Wang L, Fu BQ, Ma AJ
… +27 more, Niu SS, Zhang Y, Xu RR, Ma SH, Cao JN, Zhao HL, Wang WY, Wang HY, Ma J, Wei J, Yu JY, Li QY, Zhu LJ, Na T, Cai JL, Fan X, Peng YJ, Yu XY, Chen QB, Zhai PJ, Hu SJ, Xiang AP, Hua GQ, Zhou JX, Zhao TB, Hu BY, Hao J
Hepatocyte proliferation restores liver mass after partial hepatectomy (PHx), but the metabolic cost of this process remains unclear. Single-nucleus transcriptomics of mouse liver 48 h after 70% PHx revealed that EGFR-FO...Hepatocyte proliferation restores liver mass after partial hepatectomy (PHx), but the metabolic cost of this process remains unclear. Single-nucleus transcriptomics of mouse liver 48 h after 70% PHx revealed that EGFR-FOXM1 signalling drives mitotic entry while simultaneously suppressing PPARα-ACSL1-mediated lipid catabolism. Consequently, triglycerides and free fatty acids accumulate in regenerating tissue. Activating PPARα with the agonist Wy-14643 released this metabolic brake, accelerated hepatocyte proliferation via HIF1α-FOXM1, and improved post-PHx recovery. These data identify lipid-metabolic reprogramming as an EGFR-dependent collateral effect that can be pharmacologically reversed to enhance liver regeneration in surgical patients, offering a readily translatable strategy to reduce post-operative liver failure and shorten hospital stay after major hepatectomy.
Recombinant granulocyte colony-stimulating factor (G-CSF) is widely used to mobilise donor stem cells into peripheral blood for allogeneic haematopoietic stem cell transplantation (allo-HSCT). Studies have shown that G-C...Recombinant granulocyte colony-stimulating factor (G-CSF) is widely used to mobilise donor stem cells into peripheral blood for allogeneic haematopoietic stem cell transplantation (allo-HSCT). Studies have shown that G-CSF may reduce the incidence of acute graft-versus-host disease (aGVHD) following allo-HSCT by modulating T cell function. However, the patterns and mechanisms by which G-CSF regulates T cell function remain unclear. In this study, we used RNA sequencing combined with T cell receptor (TCR) immune repertoire sequencing to discover that G-CSF mobilisation leads to a reduction in donor TCR clonal diversity, downregulation of genes associated with TCR recombination, suppression of multiple antigen presentation processes, and varying degrees of downregulation in multiple T cell function-related signalling pathways. The results suggest that the pathway by which G-CSF mediates a low incidence of GVHD after allo-HSCT is by interfering with donor TCR recombination and antigen presentation processes, resulting in suppression of multiple T cell functions.
Dentine formation constitutes a physiological process precisely regulated by signal transduction modules governing odontoblast differentiation and mineralisation. First, by constructing a single-cell transcriptional land...Dentine formation constitutes a physiological process precisely regulated by signal transduction modules governing odontoblast differentiation and mineralisation. First, by constructing a single-cell transcriptional landscape of odontogenic tissue, we defined EFNB2+ mesenchymal cells as a primary progenitor cluster, marking the origin of the odontogenic lineage. Integrating CellRank-based fate mapping and SCENIC-based regulon specificity analysis, we identified signal transducer and activator of transcription 3 (STAT3) as a pivotal transcriptional regulator of the odontoblast lineage. Subsequently, in silico perturbations using CellOracle predicted that STAT3 ablation disrupted the developmental vector field, redirecting the fate of mesenchymal precursors away from the odontoblast lineage. To substantiate these bioinformatic predictions, functional validation using shRNA-mediated silencing and pharmacological modulation demonstrated that STAT3 was essential for the proliferation and differentiation capacity of dental mesenchymal cells. Furthermore, we generated conditional knockout mice targeting Stat3 in Osterix-expressing odontoblast progenitors, which consequently exhibited significant dentine dysplasia. Mechanistically, RNA-seq and chromatin immunoprecipitation (ChIP) assays revealed that STAT3 directly bound to the WNT2B promoter, transcriptionally activating the Wnt/β-catenin signalling pathway in dental mesenchymal cells. Overexpression of WNT2B partially rescued the odontogenic defects induced by STAT3 inactivation. This 'prediction to verification' study establishes STAT3 as a critical regulator of dentinogenesis and provides potential therapeutic targets for the treatment of dentine developmental disorders and the advancement of dentine regeneration.
