摘要: The heterogeneity of cancer-associated fibroblasts (CAFs) could affect the response to immune checkpoint inhibitor (ICI) therapy. However, limited studies have investigated the role of inflammatory CAFs (iCAFs) in ICI therapy using pan-cancer single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics sequencing (ST-seq) analysis. We performed pan-cancer scRNA-seq and ST-seq analyses to identify the subtype of GSN+ iCAFs, exploring its spatial distribution characteristics in the context of ICI therapy. The pan-cancer scRNA-seq and bulk RNA-seq data are incorporated to develop the Caf.Sig model, which predicts ICI response based on CAF gene signatures and machine learning approaches. Comprehensive scRNA-seq analysis, along with in vivo and in vitro experiments, investigates the mechanisms by which GSN+ iCAFs influence ICI efficacy. The Caf.Sig model demonstrates well performances in predicting ICI therapy response in pan-cancer patients. A higher proportion of GSN+ iCAFs is observed in ICI non-responders compared to responders in the pan-cancer landscape and clear cell renal cell carcinoma (ccRCC). Using real-world immunotherapy data, the Caf.Sig model accurately predicts ICI response in pan-cancer, potentially linked to interactions between GSN+ iCAFs and CD8+ Tex cells. ST-seq analysis confirms that interactions and cellular distances between GSN+ iCAFs and CD8+ exhausted T (Tex) cells impact ICI efficacy. In a co-culture system of primary CAFs, primary tumour cells and CD8+ T cells, downregulation of GSN on CAFs drives CD8+ T cells towards a dysfunctional state in ccRCC. In a subcutaneously tumour-grafted mouse model, combining GSN overexpression with ICI treatment achieves optimal efficacy in ccRCC. Our study provides the Caf.Sig model as an outperforming approach for patient selection of ICI therapy, and advances our understanding of CAF biology and suggests potential therapeutic strategies for upregulating GSN in CAFs in cancer immunotherapy.

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摘要: Hepatocellular carcinoma (HCC) is one of the most challenging malignancies of the digestive system. Screening for novel biomarkers and therapeutic targets is a promising strategy to enhance HCC prognosis. Recently, liquid biopsy with circulating nucleic acids as the detection targets has attracted much attention in the field of early screening of tumours. However, the diagnostic value and biological functions of transfer RNA-derived small RNAs (tsRNAs) in serum, particularly in HCC, remains unknown. In this study, we characterised the expression profile of tsRNAs in hepatitis B virus (HBV)-related HCC, and confirmed the diagnostic potential of serum tRF-3a-Pro. On this basis, we established a diagnostic model that integrates tRF-3a-Pro with the classic HCC biomarker alpha-fetoprotein (AFP) through logistic regression analysis. Besides, both in vivo and in vitro experiments demonstrated that tRF-3a-Pro, a highly expressed tsRNA, promotes HCC cell proliferation. These findings suggested that tRF-3a-Pro could serve as a novel biomarker for HBV-related HCC.

摘要: Regulated cell death (RCD) is a complex process that involves several cell types and plays a crucial role in vascular diseases. Vascular smooth muscle cells (VSMCs) are the predominant elements of the medial layer of blood vessels, and their regulated death contributes to the pathogenesis of vascular diseases. The types of regulated VSMC death include apoptosis, necroptosis, pyroptosis, ferroptosis, parthanatos, and autophagy-dependent cell death (ADCD). In this review, we summarize the current evidence of regulated VSMC death pathways in major vascular diseases, such as atherosclerosis, vascular calcification, aortic aneurysm and dissection, hypertension, pulmonary arterial hypertension, neointimal hyperplasia, and inherited vascular diseases. All forms of RCD constitute a single, coordinated cell death system in which one pathway can compensate for another during disease progression. Pharmacologically targeting RCD pathways has potential for slowing and reversing disease progression, but challenges remain. A better understanding of the role of regulated VSMC death in vascular diseases and the underlying mechanisms may lead to novel pharmacological developments and help clinicians address the residual cardiovascular risk in patients with cardiovascular diseases. Regulated vascular smooth muscle cell death, including apoptosis, necroptosis, pyroptosis, ferroptosis, parthanatos, and autophagy-dependent cell death, play a key role in the development of vascular diseases. image

