Cell Proliferation最新文献

High altitude pulmonary hypertension (HAPH) is a complex disease featured by hypoxia-induced pulmonary vasoconstriction and remodelling of small pulmonary arterioles, which could lead to increased pulmonary pressures and right ventricular hypertrophy and eventually result in heart failure. The temporal trajectory of HAPH progression can be divided into three overlapping phases: hypoxic pulmonary arterioles vasoconstriction, hypoxic pulmonary arterioles remodelling and even right heart failure. Each phase is governed by distinct molecular engines and cellular effectors that translate hypoxia physiological adaption into irreversible cardiopulmonary dysfunction. This review describes the intricate cellular signalling networks involved in the pathogenesis of HAPH, integrating canonical pathways such as HIF, MAPK and BMP with emerging targets like Wnt/β-catenin, Notch, Hippo-YAP and IL-6. Inhibiting the HIF signalling pathway, modulating the MAPK pathway and suppressing the BMP, Wnt/β-catenin, Notch, Hippo-YAP and IL-6 pathways have shown potential in reducing vascular remodelling and right ventricular dysfunction. Despite encouraging progress, the clinical translation remains constrained by a lack of deeper understanding of the signalling networks in HAPH. A comprehensive understanding of these signalling pathways in HAPH may yield critical insights into the disease's pathogenesis and facilitate the development of targeted intervention strategies. Future research should focus on elucidating the molecular mechanisms underlying these pathways, exploring genetic and environmental interactions, validating intervention targets, developing biomarkers, utilising systems biology approaches and conducting clinical trials.

Bone-related diseases (e.g., osteoporosis, osteoarthritis and fractures) exhibit a rising global incidence, imposing significant burdens on both quality of life and healthcare systems. Conventional therapeutic approaches, including anti-resorptive drugs and surgical interventions, face limitations such as long-term medication requirements, adverse effects (e.g., bisphosphonate-related osteonecrosis of the jaw) and suboptimal efficacy. Bone marrow mesenchymal stromal cells (BMSCs) have emerged as a promising therapeutic alternative due to their accessibility, multi-lineage differentiation potential, immunomodulatory properties and homing capacity. However, challenges such as disease complexity, mechanistic heterogeneity and therapeutic inconsistency hinder their clinical translation. Recent advances in genetic engineering, preconditioning strategies, bone tissue engineering (e.g., three-dimensional [3D] scaffolding), extracellular vesicle-based therapies and epigenetic regulation (e.g., histone modification) have significantly enhanced the therapeutic effects of BMSCs. Furthermore, cutting-edge technologies like organoids and 3D bioprinting, which stem from advances in tissue engineering, offer novel avenues for clinical applications. Given these rapid developments, this review systematically summarises BMSC-based treatment strategies for bone-related diseases, discusses current challenges and outlines future directions to advance translational research.

Failure of timely bone regeneration compromises structural integrity and delays functional recovery; therefore immune regulation of the early repair microenvironment is crucial for successful healing. M1 (pro-inflammatory) phenotype macrophages play pivotal roles in vascularisation during the early phase of bone regeneration and are typically activated by interferon-gamma (IFN-γ) or lipopolysaccharide (LPS) as well as by metabolite-derived signals. Lactate, a metabolite known to regulate a series of pathophysiological processes, has not yet been fully investigated for its specific immunomodulatory role in the microenvironment of bone injury healing. Our in vitro experiments demonstrated that lactate induced macrophage polarisation to the M1 phenotype and accelerated angiogenesis, with the HIF1α-NOD1-calcium influx axis identified as a key mediator. In vivo validation further confirmed the positive effects of lactate intervention in promoting vascularised bone regeneration at the early stage of injury. Thus, this study uncovers how lactate modulates immune response in association with M1 macrophages and indicates its potential as a therapeutic strategy for promoting vascularised bone healing.

Retinal neovascularisation (RNV) is manifested in various retinal pathological conditions, often leading to irreversible blindness. The oxygen-induced retinopathy (OIR) mouse model proves to be a useful tool for understanding RNV pathogenesis. In this model, retinal vascular phenotype undergoes two distinct stages: neovascular formation, followed by spontaneous regression. While microglial functions in the neovascular formation stage have been extensively studied, their behaviors and roles during regression remain unclear. In this study, we characterise the spatiotemporal dynamics and molecular heterogeneity of retinal microglia across both stages. During RNV formation, microglia exhibit an outer-to-inner and central-to-midperipheral migration pattern, whereas a reversed migration trend is observed during regression. We confirm a highly glycolytic microglia (HGM) subpopulation during RNV formation and demonstrate its pro-angiogenic role by targeting a highly expressed pyruvate kinase M2 (Pkm2), a crucial enzyme for glycolysis. Importantly, we find that microglia exhibit enhanced phagocytic activity during regression, constituting a distinct phagocytosis-associated microglia (PAM) subtype, expressing mannose receptor C-type 1 (Mrc1/CD206). Altogether, our findings reveal stage-specific microglial functional dynamics, providing novel insights into RNV pathogenesis and intervention.