Periodontitis is a prevalent oral disease characterised by chronic inflammation and irreversible alveolar bone loss. Osteoclasts (OCs) are the key cells mediating bone resorption and their excessive formation disrupts bo...Periodontitis is a prevalent oral disease characterised by chronic inflammation and irreversible alveolar bone loss. Osteoclasts (OCs) are the key cells mediating bone resorption and their excessive formation disrupts bone homeostasis. Since apoptosis of OCs normally restrains this process, its failure can sustain bone loss. However, its role in periodontitis remains unclear. Analysis of single-cell RNA sequencing (scRNA-seq) data retrieved from the Gene Expression Omnibus (GEO) database revealed impaired OC apoptosis in the periodontal tissues of individuals suffering from periodontitis. Notably, we observed a reduction in cytoskeleton-associated protein 4 (CKAP4) expression correlating with decreased OC apoptosis. Further investigations using Ckap4 knockout mice confirmed that CKAP4 promotes OC apoptosis through the activation of forkhead box O3 (FOXO3)-induced endoplasmic reticulum stress (ERS). CKAP4 regulates OC apoptosis to maintain periodontal homeostasis and its downregulation in periodontitis promotes pathological bone resorption. This study elucidates CKAP4-mediated apoptotic pathways in OCs, providing mechanistic insight and potential therapeutic strategies to restore OC balance and prevent bone loss.
Zou J, Li S, Fu H
… +29 more, Zhang M, Hu A, Tian X, Du Y, Wei L, Chen X, Gao J, Liang R, Feng X, Li Y, Wang Y, Cai X, Sun P, Ding X, Zhang B, Liu T, Liu N, Hao J, Wang L, Zhao H, Cao J, Ma A, Zhu L, Li Q, Wei Q, Ding X, Cheng Y, Zhao T, Wang S
Cell Prolif
· 2026 Jun · PMID 41964108
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Liver cancer remains a leading cause of cancer-related mortality worldwide, with limited durable responses to conventional therapies. Cancer vaccines utilising the immune system offer a promising alternative. Here, we de...Liver cancer remains a leading cause of cancer-related mortality worldwide, with limited durable responses to conventional therapies. Cancer vaccines utilising the immune system offer a promising alternative. Here, we developed a prophylactic whole-cell tumour vaccine by engineering Hepa 1-6 cells to express murine granulocyte-macrophage colony-stimulating factor (mGM-CSF), and investigated its anti-tumour efficacy and underlying mechanisms. The Hepa 1-6-mGM-CSF vaccine provided complete and durable protection against both primary and rechallenge tumour inoculations. Hepa 1-6-mGM-CSF immunisation robustly activated dendritic cells (DCs) and T cells in both lymph nodes and spleen, characterised by enhanced DC maturation and migration, as well as the differentiation of T cells toward cytotoxic and memory phenotypes. Meanwhile, the Hepa 1-6-mGM-CSF vaccine remodelled the tumour microenvironment (TME) toward an immunostimulatory state. Critically, irradiation-induced oxidative stress in mitochondria promoted the release of oxidised mitochondrial DNA (ox-mtDNA), which subsequently activated the cGAS-STING signalling pathway. Ox-mtDNA synergized with vaccine-secreted GM-CSF to promote DC activation, antigen presentation and migration. In summary, our study demonstrates that the Hepa 1-6-mGM-CSF vaccine elicits robust anti-tumour immunity through the coordinated release of ox-mtDNA and GM-CSF, with ox-mtDNA synergistically enhancing immune activation via the cGAS-STING signalling pathway. Collectively, these findings highlight the Hepa 1-6-mGM-CSF vaccine as a promising strategy for liver cancer management.
