Mesenchymal “stem” cells, or facilitators for the development of regenerative macrophages? Pericytes at the interface of wound healing

“…It is noteworthy that the ability to contribute to the generation of pro-regenerative macrophages may be further increased in MSCs by exposing them to molecules like LPS prior to extracellular vesicle harvesting and administration (Ti et al, 2015). More recently, the use of apoptotic MSCs to mitigate sepsis by promotion of M2 polarization in macrophages has been demonstrated (Pan et al, 2022), which suggests that even allogeneic MSCs induced to become apoptotic could be used to treat conditions that could be improved by increasing the number of M2 macrophages. Acute conditions that affect the brain, in which neuroinflammation greatly contributes to a negative outcome (da Silva Meirelles et al, 2017;Regner et al, 2017), represent a scenario in which these strategies may be particularly useful.…”

Immunomodulatory properties of mesenchymal stem cells/dental stem cells and their therapeutic applications

“…Apoptosis was also shown to be required for DPSCs to have immunosuppressive functions in an allergic airway inflammation model [ 139 ]. A recent study showed that ferroptosis in MSCs induced by superparamagnetic iron oxide promoted efferocytosis by macrophages and thus enhanced the protective effect on septic mice, while these benefits were impaired after MSCs were treated with inhibitors of ferroptosis [ 140 ]. Whether and how the other fates of MSCs, such as pyroptosis and necroptosis, affect the immunosuppressive functions of MSCs remain to be explored.…”