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Abstract The pathogenesis of Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) remains unclear, though increasing evidence suggests inflammatory processes play key roles. In this study, single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) was used to decipher the immunometabolic profile in 4 ME/CFS patients and 4 heathy controls. We analyzed changes in the composition of major PBMC subpopulations and observed an increased frequency of total T cells and a significant reduction in NKs, monocytes, cDCs and pDCs. Further investigation revealed even more complex changes in the proportions of cell subpopulations within each subpopulation. Gene expression patterns revealed upregulated transcription factors related to immune regulation, as well as genes associated with viral infections and neurodegenerative diseases.CD4+ and CD8+ T cells in ME/CFS patients show different differentiation states and altered trajectories, indicating a possible suppression of differentiation. Memory B cells in ME/CFS patients are found early in the pseudotime, indicating a unique subtype specific to ME/CFS, with increased differentiation to plasma cells suggesting B cell overactivity. NK cells in ME/CFS patients exhibit reduced cytotoxicity and impaired responses, with reduced expression of perforin and CD107a upon stimulation. Pseudotime analysis showed abnormal development of adaptive immune cells and an enhanced cell-cell communication network converging on monocytes in particular. Our analysis also identified the estrogen-related receptor alpha (ESRRA)-APP-CD74 signaling pathway as a potential biomarker for ME/CFS in peripheral blood. In addition, data from the GSE214284 database confirmed higher ESRRA expression in the monocyte cell types of male ME/CFS patients. These results suggest a link between immune and neurological symptoms. The results support a disease model of immune dysfunction ranging from autoimmunity to immunodeficiency and point to amyloidotic neurodegenerative signaling pathways in the pathogenesis of ME/CFS. While the study provides important insights, limitations include the modest sample size and the evaluation of peripheral blood only. These findings highlight potential targets for diagnostic biomarkers and therapeutic interventions. Further research is needed to validate these biomarkers and explore their clinical applications in managing ME/CFS.

Limb ischemia is a refractory disease characterized by persistent inflammation, insufficient angiogenesis, and tissue necrosis. Although mesenchymal stem cells (MSCs) have shown potential for treating limb ischemia, their therapeutic effects are limited by low engraftment rates. Therefore, developing an optimal MSC delivery system that enhances cell viability is imperative. Selenium, known for its cytoprotective properties in various cell types, offers a potential strategy to enhance therapeutic effect of MSCs. In this study, we evaluated the cytoprotective effects of selenium on MSCs, and developed an injectable thermosensitive selenium-containing hydrogel based on PLGA-PEG-PLGA triblock copolymer, as a cell carrier to improve MSC viability after engraftment. The biocompatibility, biodegradability, and cytoprotective capabilities of selenium-containing hydrogels were assessed. Furthermore, the therapeutic potential of MSCs encapsulated within a thermosensitive selenium-containing hydrogel in limb ischemia was evaluated using cellular and animal experiments. Selenium protects MSCs from oxidative damage by upregulating GPX4 through a transcriptional mechanism. The injectable thermosensitive selenium-containing hydrogel exhibited favorable biocompatibility, biodegradability, and antioxidant properties. It can be easily injected into the target area in liquid form at room temperature and undergoes gelation at body temperature, thereby preventing the diffusion of selenium and promoting the cytoprotection of MSCs. Furthermore, MSCs encapsulated within the selenium-containing hydrogel effectively inhibited macrophage M1 polarization while promoting macrophage M2 polarization, thus accelerating angiogenesis and restoring blood perfusion in ischemic limbs. This study demonstrated the potential of an injectable thermosensitive selenium-containing hydrogel as a promising method for MSC delivery. By addressing the challenge of low retention rate, which is a major obstacle in MSC application, this strategy effectively improves limb ischemia.

Abstract Mitochondria dysfunction contributes to acute liver injuries, and mitochondrial regulators, such as PGC-1α and MCJ, affect liver regeneration. Therefore, identification of mitochondrial modulators may pave the way for developing therapeutic strategies. Here, ZHX2 is identified as a mitochondrial regulator during acute liver injury. ZHX2 both transcriptionally inhibits expression of several mitochondrial electron transport chain genes and decreases PGC-1α stability, leading to reduction of mitochondrial mass and OXPHOS. Loss of Zhx2 promotes liver recovery by increasing mitochondrial OXPHOS in mice with partial hepatectomy or CCl4-induced liver injury, and inhibition of PGC-1α or electron transport chain abolishes these effects. Notably, ZHX2 expression is higher in liver tissues from patients with drug-induced liver injury and is negatively correlated with mitochondrial mass marker TOM20. Delivery of shRNA targeting Zhx2 effectively protects mice from CCl4-induced liver injury. Together, our data clarify ZHX2 as a negative regulator of mitochondrial OXPHOS and a potential target for developing strategies for improving liver recovery after acute injuries.

Liver-resident natural killer cells develop locally and have multiple immunological roles in situ. Here the authors investigate the gut-liver axis and show the impact of the intestinal microbiota on the development of liver-resident natural killer cells.

Radiofrequency ablation (RFA) is a widely used and effective treatment for primary or metastatic liver cancer with small-size lesions. However, the therapeutic effectiveness of RFA in controlling metastatic lesion or recurrence is still limited. As the major cell population in tumor microenvironment (TME), macrophages have been reported to be recruited to RFA-treated lesion, but their roles are still unclear. Herein, we successfully established the mouse model mimicking RFA-induced abscopal effect, in which RFA eliminated the local orthotopic liver tumor but failed to control growth of distant tumor. Correspondently, RFA suppressed protumoral activation of local tumor-associated macrophages (TAMs), but failed to reprogram TAMs in distance. Importantly, although RFA led to reduced proportion of hepatic CD169+ macrophages in local and decreased expression of immune inhibitory molecules Tim-3 and PD-L1, these alterations were not observed for CD169+ macrophages in distant TME. Further RNA-seq and flow cytometry analysis showed that hepatic CD169+ macrophages contributed to reprograming TME through recruiting CD8+ T/NK cells and suppressing accumulation of MDSCs/Tregs. Consistently, depletion of CD169+ macrophages in CD169-DTR mouse greatly promoted liver tumor progression and largely dampened RFA-induced tumor suppression. Notably, transfer of CD169+ macrophages synergistically enhanced RFA-induced inhibition of distant tumor. To our knowledge, this is the first study which demonstrates hepatic CD169+ macrophages as a key factor responsible for RFA-induced abscopal effect. Our data suggest RFA with transfer of CD169+ macrophages as a promising combination therapy to lessen metastasis or recurrence of liver cancer in patients.