Fatty acid (FA) overload imposes substantial stress on hypothalamic neurons, whilst whether cortical input could improve metabolic resilience of hypothalamic neurons remains poorly understood. Here, we reconstructed huma...Fatty acid (FA) overload imposes substantial stress on hypothalamic neurons, whilst whether cortical input could improve metabolic resilience of hypothalamic neurons remains poorly understood. Here, we reconstructed human cortical-hypothalamic assembloids (CO-HTO assembloids) to investigate how cortical input modulates hypothalamic responses to FA. Our results revealed that FA could impair neuronal survival, α-MSH secretion, and electrophysiological activity in hypothalamic organoids (HTOs). Remarkably, fusion with cortical organoids (COs) could prevent FA-induced apoptosis and functional defects, preserve mitochondrial respiration, and reduce lipid accumulation in HTOs. Also, transcriptomic and functional analyses revealed that cortical input could activate PGC1α-dependent mitochondrial biogenesis. Furthermore, pharmacological PGC1α activation or glutamate treatment rescued the FA-induced defects in HTOs. Collectively, our findings uncovered a cortico-hypothalamic regulatory axis and found glutamate-driven PGC1α activation might maintain hypothalamic neuronal stability and improve resilience to metabolic stress. Our CO-HTO assembloids provided a promising platform to investigate complex inter-regional communications and related neurological and metabolic disorders.
Bone morphogenetic protein (BMP) signalling plays a pivotal role in bone regeneration by regulating osteoprogenitor cell (OPC) function, and BMPs have been widely used in clinical treatment. However, their limited specif...Bone morphogenetic protein (BMP) signalling plays a pivotal role in bone regeneration by regulating osteoprogenitor cell (OPC) function, and BMPs have been widely used in clinical treatment. However, their limited specificity for OPCs often lead to side effects, highlighting that the regulatory mechanisms of BMP signalling remain to be further elucidated. BMPR1A, a key type I BMP receptor, has emerged as a critical regulator of bone development, yet its precise role in bone regeneration and downstream mechanisms remains unclear. Using OPC-specific conditional knockout (cKO) and constitutively activated (CA) BMPR1A mouse, we found conditional knockout of BMPR1A in OPCs during the first 2 weeks of healing significantly accelerated bone regeneration. At the cellular level, BMPR1A knockout promoted the proliferation of OPCs, thereby accelerating bone regeneration in cKO mice. Mechanistically, BMPR1A knockout reduced ID1 expression, releasing its inhibition of TCF3, which in turn induced GNG4 expression and ultimately activated the PI3K-AKT pathway. Finally, a double-knockdown cell line further demonstrated the role of the BMPR1A-ID1-TCF3-GNG4 signalling axis. This study reveals the function and mechanism of BMPR1A in bone regeneration and provides new insights for more precise BMP-targeted strategies.
Liver fibrosis represents a critical pathological stage in chronic liver disease, characterized by excessive activation of hepatic stellate cells (HSCs) and dysregulated immune cell recruitment. Our previous studies demo...Liver fibrosis represents a critical pathological stage in chronic liver disease, characterized by excessive activation of hepatic stellate cells (HSCs) and dysregulated immune cell recruitment. Our previous studies demonstrated that overexpressing tyrosine kinase receptor B (TrkB) in HSCs inhibits their activation, thereby alleviating liver fibrosis. However, its functional significance in hepatocytes-the predominant parenchymal cells orchestrating liver homeostasis-remains poorly understood. Here, we investigate the mechanistic interplay between hepatocyte-specific TrkB signalling and liver fibrosis progression. Through integrated in vivo animal models and in vitro two- and three-dimensional systems, we demonstrate that elevated TrkB expression in hepatocytes reduces pro-fibrotic and inflammatory cytokines, attenuates HSC activation via paracrine signalling, and impairs monocyte-derived macrophage (MoMF) recruitment. Mechanistically, TrkB modulates the TGFβ/SMAD3 pathway by inhibiting p-SMAD3 nuclear translocation, thus suppressing FOS transcription. As a core component of the AP-1 transcription factor complex, FOS directly regulates CCL2, a pivotal chemokine for macrophage recruitment. Collectively, these results establish TrkB as a key regulatory node in the TGFβ/SMAD3/FOS/CCL2 signalling cascade, orchestrating macrophage-mediated fibrotic responses in the liver.