摘要: Spinal cord injury (SCI) leads to secondary neuronal death, which severely impedes recovery of motor function. Therefore, prevention of neuronal cell death after SCI is an important strategy. Ferroptosis, a new form of cell death discovered in recent years, has been shown to be involved in the regulation of SCI. However, the role and potential mechanisms of ferroptosis in secondary SCI are not fully understood. In this study, we report that the E3 ubiquitin ligase Syvn1 suppresses ferroptosis and promotes functional recovery from SCI in vitro and in vivo. Mechanistically, screened with bioinformatics, immunoprecipitation, and mass spectrometry, we identified Stat3, a transcription factor that induces the expression of the ferroptosis inhibitor Gpx4, as a substrate of Syvn1. Furthermore, we identified neurons as the primary cellular source of Syvn1 signalling. Moreover, we determined the binding domains of Syvn1 and Stat3 in HEK 293 T cells using full-length proteins and a series of truncated Flag-tagged and Myc-tagged fragments. Furthermore, we created the cell and animal models with silencing or overexpression of Syvn1 and Stat3 and found that Syvn1 inhibits neuronal ferroptosis by stabilizing Stat3, which subsequently activates the ferroptosis regulator Gpx4 in SCI. In summary, the Syvn1-mediated Stat3/Gpx4 signalling axis attenuates neuronal ferroptosis, reduces neuronal death, and promotes SCI repair. Therefore, our findings provide potential new targets and intervention strategies for the treatment of SCI. Syvn1 interacts with Stat3 to regulate its ubiquitination and stability, which in turn activates Gpx4 expression and ameliorates ferroptosis in neurons after SCI. image

摘要: Hair cell (HC) damage is a leading cause of sensorineural hearing loss, and in mammals supporting cells (SCs) are unable to divide and regenerate HCs after birth spontaneously. Procollagen C-endopeptidase enhancer 2 (Pcolce2), which encodes a glycoprotein that acts as a functional procollagen C protease enhancer, was screened as a candidate regulator of SC plasticity in our previous study. In the current study, we used adeno-associated virus (AAV)-ie (a newly developed adeno-associated virus that targets SCs) to overexpress Pcolce2 in SCs. AAV-Pcolce2 facilitated SC re-entry into the cell cycle both in cultured cochlear organoids and in the postnatal cochlea. In the neomycin-damaged model, regenerated HCs were detected after overexpression of Pcolce2, and these were derived from SCs that had re-entered the cell cycle. These findings reveal that Pcolce2 may serve as a therapeutic target for the regeneration of HCs to treat hearing loss.

摘要: Ageing and cell senescence of mesenchymal stem cells (MSCs) limited their immunomodulation properties and therapeutic application. We previously reported that nucleosome assembly protein 1-like 2 (Nap1l2) contributes to MSCs senescence and osteogenic differentiation. Here, we sought to evaluate whether Nap1l2 impairs the immunomodulatory properties of MSCs and find a way to rescue the deficient properties. We demonstrated that metformin could rescue the impaired migration properties and T cell regulation properties of OE-Nap1l2 BMSCs. Moreover, metformin could improve the impaired therapeutic efficacy of OE-Nap1l2 BMSCs in the treatment of colitis and experimental autoimmune encephalomyelitis in mice. Mechanistically, metformin was capable of upregulating the activation of AMPK, synthesis of l-arginine and expression of inducible nitric oxide synthase in OE-Nap1l2 BMSCs, leading to an increasing level of nitric oxide. This study indicated that Nap1l2 negatively regulated the immunomodulatory properties of BMSCs and that the impaired functions could be rescued by metformin pretreatment via metabolic reprogramming. This strategy might serve as a practical therapeutic option to rescue impaired MSCs functions for further application. In this study, we demonstrated that overexpression of Nap1l2 impaired the immunomodulation capacities of BMSCs through reduced NO production. Interestingly, metformin could rescue the impaired immunomodulatory ability of OE-Nap1l2 BMSCs both in vitro and in vivo by activating the AMPK signalling pathway. image

