Search Results (246)

Hemostasis and wound healing are highly coordinated processes that involve rapid clot formation followed by controlled remodeling of the injured tissue microenvironment. Prior work on Akhirin (AKH), a secreted extracellular matrix protein containing two von Willebrand factor A domains and an LCCL domain, has established it as a regulator of the neural stem niche in the developing brain and spinal cord injury microenvironment. However, its role as a non-hematopoietic molecule in the vascular injury response remains unknown. Here, we present evidence that AKH contributes to hemostasis and wound repair outside the neural niche. Our immunohistochemical and biochemical analyses demonstrated AKH around arterial tissues, suggesting a potential role at the blood-vessel interface. AKH-deficient mice exhibited a striking phenotype characterized by prolonged tail bleeding and delayed wound closure, indicating impaired vascular injury repair in vivo. Furthermore, bone marrow transplantation failed to rescue the prolonged bleeding phenotype, supporting a predominant non-hematopoietic contribution. Intriguingly, analysis of classical coagulation revealed an apparent paradox: activated partial thromboplastin time was shortened, whereas prothrombin time was not significantly altered. In contrast, increased expression of tissue plasminogen activator, urokinase-type plasminogen activator, and urokinase-type plasminogen activator receptor in AKH-deficient samples suggested dysregulated local fibrinolytic remodeling. Together, these findings identify AKH as a previously unrecognized extracellular regulator of hemostatic wound repair. Rather than indicating a defect in classical coagulation cascade activation, the findings associate AKH deficiency with impaired hemostatic control and altered expression of plasminogen activator system components, suggesting a role for AKH in the local vascular injury response. Full article

Hydrogels are hydrated three-dimensional polymeric networks with biomedical potential because they can encapsulate therapeutic agents and provide localised, sustained, or stimulus-responsive drug delivery. Their performance is determined by interacting variables, including polymer composition, synthesis route, crosslinking chemistry, drug loading, swelling, degradation, and the biological microenvironment. This multidimensional design space often makes hydrogel development slow and dependent on trial-and-error experimentation. This review examines the data-driven development of biomedical hydrogels for controlled drug delivery, focusing on clinical applications and emerging machine-learning approaches that support material selection, formulation design, synthesis optimisation, and release prediction. The review first discusses natural and synthetic hydrogels, including alginate, chitosan, gelatin-based systems, hyaluronic acid, and polyethylene glycol, with emphasis on how their physicochemical properties influence biocompatibility, synthesis flexibility, and drug-release behaviour. Key applications are then considered, including wound healing, cancer therapy, glucose-responsive insulin delivery, and inflammatory disease management. Particular attention is given to injectable and stimuli-responsive hydrogels, where formulation conditions and synthesis parameters can be tuned to improve localisation, therapeutic exposure, and release control. The review evaluates machine-learning methods, including random forest, gradient boosting, artificial neural networks, Gaussian process regression, and active learning, for predicting hydrogel properties, modelling release profiles, optimizing synthesis and formulation variables, and prioritizing experimental candidates. Finally, translational challenges are addressed, including small non-standardised datasets, limited external validation, weak in vitro-clinical correlations, material safety, explainability, reproducibility, scalability, and regulatory requirements. By integrating clinical, materials, synthesis, and machine-learning perspectives, this review highlights opportunities for developing safer and clinically relevant hydrogel-based drug-delivery systems. Full article