Liver grafts from donation-after-cardiac-death (DCD) are vulnerable to ischemia-reperfusion injury, which compromises graft function after transplantation. Agrimoniin has been shown to possess antioxidant and anti-inflammatory properties, making it a potential therapeutic agent for organ preservation. This study investigated whether supplementing agrimoniin to the University of Wisconsin (UW) cold storage solution protected liver grafts from DCD rats or cold preserved human liver cell lines (QSG-7701 and HepG2). Agrimoniin supplementation significantly reduced oxidative damage, alleviated ferroptosis, and mitigated liver injury by activating the Nrf-2 pathway, both in vivo and in vitro. These findings suggest that ferroptosis is a mediator in DCD liver injury, and agrimoniin, through its activation of the Nrf-2 pathway, may be an effective therapeutic agent for enhancing liver graft preservation and improving outcomes in DCD liver transplantation.

Intervertebral disc degeneration (IDD) is a primary cause of low back pain, with the development of new blood vessels being a key pathological feature. Fibroblast activation protein-alpha (FAP-α), a member of the Type II serine protease family, possesses dipeptidase and collagenase activities and is closely linked to angiogenesis. Bioinformatics and immunohistochemical analysis revealed elevated FAP-α expression and increased angiogenesis in degenerated cartilage endplate (CEP). Co-culture of FAP-α-silenced CEP cells or conditioned media with human umbilical vein endothelial cells (HUVECs) demonstrated a reduction in hypoxia-inducible factor-α (HIF-α) levels, vascular endothelial growth factor (VEGF)-A and PI3K/AKT phosphorylation, which impaired HUVEC migration and tube formation. Conversely, FAP-α overexpression enhanced angiogenesis via the PI3K/AKT/HIF-α/VEGF-A signalling pathway. In rats with IDD induced by lumbar instability, FAP-α inhibitors reduced angiogenesis and ossification of the CEP, thereby delaying IDD progression associated with CEP degeneration. Genetic deletion of FAP further slowed IDD progression. Collectively, these findings provide compelling evidence that FAP-α accelerates IDD by promoting angiogenesis, which disrupts disc homeostasis. Targeting FAP-α may offer a novel therapeutic approach for mitigating IDD.

This study elucidates the critical role of macrophage-myofibroblast transition (MMT) in the pathogenesis of intestinal fibrosis in Crohn's disease (CD). Through analysis of stricturing intestinal tissues from CD patients and TNBS-induced CD mouse models, we demonstrated that TGF-β1 activates the MAPK signalling pathway to induce MMT in macrophages (Mø), resulting in increased expression of α-SMA and collagen production. Importantly, these MMT-derived myofibroblasts secrete CCL17, which recruits CCR4⁺ regulatory T cells (Tregs) to fibrotic lesions, creating a pro-fibrotic microenvironment. Further investigation showed that the adoptive transfer of Mø exacerbated fibrosis in CD mice, whilst Mø depletion attenuated this process. Therapeutically, adipose-derived mesenchymal stromal cells-derived extracellular vesicles (AMSC-sEVs) could effectively deliver MFGE8 to inhibit MAPK activation, thereby suppressing MMT and reducing CCL17-mediated Treg recruitment. Treatment with AMSC-sEVs significantly improved intestinal fibrosis in CD mice, as evidenced by reduced collagen deposition and improved histological scores, whereas MFGE8 knockdown in AMSC-sEVs diminished these protective effects. These findings not only establish MMT as a key mechanism driving CD-associated intestinal fibrosis through the CCL17-CCR4 axis but also highlight AMSC-sEVs as a promising cell-free therapeutic strategy targeting this pathological process.

‘Human spinal cord GABAergic neural progenitor cell’ is the latest set of guidelines on human spinal cord GABAergic neural progenitor cells in China, jointly drafted and agreed upon by experts from the Standard Committee of Chinese Society for Cell Biology. This standard specifies requirements for human spinal cord GABAergic neural progenitor cells, including the technical requirements, test methods, test regulations, instructions for use, labelling requirements, packaging requirements, storage and transportation requirements and waste disposal requirements. This standard is applicable for the quality control of human spinal cord GABAergic neural progenitor cells, whether derived from human tissues or differentiated/transdifferentiated from stem cells. It was originally released by the Chinese Society for Cell Biology on 28 October, 2024. We hope that the publication of these guidelines will promote institutional establishment, acceptance and execution of proper protocols, thereby accelerating the international standardisation of human spinal cord GABAergic neural progenitor cells for various applications.

This document specifies the general requirements, technical requirements, detection methods, inspection rules, instructions for use, labelling, transportation and storage of human spinal cord GABAergic neural precursor cells.