摘要: Cancer-associated fibroblasts (CAFs), a phenotypically and functionally heterogeneous stromal cell, are one of the most important components of the tumour microenvironment. Previous studies have consolidated it as a promising target against cancer. However, variable therapeutic efficacy-both protumor and antitumor effects have been observed not least owing to the strong heterogeneity of CAFs. Over the past 10 years, advances in single-cell RNA sequencing (scRNA-seq) technologies had a dramatic effect on biomedical research, enabling the analysis of single cell transcriptomes with unprecedented resolution and throughput. Specifically, scRNA-seq facilitates our understanding of the complexity and heterogeneity of diverse CAF subtypes. In this review, we discuss the up-to-date knowledge about CAF heterogeneity with a focus on scRNA-seq perspective to investigate the emerging strategies for integrating multimodal single-cell platforms. Furthermore, we summarized the clinical application of scRNA-seq on CAF research. We believe that the comprehensive understanding of the heterogeneity of CAFs form different visions will generate innovative solutions to cancer therapy and achieve clinical applications. The origin heterogeneity of CAFs: Multiple types of cells, under certain conditions, may become tumour-associated fibroblasts (CAFs). A variety of normal fibroblasts, including resident breast fibroblasts, pancreatic stellate cells (PSCs) and hepatic stellate cells (HSCs), bone marrow-derived mesenchymal stem cells (BM-MSCs) transformed into CAFs under the action of cytokines such as TGF-beta. Endothelial cells convert into CAFs through endothelial-mesenchymal transition (EndMT), and epithelial cells differentiate toward CAFs through epithelial mesenchymal-transition (EMT). Adipocytes, pericytes and smooth muscle cells can also be the source of CAFs.image

摘要: This study aims to determine the molecular mechanisms and analgesic effects of transient receptor potential vanilloid 1 (TRPV1) in the treatments of osteoarthritis (OA) and rheumatoid arthritis (RA). We summarize and analyse current studies regarding the biological functions and mechanisms of TRPV1 in arthritis. We search and analyse the related literature in Google Scholar, Web of Science and PubMed databases from inception to September 2023 through the multi-combination of keywords like 'TRPV1', 'ion channel', 'osteoarthritis', 'rheumatoid arthritis' and 'pain'. TRPV1 plays a crucial role in regulating downstream gene expression and maintaining cellular function and homeostasis, especially in chondrocytes, synovial fibroblasts, macrophages and osteoclasts. In addition, TRPV1 is located in sensory nerve endings and plays an important role in nerve sensitization, defunctionalization or central sensitization. TRPV1 is a non-selective cation channel protein. Extensive evidence in recent years has established the significant involvement of TRPV1 in the development of arthritis pain and inflammation, positioning it as a promising therapeutic target for arthritis. TRPV1 likely represents a feasible therapeutic target for the treatment of OA and RA. TRPV1, a member of the TRP family, is widely expressed in primary sensory neurons and various cells and participates in pain signal transduction of thermal, mechanical and chemical stimulation. Recently, functional changes in TRPV1 channels have been considered as risk factors for OA and RA. Abnormal expression and function of TRPV1 channels are associated with chondrocyte ferroptosis, synovial inflammatory response, macrophage polarization and bone homeostasis. In addition, TRPV1 channels play important roles in neural sensitization, defunctionalization or central sensitization and are involved in the occurrence of pain in OA and RA. Based on clinical and preclinical evidence, TRPV1-targeting drugs and regulation of its expression exhibit prominent curative effects in OA and RA. TRPV1 may be a novel potential therapeutic target for OA and RA treatment.image

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