Colorectal cancer progression and therapeutic response are determined not only by tumor-intrinsic programs but also by neural, stromal, and immune components of the tumor microenvironment. However, biologically interpretable transcriptomic scores that jointly capture neural/stromal remodeling and immune activation remain limited. We developed a neuro-immune score (NIS), defined as the neural/stromal module score minus the immune activation module score. NIS was constructed using the combined TCGA-COAD/READ colorectal cancer cohort and externally evaluated in independent Gene Expression Omnibus (GEO) datasets. Single-cell RNA sequencing, focused ligand–receptor analysis, and spatial transcriptomics were further integrated to characterize the cellular origins, spatial organization, and potential mechanisms underlying NIS-associated biology. A high NIS (NIS-high) was associated with adverse prognosis in bulk transcriptomic cohorts. External validation demonstrated that a high NIS was significantly associated with worse disease-free survival/relapse-free survival (DFS/RFS) in GSE39582 and worse overall survival in GSE17536. A multi-cohort meta-analysis further supported a consistent association between NIS-high and poor clinical outcomes. Single-cell analysis localized the NIS-high signal mainly to glial-like cells, fibroblasts, pericytes, endothelial cells, and malignant epithelial cells, whereas CD8+ T cells and natural killer cells exhibited low NIS. Focused ligand–receptor analysis suggested that NIS-high cellular compartments may communicate with immune and tumor compartments through MIF-CD74/CXCR4, SPP1-CD44, extracellular matrix (ECM)–integrin, TGF-β, and immune checkpoint-related axes. Spatial transcriptomics further demonstrated that NIS-high regions were enriched in stromal, neural/glial-like, vascular/pericyte, and tumor–stromal niches, whereas NIS-low regions were associated with immune-activated and cytotoxic T/NK cell-rich areas. NIS captures a spatially organized state of the colorectal cancer microenvironment characterized by neural/stromal remodeling, activation of ECM and vascular/pericyte niches, and relatively reduced or spatially segregated immune activation. NIS may serve as a biologically interpretable microenvironment stratification score associated with adverse outcomes. It also provides a framework for future studies targeting stromal remodeling, myeloid-mediated immune regulation, neural-associated signaling, and antitumor immunity. Full article

Functional nanomaterials, such as functionalized nanoparticles, nanofibers, nanocrystals, MXene and liposomes, have emerged as game-changers in tissue engineering, enabling precise modulation of cellular behaviors and dynamic biomimetic microenvironments. This review comprehensively summarizes and discusses the cutting-edge applications of nanomaterials in tissue regeneration (including bone, skin, neural and cardiac tissue regeneration), with a focus on their unique physicochemical properties (e.g., stimuli-responsiveness, nano-topography) and hybrid system design. Recent breakthroughs include 4D-printed shape-memory nanocomposites for irregular bone defects and “smart” wound dressings integrating antibacterial nanoparticles with real-time biosensing. However, clinical adoption remains constrained by unresolved challenges in biocompatibility, scalability of nanomanufacturing, and regulatory ambiguities. We critically analyze these barriers and propose a translational roadmap leveraging AI-driven material design and multi-omics validation platforms to accelerate commercialization. Full article

Transplanted neural precursor cells (NPCs) can support repair after spinal cord injury (SCI) but often face poor survival and limited differentiation within the hostile post-injury microenvironment. We tested whether subacute activation of Sonic hedgehog (Shh) signaling improves NPC engraftment and functional recovery over the duration of 6 weeks. Female Wistar rats underwent T9/T10 clip-contusion SCI and were assigned to vehicle, Shh-only, NPC-only, Shh + NPC, or sham groups (n = 8 per SCI arm, n = 5 sham, total n = 37). GFP + NPCs (4 × 10⁵) were grafted at 7 days post injury. Recombinant Shh or vehicle was delivered intrathecally via osmotic pumps for 7 days thereafter. Outcome measures included pathway activation (GLI1, SMO), NPC differentiation (NeuN, Olig2, Nestin, GFAP), astrogliosis (GFAP), CSPG deposition, immune cell infiltration (CD3, Iba1), apoptosis (cleaved Caspase-3), and locomotion (BBB, Gridwalk, CatWalk) over 6 weeks. Shh delivery increased GLI1/SMO expression and, when combined with NPCs, significantly elevated NPC-derived neurons and oligodendrocytes while preserving undifferentiated NPCs. Combined therapy reduced astrogliosis, CSPG deposition, T-cell and macrophage/microglial densities, cyst size and apoptotic cells compared with controls. These histological benefits were accompanied by improved locomotor scores in BBB, Gridwalk and selected CatWalk parameters. Our findings highlight the synergistic effects of Shh pathway activation and NPC transplantation in promoting neuroregeneration after SCI. The data support Shh as an adjunct to NPC transplantation for SCI repair. Full article