Xu YJ, Duan CH, Tang TS
… +42 more, Wang YK, Song W, Fu BQ, Ma AJ, Hu BY, Luo ZG, Zhang XQ, Liu Y, Teng ZQ, Hao J, Wei Q, Wu ZH, Zhang Y, Zhao B, Bian S, Zhang JZ, Peng B, Li TQ, Chen YJ, Liu J, Wang L, Zhao Y, Zhang WQ, Peng YJ, Zhang BY, Bao XJ, Wang YL, Tang Y, Hu SJ, Li Q, Zhu GX, Zhang A, Zhu L, Li QY, Na T, Zhao L, Ping YF, Zhao HL, Niu SS, Zhou Q, Zhao TB, Liu CM
Cell Prolif
· 2026 May · PMID 41914800
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Human embryos undergo pivotal morphogenetic remodelling shortly after implantation. The understanding of this crucial stage is severely impeded by the scarcity of embryonic samples and ethical constraints. Pluripotent st...Human embryos undergo pivotal morphogenetic remodelling shortly after implantation. The understanding of this crucial stage is severely impeded by the scarcity of embryonic samples and ethical constraints. Pluripotent stem cells with the competence for somatic and germline differentiation serve as in vitro models of epiblast. In this study, we established human formative pluripotent stem cell-like cells (hfPSC-LCs) from naïve human embryonic stem cells (hESCs), conventional hESCs, human induced pluripotent stem cells (hiPSCs), as well as human blastocysts using the three-dimensional (3D) Matrigel culture system. Similar to pre-gastrula stage epiblast, hfPSC-LCs self-organise into self-renewing colonies with an apical lumen and exhibit several hallmarks of formative pluripotency, consistent with the properties observed in mouse fPSCs. Notably, single cells of hfPSC-LCs could differentiate into amnion-like precursor cells (hALPCs) which are transcriptionally and morphologically similar to the bona fide amnion. Meanwhile, hfPSC-LCs directly respond to primordial germ cell (PGC) induction signals, generating PGC-like cells (PGCLCs) either as single-cell aggregates or intact colonies, with an efficiency of approximately 50%. Chromatin accessibility analysis revealed that the differentiation capacity of hfPSC-LCs for gametes and amnion lineages might correlate with the accessible chromatin architecture of PGC and amnion associated genes. Loss of 3D-Matrigel niche disrupts formative pluripotency in both mouse and human, manifesting as downregulated formative markers and compromised differentiation capacity. Collectively, our findings establish hfPSC-LCs as a 3D model for investigating formative pluripotency of humans, thereby probably addressing a critical gap in the understanding of human pluripotency transitions.
Cell Prolif
· 2026 May · PMID 41852197
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of the functions of the NTRK2 receptor during lung injury and regeneration. Our recent work using both human organoid and mouse disease models highlights the non-conventional role of NTRK2 isoforms in regulating pulmonar...of the functions of the NTRK2 receptor during lung injury and regeneration. Our recent work using both human organoid and mouse disease models highlights the non-conventional role of NTRK2 isoforms in regulating pulmonary vasculature and alveolar regeneration during bronchopulmonary dysplasia.
Cell Prolif
· 2026 May · PMID 41821387
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Bioprinting with stem cells is an emerging technique for creating human tissues from scratch, transforming our understanding of biology and its biomedical applications. While significant attention has been paid to bioche...Bioprinting with stem cells is an emerging technique for creating human tissues from scratch, transforming our understanding of biology and its biomedical applications. While significant attention has been paid to biochemical cues, mechanobiology is emerging as an equally important regulator in stem cell-based bioprinting, yet it has long been unexplored. Recent advances in elucidating mechanotransduction pathways underscore the need to comprehend bioink mechanics to bridge printability and stem cell fate regulation. This review emphasises the central role of mechanobiology in stem cell-based bioprinting: ensuring adequate printability while maintaining and programming stem cell functionality through biomechanical signals. We discuss how the mechanical properties of bioinks influence stem cell behaviour, with a focus on mechanosensitive stem cells, including pluripotent, mesenchymal, neural, hepatic and lung stem cells. Special attention is given to stem cell-based organoids and their associated mechanotransduction signalling pathways. We further identify four key mechanobiological requirements that define the relationship between print fidelity and the mechanical cues governing stem cell mechanosensing. We propose integrative strategies drawing from innovations in materials science and bioprinting to reframe mechanics as a tunable parameter rather than a constraint. Our roadmap aims to leverage bioink mechanics not only to facilitate biofabrication but also to guide stem cell fate and functional remodelling of engineered tissues for potential clinical applications.
