AIF1+CSF1R+ MSCs, induced by TNF‐α, act to generate an inflammatory microenvironment and promote hepatocarcinogenesis

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Abstract
Background and Aims: Increasing evidence suggests that mesenchymal stem cells (MSCs) home to injured local tissues and the tumor microenvironment in the liver. Chronic inflammation is regarded as the major trait of primary liver cancer. However, the characteristics of endogenous MSCs in the inflammatory environment and their role in the occurrence of liver cancer remain obscure. Approach and Results: Using single‐cell RNA sequencing, we identified a distinct inflammation‐associated subset of MSCs, namely AIF1+CSF1R+ MSCs, which existed in the microenvironment before the occurrence of liver cancer. Furthermore, we found that this MSC subgroup is likely to be induced by TNF‐α stimulation through the TNFR1/SIRT1 (sirtuin 1) pathway. In a rat primary liver cancer model, we showed that MSCs with high SIRT1 expression (Ad‐Sirt1‐MSCs) promoted macrophage recruitment and synergistically facilitated liver cancer occurrence by secreting C‐C motif chemokine ligand (CCL) 5. Interestingly, depletion of macrophages or knockdown of CCL5 expression in Ad‐Sirt1‐MSCs attenuated the promotive effect of Ad‐Sirt1‐MSCs on liver inflammation and hepatocarcinogenesis (HCG). Finally, we demonstrated that SIRT1 up‐regulated CCL5 expression through activation of the AKT/HIF1α signaling axis in MSCs. Conclusions: Together, our results show that MSCs, which are mobilized to the injured site, can be educated by macrophages. In turn, the educated MSCs are involved in generating a chronic inflammatory microenvironment and promoting HCG.

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