Diabetic retinopathy (DR) is a prevalent microvascular complication of diabetes and a leading cause of vision loss among diabetic individuals. Retinal pigment epithelium (RPE) cells play a crucial role in the pathophysiology of DR by releasing cytokines and exosomal cargo, such as long non-coding RNAs (lncRNAs), that modulate local immune responses, maintain retinal immune homeostasis and influence macrophage polarisation. Recent studies suggest that lncRNA cancer susceptibility candidate 2 (CASC2) may be involved in the regulation of DR progression. However, the regulatory mechanisms linking CASC2 with RPE cells and its role in macrophage polarisation remain insufficiently understood.
Various types of cells, including human retinal pigment epithelial cells (ARPE-19), THP-1 monocytes and additional retinal cell lines, were cultured under normal glucose and high glucose conditions. ARPE-19 cells were exposed to oxidative stress, inflammatory stimulation, or hypoxic conditions. Plasma and aqueous humour samples were collected from DR patients and diabetic controls. Exosomes were extracted from AREP-19 cells and characterised. Various gene and protein expression analyses were performed using techniques including quantitative reverse transcription polymerase chain reaction, Western blot, immunofluorescence, flow cytometry, enzyme-linked immunosorbent assay, and histological staining. Cell proliferation and migration were assessed using Cell Counting Kit-8 assays and Transwell migration assays, respectively. The interactions among CASC2, suppressor of cytokine signalling 6 (SOCS6), and U2 small nuclear RNA auxiliary factor 2 (U2AF2) were explored using RNA immunoprecipitation and dual-luciferase reporter assays. An in vivo diabetic rat model was established.
lncRNA CASC2 expression levels were significantly lower in plasma and aqueous humour from DR patients compared to those from diabetic patients without retinopathy. Overexpression of CASC2 significantly attenuated DR and inflammatory damage both in vitro and in vivo. We demonstrated that exosomal CASC2 from ARPE-19 cells mediated macrophage polarisation by inhibiting M1 polarisation and promoting M2 polarisation. Our findings suggest that CASC2 regulates this polarisation through the stabilisation of SOCS6 mRNA via U2AF2.
CASC2 derived from RPE cells was transported to macrophages, inducing M2 polarisation by stabilising SOCS6 mRNA through the recruitment of U2AF2. This research may provide a foundation for developing novel therapeutic strategies for DR.
© 2025 Diabetes UK.

Acute rejection is a critical complication after liver transplantation, contributing significantly to transplant dysfunction and recipient mortality. Yin Yang 1 (YY1), a zinc-finger transcription factor, has an undefined role in liver allograft acute rejection, despite its broad expression and regulatory potential in immune responses.
To investigate YY1's role, we used an MHC Class II-mismatched rat liver transplantation model. Allografts were harvested on post-transplant days 5 and 10 for YY1 expression analysis in inflammatory cells around recipient liver central veins. In vitro, dendritic cells (DCs) were transfected to overexpress YY1, and their surface markers (CD80, CD86, MHC II) and cytokine production (TNF-α, IL-6) were assessed. Naïve CD4+ T cells were co-cultured with YY1-overexpressing DCs to evaluate their polarization towards inflammatory phenotypes (IL-17, IFN-γ production).
YY1 expression was elevated in inflammatory cells of allografts on days 5 and 10 post-transplant, correlating with increased serum transaminases and inflammatory cytokines. YY1-overexpressing DCs showed heightened expression of CD80, CD86, and MHC II, along with augmented TNF-α and IL-6 production. These YY1-activated DCs drove naïve CD4+ T cells to produce higher levels of IL-17 and IFN-γ, indicating polarization towards a proinflammatory Th17/Th1 phenotype.
YY1 promotes DC activation and naïve T cell polarization towards inflammatory phenotypes, thereby contributing to acute rejection in liver transplantation. Targeting YY1 may offer a therapeutic strategy to mitigate acute rejection and improve transplant outcomes. Further research is warranted to explore YY1's regulatory mechanisms and therapeutic potential in liver transplantation.
Copyright © 2025 Chen, Wang, Hong, Wang, He and Chen.