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the selective loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the intracellular accumulation of alpha-synuclein (α-syn) aggregates. Historically, research has focused on neuronal mechanisms; however, growing evidence indicates that the progression of neurodegeneration is influenced by changes in the brain microenvironment, particularly through the dynamic interplay between microglia and the extracellular matrix (ECM). ECM in the central nervous system is an organized network of structural proteins, glycoproteins, and proteoglycans that encases neurons and glial cells, regulating processes such as synaptic stability, neural plasticity, and intercellular signaling. In PD, the aggregation of α-syn and neuronal damage induce sustained microglial activation, which can alter ECM structure. Activated microglia release proteases, including matrix metalloproteinases and cathepsins, which can degrade critical ECM components such as collagens, laminins, and proteoglycans. This remodeling can modify synaptic architecture, regulate cellular signaling, and disrupt neuron-glia interactions, fostering an environment conducive to dopaminergic degeneration. Furthermore, ECM remodeling and microglial activation exhibit regional variability within the brain. Regions notably prone to degeneration, such as the SNpc and striatum, display significant alterations in matrix organization and inflammatory activity, while other dopaminergic regions, including the ventral tegmental area, show increased resilience. We suggest that microglia-mediated ECM remodeling serves as a mechanistic link between neuroinflammation and neuronal susceptibility in PD. This review consolidates the existing knowledge on microglial modulation of ECM dynamics during neurodegeneration, explores regional differences in these processes, and evaluates their significance as possible treatment targets. Full article

The human true vocal fold exhibits a complex microvascular organization essential for its biomechanical and metabolic function. This study aimed to quantitatively assess CD31/PECAM-1-positive microvascular structures across the superficial lamina propria (SLP), deep lamina propria (DLP), and vocalis muscle (MV), and to integrate these findings with neuron-specific enolase (NSE) and scanning electron microscopy (SEM) observations. A retrospective analysis was performed on 21 formalin-fixed specimens. CD31 immunohistochemistry was used for endothelial identification, NSE immunohistochemistry was applied for the evaluation of neural elements, while SEM provided complementary ultrastructural information on extracellular matrix organization. Total microvascular density differed significantly among layers (χ² = 32.12, df = 2, p = 1.06 × 10⁻⁷; Kendall’s W = 0.77), with highest values in MV (19.11 ± 6.22 vessels/field), followed by SLP (13.55 ± 3.93), and DLP (8.11 ± 2.41). Capillary density also showed significant inter-layer differences (p = 1.99 × 10⁻⁷), whereas small- and medium-caliber vessels did not (p = 0.081 and p = 0.538). NSE-positive neural profiles exhibited a similar distribution pattern, with higher density in the MV and lower values in the DLP. Inter-observer agreement was excellent (ICC = 0.91). Integrated analysis indicated a parallel spatial distribution of vascular, neural, and extracellular matrix components across vocal fold layers. This study provides a quantitative and structural baseline of the vocal fold microenvironment. This descriptive framework may inform future investigations of the layer-specific organization of vascular and neural-associated structures within the human vocal fold microenvironment. Full article

Huntington’s disease (HD) has traditionally been conceptualized as a neuron-centric disorder primarily attributed to cell-autonomous toxicity of mutant huntingtin (mHTT) in striatal medium spiny neurons. However, this framework inadequately explains the prolonged presymptomatic phase, selective network vulnerability, early non-motor manifestations, and limited success of neuron-targeted therapeutic interventions. Accumulating evidence from molecular biology, transcriptomics, neuroimaging, and preclinical therapeutics supports a reframing of HD as a disorder of neuroglial systems dysfunction. We synthesize data demonstrating that astrocytes, microglia, and oligodendrocyte lineage cells are not passive bystanders but play direct and interactive roles in HD pathogenesis through defined molecular mechanisms. Expression of mHTT in glial populations impairs synaptic homeostasis, metabolic coupling, immune resolution, and myelin integrity, generating self-amplifying pathological feedback loops that destabilize neural circuits long before overt neuronal death. Critically, we evaluate glial replacement therapy as a potential disease-modifying strategy. Preclinical studies demonstrate that transplantation of healthy human glial progenitor cells substantially ameliorates motor, cognitive, and neuropathological deficits in multiple HD models through oligodendroglial remyelination and lactate-mediated metabolic support, despite persistent neuronal mHTT expression. Effective HD therapy will likely require strategies that jointly target the genetic cause and the dysfunctional neuroglial microenvironment. By integrating systems neuroscience with glial biology and translational strategy, this review defines a neuroglial framework for HD that opens a plausible path toward meaningful disease modification and positions HD as a model disorder for glial-centric interventions in neurodegeneration. Full article

