Background and aimsTo explore the therapeutic effects of human umbilical cord mesenchymal stem cells (HUMSCs) on repairing CCl₄-induced chronic liver injury in rats via intravenous injection and to identify the associated key metabolites.MethodsCell experiments: THLE-2 cells were divided into blank control, CCl₄-treated, and CCl₄ + Exos groups. Cell viability was assessed using the CCK-8 assay, while levels of AST, ALT, and MDA were determined using commercial kits. Targeted metabolomics analysis was employed to identify differentially expressed metabolites. Transmission electron microscopy (TEM) was used to evaluate mitochondrial morphology, and immunofluorescence staining was performed to examine the colocalization of Exos with mitochondria. Animal experiments: 24 healthy SPF SD rats were randomly divided into healthy, CCl₄, and CCl₄ + HUMSCs groups (n = 8 per group). Serum samples were collected for biochemical detection and targeted metabolomics analyses, while liver tissues underwent histopathological examination. Immunofluorescence staining was employed to monitor HUMSCs enrichment.ResultsIn the CCl₄ + Exos group, cell viability was significantly restored, and the elevated levels of AST, ALT, and MDA were reversed, while mitochondrial ultrastructure was ameliorated with successful Exos-mitochondria colocalization. Targeted metabolomics confirmed the presence of differentially expressed metabolites exhibiting consistent trends in both cellular and animal models. In the animal study, the CCl₄ group showed significant liver dysfunction and hepatic pathology characterized by hepatocyte steatosis and fibrous tissue hyperplasia. In contrast, the CCl₄ + HUMSCs group demonstrated markedly improved liver function and reduced pathological changes. Biochemical analysis revealed significant differences in ALT, AST, ALB, TBIL, TP, UREA, CR, and UA levels between the CCl₄ + HUMSCs and CCl₄ groups. Serum metabolomics analysis showed that compared with the CCl₄ group, 1,7-Dimethylxanthine and Xanthosine were significantly upregulated, while Succinic Acid, (S)-2-Hydroxybutanoic Acid, oxidized glutathione, and 3'-Sialyllactose were significantly downregulated in the CCl₄ + HUMSCs group.ConclusionHUMSCs treatment significantly reduced hepatic steatosis and fibrosis compared with the CCl₄ group alone. Metabolomic analysis suggests that the underlying mechanisms may involve upregulation of propanoate metabolism and increased taurochenodeoxycholic acid levels, which warrant further investigation.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13619-026-00282-0.

METTL3 is a crucial mRNA methyltransferase in mammals, essential for the regulation of gene expression and various biological processes. Here, we demonstrate that Mettl3 knockout (KO) in mouse embryonic stem cells (mESCs) leads to widespread upregulation of transposable elements (TEs) and 2-cell (2C)-like genes in a m6A enzyme activity-dependent manner, independent of culture conditions. Furthermore, embryo chimera experiments using a transient METTL3 degradation system (dTAG) revealed that METTL3-deficient mESCs can contribute to trophectoderm lineages at the blastocyst stage, indicative of expanded developmental potential. These findings highlight the role of METTL3-mediated m6A modifications in regulating the transcriptional and developmental plasticity of mESCs and suggest a link between m6A loss and the acquisition of a 2C-like state with features of extended potency.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13619-025-00262-w.

Embryo models derived from pluripotent stem cells (PSCs) have become powerful tools for dissecting mammalian embryonic development and advancing regenerative medicine. Two recent studies in Cell and Cell Stem Cell report major advances in generating mouse embryo models that replicate development up to early organogenesis (equivalent to embryonic day 8.5~8.75). Li et al. describe a purely chemical strategy to reprogram mouse embryonic stem cells (mESCs) into induced embryo founder cells (iEFCs) capable of forming complete embryo models (iEFC-EMs). In parallel, Yilmaz et al. demonstrate transgene-free generation of post-gastrulation models (TF-SEMs) from naive mESCs and induced pluripotent stem cells (iPSCs) using a similar chemical cocktail. Both models faithfully recapitulate key developmental events, including gastrulation, neural tube formation, cardiogenesis, and somitogenesis. These advances not only deepen understanding of early mammalian development but also pave the way for applications in regenerative medicine and disease modeling.

Aging is characterized by progressive functional decline driven by stem cell exhaustion, chronic inflammation, and cellular senescence. Mesenchymal progenitor cells (MPCs), which play a central role in tissue repair, are particularly vulnerable to age-associated dysfunction. Lei et al. (Cell 188:1-22, 2025) address this limitation by engineering human embryonic stem cell-derived MPCs with enhanced FOXO3 activity (termed SRCs). Intravenous administration of FOXO3-SRCs to aged cynomolgus macaques significantly slowed aging across multiple organs compared to wild-type MPCs. SRC treatment improved cognitive performance, preserved brain structure, protected bone integrity, and rejuvenated immune function. Transcriptomic and DNA methylation aging clocks revealed substantial reductions in biological age, with the most pronounced rejuvenation observed in the reproductive system, skin, lung, muscle, and hippocampus. These effects were partly attributed to SRC-derived exosomes enriched in gero-protective proteins and metabolites. Importantly, SRCs exhibited robust safety, showing no tumorigenicity or immunogenicity. This work positions FOXO3-enhanced MPCs and their exosomes as promising candidates for systemic anti-aging interventions, shifting the therapeutic paradigm from treating individual diseases to targeting the aging process itself.

