Cell Proliferation最新文献

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.

Acute monocytic leukaemia, a subtype of acute myeloid leukaemia (AML), is a highly aggressive malignancy characterised by a poor prognosis, primarily due to the ability of leukaemic cells to evade immune surveillance. In this study, we demonstrate that homoharringtonine (HHT), an FDA-approved therapeutic agent for chronic myeloid leukaemia (CML), inhibits this immune evasion by targeting the FTO/m6A/LILRB4 signalling pathway in monocytic AML. Utilising RNA sequencing (RNA-seq) and various functional assays, we reveal that HHT treatment significantly reduces LILRB4 expression at both the RNA and protein levels, suggesting that the effects of HHT on LILRB4 are distinct from its well-established role as a protein synthesis inhibitor. Mechanistically, HHT treatment markedly increases global levels of RNA m6A in THP-1 cells by promoting the degradation of FTO, which subsequently diminishes the expression of its downstream targets, MLL1 and LILRB4. Furthermore, in vitro and in vivo analyses employing monocytic AML cell lines, mouse-derived AML xenograft models, and patient samples collectively support the conclusion that HHT suppresses immune evasion in monocytic AML by reducing LILRB4 expression. Importantly, the downregulation of LILRB4 resulting from HHT treatment enhances the susceptibility of THP-1 cells to CD8⁺ T cell cytotoxicity, accompanied by increased markers of immune activation. Overall, our findings position HHT as a promising clinical agent for enhancing CD8⁺ T cell-based cancer immunotherapy by mitigating immune evasion in monocytic AML.

During early brain development, the nervous system evolves as cells connect to form a unique neural network, with communication between cell populations vital for neurological balance. This study investigates how the loss of PD-1 in myeloid cells disrupts nervous system development. Specific ablation of PD-1 affects myeloid cell proliferation and classification. As astrogenesis begins, astrocyte proliferation ceases, continuous astrocyte proliferation is observed. Immunofluorescence staining revealed high expression of astrocyte-related genes in PD-1^{f/f; LysM-Cre} mice, which also exhibited more extroverted behaviour. Additionally, the absence of PD-1 enhances CXCL1 expression through the NF-κB pathway, promoting astrocyte proliferation by interacting with CXCR2. These findings underscore PD-1's regulatory role in myeloid cells and its implications for the myeloid-brain axis.

Benign prostatic hyperplasia (BPH) is a common condition in older men, with its prevalence increasing as age advances. Chronic inflammation orchestrates oxidative stress to exacerbate BPH. YAP1, which regulates organ size, cellular homeostasis, and tissue fibrosis, can be activated by ROCK1. Given the urgent clinical need for more effective therapies, this study explored whether targeting the ROCK1/YAP1 axis could mitigate BPH progression. Here, rats received in situ adeno-associated virus (AAV) injection to induce prostate-specific YAP1 overexpression. An inflammation-associated experimental autoimmune prostatitis (EAP) model was established by prostate antigen immunisation, followed by treatment with ROCK1 inhibitor fasudil and YAP1 inhibitor verteporfin. Cell models were treated with specific inhibitors to confirm the critical role of YAP1 in modulating mitochondrial function. As a result, YAP1 overexpression was sufficient to induce a pathological BPH phenotype. Specifically, YAP1 activated the inflammatory cascade to provoke an immune response, disrupted proliferation/apoptosis balance to induce tissue hyperplasia, triggered epithelial-mesenchymal transition (EMT) and reactive stroma to drive fibrosis, and promoted NOX4/ROS generation and antioxidant depletion to cause oxidative stress. The inflammation-induced experimental autoimmune prostatitis (EAP) model also presented analogous BPH lesions, which were significantly alleviated when treated with ROCK1 inhibitor fasudil and YAP1 inhibitor verteporfin. Mechanistically, YAP1 activation under inflammatory conditions suppressed SIRT1 expression, thereby exacerbating oxidative stress through the disruption of DRP1/MFN2-mediated mitochondrial dynamics. Overall, inflammation-driven activation of the ROCK1/YAP1 axis aggravates oxidative stress, promoting BPH hyperplasia and fibrosis by impairing SIRT1-regulated mitochondrial dynamics. These findings provide a preclinical rationale for developing ROCK1 or YAP1 inhibitors as targeted therapies for BPH patients with chronic inflammation.

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.

Brain organoids have become an essential platform for studying human neural development and neurological disorders. Yet, one major limitation of conventional brain organoids is their lack of vascular structures. This deficiency restricts organoid size, contributes to necrotic core formation, and hampers their functional maturation. Introducing vascularization offers a compelling solution-it enhances nutrient delivery, supports neurogenesis, and fosters the development of interfaces that resemble the blood-brain barrier (BBB). In this review, we explore how vascularization enhances the structural and physiological relevance of brain organoids and its growing significance in disease modelling and therapeutic screening. We examine current methodologies for engineering vascularized brain organoids (vBOs), including co-culturing with endothelial cells (ECs), transcriptional programming, tissue fusion techniques, microfluidic perfusion systems, and 3D bioprinting. These strategies vary in complexity, scalability, and the extent to which they achieve vascular integration. Functionally, vBOs demonstrate improved oxygen diffusion, enhanced synaptic development, and more robust barrier properties. Such advances enable modelling of complex neurovascular conditions like stroke, glioblastoma, and BBB dysfunction. Moreover, vBOs are emerging as valuable tools in developmental studies and personalised medicine, supporting patient-derived modelling and large-scale drug testing in BBB-relevant contexts. Despite these advances, replicating the structural complexity, functionality, and long-term stability of native vasculature remains challenging. We discuss current limitations and highlight innovative approaches, including the use of next-generation biomaterials and dynamic perfusion technologies. Ultimately, vBOs mark a significant step towards creating physiologically accurate in vitro models of the human brain-offering new opportunities for neuroscience research, drug development, and regenerative medicine.