3D-printed hydrogel scaffolds have emerged as important platforms in tissue engineering and regenerative medicine owing to their extracellular matrix-like three-dimensional hydrated networks, tunable physicochemical properties, and ability to spatially organize cells, bioactive factors, and scaffold architectures. Early studies mainly focused on the printability, shape fidelity, and biocompatibility of hydrogel inks, whereas current research has gradually shifted toward the construction of bioactive scaffolds with tissue-specific functions. Because different tissues exhibit distinct requirements in terms of mechanical properties, cellular microenvironment, vascularization, innervation, degradation behavior, and functional maturation, the design of 3D-printed hydrogel scaffolds should comprehensively consider material composition, printing strategy, biofactor delivery, and tissue-specific functional demands. In this review, we focus on the transition from printability to biofunctionality and systematically summarize recent advances in 3D-printed hydrogel scaffolds for multi-tissue engineering. Particular emphasis is placed on regenerative applications of 3D-printed hydrogel scaffolds in bone, cartilage, vascular, neural, and skin tissue engineering. Finally, we discuss the major challenges associated with 3D-printed hydrogel scaffolds and further highlight future directions. This review aims to provide a systematic reference for the functional design and application of 3D-printed hydrogel scaffolds in multi-tissue engineering. Full article

Radiotherapy-associated pain is among the most common and debilitating complications in head and neck cancer. Although historically viewed primarily as a treatment-related adverse effect, growing evidence suggests that pain is deeply intertwined with tumor biology, immune remodeling, and therapeutic outcomes. At the same time, recent advances in cancer neuroscience have identified sensory nerves as active components of the tumor microenvironment (TME), capable of influencing antitumor immunity through complex neuroimmune crosstalk. These observations raise the possibility that radiotherapy-associated pain is not merely a clinical symptom but also a biological indicator of dynamic changes within the tumor immune microenvironment (TIME). In this review, we outline the major clinical manifestations of radiotherapy-associated pain in head and neck cancer, including inflammatory or mucositis-related pain, neuropathic pain, and long-term chronic pain, with emphasis on their underlying biological features and potential therapeutic relevance. Given that oral mucositis is the dominant source of acute radiotherapy-associated pain in head and neck cancer, we further summarize evidence-based preventive and supportive strategies, including photobiomodulation, mucosal barrier-forming agents, anti-inflammatory mouthwashes, nutritional interventions, pain control, and multidisciplinary oral care. We further discuss how radiotherapy reshapes the TIME through mechanisms such as immunogenic cell death, activation of the cGAS-STING pathway, vascular and stromal remodeling, and regulation of lymphoid compartments, while also triggering compensatory immunosuppressive responses. Preclinical and translational studies suggest that nociceptive signaling pathways may modulate T-cell function, myeloid-cell activity, and immune-evasive programs. Through these neuroimmune interactions, radiotherapy-induced neural injury and persistent pain may contribute to the establishment of an immunosuppressive, wound-like microenvironment that ultimately affects treatment response and tumor progression. Finally, we discuss the translational significance of incorporating pain phenotyping into combined radiotherapy and immunotherapy strategies for head and neck cancer. Opioid-sparing multimodal analgesia, neuromodulation, and neuroimmune-targeted interventions may represent promising approaches to simultaneously improve symptom control and antitumor immunity. We propose that radiotherapy-associated pain may be considered a candidate neuroimmune phenotype rather than a passive adverse event, providing a new conceptual framework for precision management and translational research in head and neck cancer. Full article