This document is applicable to the detection of human spinal cord GABAergic neural precursor cells that are isolated from human tissues or obtained through stem cell differentiation or transdifferentiation.

The contents in the following documents constitute indispensable clauses of this document through normative references in the text. Among them, for dated references, only the version corresponding to the date is applicable to this document; for undated references, the latest version (including all amendments) is applicable to this document.

Pharmacopoeia of the People's Republic of China (2020 edition, Volume III)

National clinical laboratory operating procedures

WS 213 diagnosis of hepatitis C

WS 273 diagnosis of syphilis

WS 293 diagnostic criteria for AIDS and HIV infection

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Hong Chen and Jia Xu contributed to conception and design. Baoyang Hu, Xiaoqing Zhang, Tongbiao Zhao, Aijin Ma, Jie Hao, Tianqing Li and Boqiang Fu revised the manuscript. Lixiang Ma, Yan Liu, Peng Xiang, Kun Qian, Xiaohua Han, Yajie Li, Lijun Zhu, Qiyuan Li, Qiang Wei, Tingting Wu, Lei Wang, Jiani Cao, Ka Li, Hongling Zhao and ShuaiShuai Niu critically read and revised the manuscript.

This work was supported by grants from the National Key R&D Program of China (Grant/Award Numbers: 2023YFC3605100 and 2023YFC2308600) and the National Natural Science Foundation of China (Grant/Award Numbers: 82472621 and 82171422).

Meiosis, a specialised form of cell division, is essential for sexual reproduction, which requires the proper formation of synaptonemal complex (SC) and homologous recombination (HR). However, the regulatory mechanisms underlying these processes remain incompletely understood. Here, we demonstrate that SOX30 is a key transcriptional regulator of male meiotic synapsis and recombination. In Sox30-knockout mice, zygotene spermatocytes accumulate with synapsis defects. SOX30 deficiency disrupts the SC central element components SYCE1, SYCE2, and TEX12 distribution. Furthermore, disrupted γ-H2AX distribution reveals impaired DNA double-strand break repair and the persistence of recombination proteins RAD51 and RPA2 in late spermatocytes confirms defective homologous recombination repair (HRR) which results in reduced crossover formation in Sox30-knockout mice spermatocytes. Mechanistically, SOX30 directly binds to SYCE1/SYCE2 promoters to modulate their transcription, thereby regulating SC assembly and HRR. Restoring SOX30 expression effectively rescues meiotic defects. Importantly, transcriptome co-expression analysis in non-obstructive azoospermia (NOA) testes identifies SOX30 as a central regulator of NOA transcriptional networks. Collectively, these findings underscore SOX30's crucial role in meiotic synapsis and recombination, highlighting its therapeutic potential for NOA.

Periapical periodontitis is one of the most common inflammatory bone destructive diseases. Epidemiological evidence suggests that hypoxia exposure, such as that resulting from high-altitude exposure or sleep apnea syndrome, may be a significant risk factor that exacerbates the disease process. However, its specific role and the underlying molecular mechanisms remain unclear. In this study, we established a mouse model of periapical periodontitis under conditions of chronic hypoxia to evaluate its impact on pathological bone loss using micro-computed tomography, histological staining, and serum cytokine analysis. Furthermore, we explored the potential molecular regulatory mechanisms using in vitro osteoclast differentiation models, adeno-associated virus-mediated in vivo gene knockdown, and cleavage under targets and tagmentation (CUT&Tag) sequencing. Our study revealed that hypoxia exposure significantly aggravated alveolar bone resorption, osteoclast activation, and systemic inflammation in the mouse model of periapical periodontitis compared to normoxia. At the molecular level, hypoxia-inducible factor-1α (HIF-1α) showed a rapid but transient increase under hypoxia, whereas HIF-2α displayed a progressive and sustained elevation throughout osteoclast differentiation. These dynamics indicate that HIF-2α plays a more prominent role than HIF-1α in mediating the hypoxia-accelerated osteoclastogenic response. In vivo, local knockdown of HIF-2α in the periapical region markedly attenuated bone destruction exacerbated by hypoxia exposure. Further mechanistic investigation, combining CUT&Tag sequencing and functional validation experiments, revealed that HIF-2α mediates its pro-osteoclastogenic function by directly binding to the promoter region of the calmodulin-dependent protein kinase IV (Camk4) gene and activating its transcription. This study unveils that hypoxia exposure, acting as a critical environmental risk factor, functions as a 'synergistic amplifier' to enhance pathological osteoclastic responses in periapical periodontitis through the HIF-2α-CAMK4 regulatory axis. The findings deepen our understanding of periapical periodontitis and suggest that targeting HIF-2α or downstream pathways may be an adjunctive therapeutic strategy for hypoxia-associated inflammatory bone loss.