ISG15, an interferon-stimulated ubiquitin-like protein, plays a multifaceted role in tumorigenesis and immune regulation. This study comprehensively evaluates ISG15 as a prognostic biomarker and predictor of immunotherapy response through pan-cancer bioinformatics analysis and experimental validation. By integrating multiomics data from TCGA, GEO, and clinical cohorts, we found that ISG15 is significantly overexpressed in multiple cancers and generally correlates with poor prognosis. Elevated ISG15 expression is associated with increased immune checkpoint gene expression, particularly PD-L1, and immune infiltration, notably M2-like tumor-associated macrophages. Immunohistochemistry and multiplexed immunofluorescence confirmed a strong positive correlation between ISG15, PD-L1, and M2-TAM infiltration in lung and gastric cancer samples. Functional analysis at the single-cell level revealed significant associations between ISG15 and tumor proliferation, angiogenesis, and immune suppression. Immunotherapy cohort analysis demonstrated that tumors with high ISG15 expression responded favorably to PD-L1 inhibitors but exhibited resistance to CTLA-4 blockade, findings further validated in lung cancer patients receiving anti-PD-1 therapy. These results suggest that ISG15 is a promising biomarker for prognosis and immunotherapy response prediction across cancers. Its integration into clinical decision-making may enhance personalized treatment strategies, improve immunotherapy outcomes, and provide new insights into the tumor immune microenvironment, cancer progression, and potential therapeutic targets for future drug development.
© 2025. The Author(s).

The ovary is crucial for female reproduction and health, as it generates oocytes and secretes sex hormones. Transplantation of mesenchymal stem cells (MSCs) has been shown to alleviate pathological ovarian aging. However, it is unclear whether MSCs could benefit the naturally aging ovary. In this study, we first examined the dynamics of ovarian reserve of Chinese women during perimenopause. Using a naturally aging cynomolgus monkey (Macaca fascicularis) model, we found that transplanting human embryonic stem cells-derived MSC-like cells, which we called M cells, into the aging ovaries significantly decreased ovarian fibrosis and DNA damage, enhanced secretion of sex hormones and improved fertility. Encouragingly, a healthy baby monkey was born after M-cell transplantation. Moreover, single-cell RNA sequencing analysis and in vitro functional validation suggested that apoptosis, oxidative damage, inflammation, and fibrosis were mitigated in granulosa cells and stromal cells following M-cell transplantation. Altogether, these findings demonstrate the beneficial effects of M-cell transplantation on aging ovaries and expand our understanding of the molecular mechanisms underlying ovarian aging and stem cell-based alleviation of this process.
© 2024. The Author(s).

In allogeneic-hematopoietic stem cell transplantation for acute myeloid leukemia (AML), donor T cells combat leukemia through the graft-versus-leukemia (GVL) effect, while they also pose a risk of triggering life-threatening graft-versus-host disease (GVHD) by interacting with recipient cells. The onset of GVHD hinges on the interplay between donor T cells and recipient antigen-presenting cells (APCs), sparking T-cell activation. However, effective methods to balance GVHD and GVL are lacking.
In our study, we crafted nanocapsules by layering polycationic aminated gelatin and polyanionic alginate onto the surface of T cells, examining potential alterations in their fundamental physiological functions. Subsequently, we established an AML mouse model and treated it with transplantation of bone marrow cells (BMCs) combined with encapsulated T cells to investigate the GVL and anti-GVHD effects of encapsulated T cells. In vitro co-culture was employed to probe the effects of encapsulation on immune synapses, co-stimulatory molecules, and tumor-killing pathways.
Transplantation of BMCs combined with donor T cells selectively encapsulated onto AML mice significantly alleviates GVHD symptoms while preserving essential GVL effects. Encapsulated T cells exerted their immunomodulatory effects by impeding the formation of immune synapses with recipient APCs, thereby downregulating co-stimulatory signals such as CD28-CD80, ICOS-ICOSL, and CD40L-CD40. Recipient mice receiving encapsulated T-cell transplantation exhibited a marked increase in donor Ly-5.1-BMC cell numbers, accompanied by unaltered in vivo expression levels of perforin and granzyme B. While transient inhibition of donor T-cell cytotoxicity in the tumor microenvironment was observed in vitro following single-cell nanoencapsulation, subsequent restoration to normal antitumor activity ensued, attributed to selective permeability of encapsulated vesicle shells and material degradation. Moreover, the expression of apoptotic proteins and FAS-FAS ligand pathway at normal levels was still observed in leukemia tumor cells.
Encapsulated donor T cells effectively mitigate GVHD while preserving the GVL effect by minimizing co-stimulatory signaling with APCs through early immune isolation. Subsequent degradation of nanocapsules restores T-cell cytotoxic efficacy against AML cells, mediated by cytotoxic pathways. Using transplant-encapsulated T cells offers a promising strategy to suppress GVHD while preserving the GVL effect.
© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.