Mechanical properties of cells have been proposed as potential biophysical markers for cell phenotypes and functions since they are vital for maintaining biological activities. However, current approaches used to measure single-cell mechanics suffer from low throughput, high technical complexity, and stringent equipment requirements, which cannot satisfy the demand for large-scale cell sample testing. In this study, we proposed to evaluate cell stiffness at the single-cell level using deep learning. The image-based deep learning models could non-invasively predict the stiffness ranges of mesenchymal stem cells (MSCs) and macrophages in situ with high throughput and high sensitivity. We further applied the models to evaluate MSC functions including senescence, stemness, and immunomodulatory capacity as well as macrophage diversity in phenotypes and functions. Our image-based deep learning models provide potential techniques and perspectives for cell-based mechanobiology research and clinical translation.

The efficient differentiation of adult gastric stem cells into specific epithelial cell types is crucial for gastric homeostasis. Although it is well appreciated that the niche plays a critical role in gastric epithelium cell differentiation, the relevant molecular factors and the underlying regulatory mechanisms remain poorly understood. In this study, by combining the knowledge of the niche cells obtained from single-cell RNA sequencing and manipulation of signaling pathways, we achieved effective differentiation of various gastric epithelial cell types in mouse and human gastric organoids. These in vitro differentiated cells showed a similar gene expression profile to those in gastric tissues. Specifically, BMP4 signaling stimulates pit cell and parietal cell differentiation. Furthermore, BMP4 and EGF signaling cooperate to enhance pit cell differentiation, whereas inhibition of TGF-β and BMP4 signaling promotes chief cell differentiation. We demonstrated that Zbtb7b is a novel regulator controlling pit cell differentiation. In addition, BMP4, together with the small molecule Isoxazole 9, promotes parietal and enteroendocrine cell differentiation. Our data also revealed the different requirements of parietal and chief cell differentiation between mouse and human. Together, our findings provide a mechanistic insight into gastric epithelial cell differentiation and uncover its similarities and differences between mouse and human, laying a foundation for future investigation and potential clinical use of gastric organoids.

Retinal ganglion cells (RGCs) are the visual gateway of the brain, with their axons converging to form the optic nerve, making them the most vulnerable target in diseases such as glaucoma and traumatic optic neuropathy (TON). In both diseases, the disruption of the blood-retinal barrier(BRB) is considered an important mechanism that accelerates RGC degeneration and hinders axon regeneration. The BRB consists of the inner blood-retinal barrier (iBRB) and the outer blood-retinal barrier (oBRB), which are maintained by endothelial cells(ECs), pericytes(PCs), and retinal pigment epithelial (RPE), respectively. Their functions include regulating nutrient exchange, oxidative stress, and the immune microenvironment. However, in glaucoma and TON, the structural and functional integrity of the BRB is severely damaged due to mechanical stress, inflammatory reactions, and metabolic disorders. Emerging evidence highlights that BRB disruption leads to heightened vascular permeability, immune cell infiltration, and sustained chronic inflammation, creating a hostile microenvironment for RGC survival. Furthermore, the dynamic interplay and imbalance among ECs, PCs, and glial cells within the neurovascular unit (NVU) are pivotal drivers of BRB destruction, exacerbating RGC apoptosis and limiting optic nerve regeneration. The intricate molecular and cellular mechanisms underlying these processes underscore the BRB's critical role in glaucoma and TON pathophysiology while offering a compelling foundation for therapeutic strategies targeting BRB repair and stabilization. This review provides crucial insights and lays a robust groundwork for advancing research on neural regeneration and innovative optic nerve protective strategies.Graphical

Organs-on-chips are microphysiological systems designed to replicate key functions of human organs, thereby accelerating innovation in life sciences, such as disease modeling, drug development, and precision medicine. However, the lack of standardized definitions, structural designs, cell sources, model constructions, and functional validations has posed challenges to their widespread translational applications. On April 29, 2024, the Chinese Society of Biotechnology introduced "Organs-on-chips: Liver", China's first group standard for human liver-on-a-chip technology. This pioneering standard provides comprehensive guidelines, including scope, terminology, definitions, technical requirements, detection methods, and quality control measures for developing liver models on chips. The introduction of this standard is set to facilitate the establishment of institutional protocols, promote widespread adoption, and drive the international standardization of liver-on-a-chip technologies.