Osteoporosis (OP) and osteoarthritis (OA) are two common degenerative musculoskeletal disorders associated with aging and are traditionally classified and managed as distinct disease entities. Emerging evidence suggests that OP and OA may share bidirectional associations and common biological mechanisms, and that under specific pathological conditions they may develop into a mutually reinforcing comorbid state. The comorbidity of osteoporosis and osteoarthritis (OP–OA) is not a simple superimposition of bone loss and cartilage degeneration; rather, it represents a disorder of the osteochondral unit centered on disruption of the subchondral bone microenvironment. Alterations in the structural strength, remodeling dynamics, vascular and neural status, and bone marrow lesions of subchondral bone collectively reshape the local microenvironment, thereby directly affecting mechanical signal transmission and cellular behavior within the joint. Focusing on the subchondral bone microenvironment as the central pathological nexus, this review systematically summarizes how mechanical imbalance, aberrant bone remodeling, inflammatory activation, metabolic dysregulation, and cellular senescence jointly remodel the local niche in OP–OA comorbidity. These microenvironmental changes further induce phenotypic remodeling and fate deviation of bone marrow mesenchymal stem cells, bone remodeling-related cells, osteoimmune cells, and chondrocytes. On this basis, we integrate the regulatory roles of developmental signaling, mechanotransduction pathways, and inflammatory–immune signaling networks, and propose that microenvironment-driven cell fate plasticity may serve as a key mechanistic hub promoting the initiation and progression of OP–OA comorbidity as well as the persistent destabilization of the osteochondral unit. This perspective may help overcome the limitations of current studies that address OP and OA separately, and may provide a theoretical framework for early identification and stratification, biomarker discovery, and combined precision-targeted interventions for this comorbid condition. Full article

Following spinal cord injury (SCI), a complex lesion scar forms at the injury site that matures and remodels over weeks, profoundly influencing neural repair and functional recovery. This lesion consists of a fibrotic scar at its core surrounded by an astrocytic scar (or border). While the astrocytic scar has been extensively studied for decades, the fibrotic scar has only recently emerged as a critical player in post-injury pathophysiology. Fibrotic scarring plays a dual role: it contributes to tissue stabilization and limits secondary damage, yet its persistence can pose a barrier that inhibits axonal regeneration and hinders recovery. Despite growing interest, key aspects of fibrotic scar formation and function remain poorly understood. This review synthesizes the current knowledge of fibrotic scarring after SCI, including its temporal progression, cellular composition, molecular mechanisms, and interactions with other cell types at the injury site, and we discuss emerging therapeutic strategies targeting fibrosis. We further highlight critical knowledge gaps and outline future directions to define how fibrotic scarring shapes the injury microenvironment and influences neural repair. Full article

Fine particulate matter (PM_2.5) exposure increases the risk of neurodevelopmental abnormalities by disrupting neural stem cell (NSC) proliferation and cell cycle homeostasis, which are critical for normal neurodevelopment. This study investigated the impact of fine particulate matter (PM_2.5) on NSC proliferation and cell cycle using a three-dimensional (3D) graphene oxide (GO) scaffold that mimics the NSC microenvironment. PM_2.5 exposure led to concentration-dependent decreases in NSC viability and induced G0/G1 phase arrest via the marked downregulation of Cyclin D1-Cdk4 and Cyclin E-Cdk2, which critically impact G1/S transition. NSCs in 3D GO scaffolds maintained higher expression of key cell cycle regulators (Cyclin A, Cdk1/Cdk2, APC, and Cdc20) and superior cell viability when suffering PM_2.5 exposure, demonstrating the 3D culture environment was beneficial for NSC proliferation. We speculate that the 3D culture environment is more favorable and protective for cell proliferation. Therefore, these findings highlight the utility of the 3D GO scaffold for studying PM_2.5 effects on growing neural stem cells. This work provides a physiologically relevant in vitro platform that captures microenvironment-dependent neurotoxic responses, consequently offering valuable mechanistic insights into PM_2.5-induced developmental neurotoxicity. Full article