Heat stress is a common challenge for cells, causing multiple types of cellular damage while triggering complex stress responses, including the highly conserved mechanism known as the heat shock response (HSR). However,...Heat stress is a common challenge for cells, causing multiple types of cellular damage while triggering complex stress responses, including the highly conserved mechanism known as the heat shock response (HSR). However, the subcellular coordination of these stress responses remains poorly understood. In this study, we identify reversible nuclear morphological changes under heat stress, characterised by kidney-shaped invaginations. These nuclear invaginations are associated with intermediate filament collapse and the regional clustering of organelles. Through immunofluorescence imaging and proteomic analysis, we further reveal that nuclear invagination regions function as specialised compartments where newly synthesised proteins are concentrated and protein degradation demand is heightened. Moreover, this compartmentalization is not only essential for cellular adaptation and recovery from heat stress but also correlates with the differential heat tolerance across cell lines. Our findings highlight a previously unappreciated mechanism by which cells spatially reorganise protein metabolism to optimise stress responses, providing new insights into cellular stress adaptation.
Liu J, Liang W, Xia W
… +29 more, Wang P, Hao J, Na T, Yan S, Zhang Y, Li K, Li Q, Pan G, Wei J, Chen Q, Cao J, Zhai P, Fu B, Gao H, Zhang Y, Wang L, Guo M, Hu S, Zhu L, Zhao Y, Zhang W, Wu Z, Ping Y, Zhao H, Niu S, Zhao T, Ma A, Xiang AP, Chen X
Cell Prolif
· 2026 Apr · PMID 41814993
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'Technical specification for haemocompatibility assessment of human mesenchymal stem cells' is the first set of guidelines on haemocompatibility assessment of human mesenchymal stem cells (MSCs) in China, jointly drafted...'Technical specification for haemocompatibility assessment of human mesenchymal stem cells' is the first set of guidelines on haemocompatibility assessment of human mesenchymal stem cells (MSCs) in China, jointly drafted and agreed upon by experts from the Chinese Society for Stem Cell Research. This standard outlines the methods for assessing the hemocompatibility of human mesenchymal stem cells and specifies the requirements for the selection of evaluation indicators, calculation of indicator values, and determination of hemocompatibility levels. It is applicable for evaluating the hemocompatibility of MSCs prior to their contact with blood. This guideline was originally released by the Chinese Society for Cell Biology on October 28, 2024. We anticipate that the publication of this specification will promote the institutional adoption, acceptance, and execution of proper testing protocols, thereby accelerating the international standardization of MSCs for clinical development and therapeutic applications.
Ovarian endometriosis (OEM) is characterised by ectopic endometrial tissue growth within the ovary. In these ectopic lesions, the ectopic epithelium plays a crucial role in OEM progression and has been associated with ma...Ovarian endometriosis (OEM) is characterised by ectopic endometrial tissue growth within the ovary. In these ectopic lesions, the ectopic epithelium plays a crucial role in OEM progression and has been associated with malignant transformation in a subset of cases. However, conventional histology limits understanding of ectopic epithelial distribution, structure, and its perivascular microenvironment, thus impeding pathogenesis studies. To address this, we employed a modified tissue-clearing method and three-dimensional (3D) imaging to systematically characterise OEM, revealing key, previously unreported spatial characteristics. We found significantly higher densities of ectopic epithelium and vasculature in the outer cystic wall versus the inner. Furthermore, our method improved the detection rate of ectopic epithelium and revealed its morphological polymorphism at both tissue and cellular levels. Besides, we demonstrated that vessels preferentially cluster around ectopic epithelium, with their distribution pattern strongly linked to the location of ectopic epithelium. Strikingly, we observed endometrial-like structures in lesional vasculature in 3 of 49 cases, representing a novel morphological observation that warrants further investigation. This study significantly advances our understanding of OEM histopathology, offering insights for clinical diagnosis and treatment.