Neuroblastoma (NB), the most common extracranial solid tumor of childhood, exemplifies one of the most formidable paradigms of tumor immune evasion (TIME) in pediatric oncology. Despite significant advances in multimodal therapy and the clinical integration of immunotherapeutic strategies, high-risk NB (HR-NB) remains largely refractory to durable immune control. This failure reflects not an absence of immune engagement, but the presence of a highly evolved and developmentally wired immune escape architecture. In this review, we synthesize emerging insights from single-cell, multi-omics, and functional studies to define how developmental lineage, cellular plasticity, metabolic rewiring, epigenetic regulation, and therapy-induced adaptation converge to engineer immune blindness in NB. We discuss how NB’s neural crest origin establishes a baseline of low immunogenicity, which is subsequently reinforced through coordinated suppression of antigen presentation, dominance of immune checkpoint signaling, and profound dysfunction of cytotoxic T and natural killer cells within an immunosuppressive tumor microenvironment. Central to this process is tumor-intrinsic plasticity, whereby lineage instability and dedifferentiation, exacerbated by therapeutic pressure, embed immune silence as a stable tumor state. We highlight evidence positioning RD3 as a master upstream regulator linking cellular identity to immune visibility, governing antigen presentation, innate immune sensing, checkpoint expression, and cytotoxic lymphocyte engagement. Beyond tumor-intrinsic mechanisms, we examine the roles of immunosuppressive myeloid populations, tumor-derived exosomes, metabolic stress, hypoxia, and ferroptosis-associated pathways in reinforcing immune paralysis. Finally, we outline emerging therapeutic strategies aimed at dismantling this architecture, including combinatorial checkpoint blockade, metabolic and epigenetic reprogramming, exosome-targeted interventions, and next-generation immune engineering platforms. Together, this review reframes TIME in NB as a programmable, developmentally rooted process and provides a mechanistic roadmap for restoring immune competence and therapeutic susceptibility in HR disease. Full article

Objectives: Alzheimer’s disease (AD) is associated with impaired adult hippocampal neurogenesis (AHN). This study aimed to establish an in vitro model of Aβ_1–42 oligomer-damaged neural stem cells (NSCs) and to employ the 5×FAD mouse model of AD in vivo, and to evaluate the therapeutic effects of brain-derived neurotrophic factor-loaded hyaluronic acid hydrogel (BDNF-HA gel) on AHN. Methods: In vitro, BDNF-HA gel was co-cultured with Aβ_1–42 oligomer-impaired NSC spheres and evaluate NSC proliferation, migration, and differentiation. In vivo, BDNF-HA gel was infused intracerebroventricularly into 5×FAD mice. Using BrdU labeling, immunofluorescence, anterograde transsynaptic viral tracing, and behavioral tests, we assessed the effects of BDNF-HA gel on adult neurogenesis, newborn neuron integration into memory circuits, and cognitive function. Results: In vitro, BDNF-HA gel attenuated Aβ_1–42-induced NSC apoptosis, restored proliferation and migration, promoted differentiation into neuroblasts, newborn neurons, and oligodendrocytes, and alleviated mitochondrial depolarization and loss of mitochondrial mass. In vivo, despite the absence of significant Aβ plaques reduction in 5×FAD mice, BDNF-HA gel markedly enhanced NSC proliferation and neurogenesis in the subventricular zone (SVZ) and subgranular zone (SGZ). Behavioral tests further revealed significant improvements in object recognition, spatial working memory, and spatial reference memory. Conclusions: BDNF-HA gel can effectively counteract the toxic microenvironment induced by Aβ oligomers, promoting NSC proliferation, migration, and differentiation into neurons. Without altering the Aβ burden, it significantly enhances adult neurogenesis and rescues cognitive deficits in AD mice. Full article