Chronic stress induces psychiatric disorders, including depression and anxiety, yet effective therapies remain limited. Myelin in adult brains undergoes dynamic remodeling through oligodendrocyte precursor cells (OPCs) differentiation into oligodendrocytes (OLs) and the degeneration of pre-existing myelin. However, how chronic stress alters myelin dynamics and whether this represents a therapeutic target remains unclear. Here, adult mice subjected to 4-h daily restraint for 2 weeks exhibited significant anxiety, depression, and social deficits. Histological examinations revealed reduced OPC and OL density, decreased c-Fos-positive neurons, and loss of synaptic proteins in the brains exposed to chronic stress. To understand the dynamic changes of myelin, cell-lineage labeling and tracing demonstrated that chronic stress exposure remarkably inhibited oligodendrogenesis in the medial prefrontal cortex (mPFC), motor cortex, hippocampus, and amygdala, as revealed by the NG2CreERT; Tau-mGFP line, but did not significantly change pre-existing myelin as revealed by a newly generated line for mature OLs and myelin. To explore the role of myelinogenesis changes, adult myelin formation was inhibited by Olig2 conditional knockout in OPCs, resulting in decreased neuronal synaptic proteins and activity, accompanied by anxiety and depressive-like behaviors. Conversely, enhancing myelinogenesis through conditional deletion of the M1R in OPCs of stressed mice resulted in higher number of c-Fos-positive neurons, elevated synaptic protein expression, and a partial reversal of the behavioral deficits. Importantly, treating the stressed animal with the pro-myelination drug clemastine phenocopied the effects of M1R deletion on histological and behavioral disorders. Together, our findings demonstrate that enhancing oligodendrogenesis represents a promising strategy to rescue CRS-caused behavioral disorders.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease affecting the central nervous system (CNS), and represents the most common non-traumatic cause of disability among young adults. Although current immunomodulatory therapies have demonstrated beneficial effects in mitigating disease progression, their associated side effects and limitations render MS a condition without a definitive cure. A major obstacle in achieving effective treatment and recovery is the pathological microenvironment within the MS-affected CNS, which severely impairs endogenous tissue repair and diminishes the efficacy of existing interventions. Recently, non-pharmacological approaches have gained increasing attention for their potential to treat MS-related pathology. In this review, we summarize how non-pharmacotherapeutic interventions, including physical exercise, dietary adjustments, cognitive training, social participation, and mixed rehabilitation programs, can affect key pathological elements of neuroinflammation in MS by elucidating the molecular mechanisms, such as modulation of neuroinflammation, suppression of glial cell activation, promotion of remyelination, and enhancement of neuroprotective processes. By integrating preclinical experimental data from animals with clinical evidence from MS patients, we also illustrate how various non-pharmacological strategies can dynamically modulate the disease microenvironment. We emphasize the capacity of non-pharmacological approaches to enhance endogenous repair by fostering a more supportive CNS microenvironment, highlighting their potential to transform disease management.

Myelinogenesis is insufficient in numerous myelin-related diseases in the CNS, leading to functional impairments. Myelinogenesis couples with angiogenesis to ensure adequate need of oxygen and nutrients for oligodendrocyte (OL) differentiation. However, approaches to synchronize myelino-vascular coupling remain unavailable. We hypothesize the identification of shared signaling pathways in vascular cells and oligodendroglia may yield novel strategies to promote myelin repair through strengthening the blood vessel-myelination coupling. Here, single-cell sequencing and in situ hybridization revealed high expression of G-protein-coupled receptor 30 (Gpr30) in both vascular cells and oligodendroglia, with selective enrichment in pericytes and oligodendrocyte precursor cells (OPCs). Cell-specific deletion of GPR30 in pericytes driven by PDGFRβCreERT2 resulted in enhanced angiogenesis and myelination in developing brains. GPR30 deletion in OPCs or antagonizing GPR30 by G15 resulted in increased MBP-positive cell density and enhanced nanofiber wrapping capacity in vitro, thereby demonstrating an inhibiting role of GPR30 on OPC differentiation. To elucidate the coordinative role of GPR30 in both cell types, we employed NG2CreERT to induce a conditional knockout of GPR30 in both NG2-positive pericytes and OPCs. The conditional deletion of GPR30 enhanced myelination and increased vascular density in developing brains. Further, GPR30 cKO or G15 treatment enhanced myelin repair and functional recovery in the chronic neonatal hypoxia and lysolecithin-induced demyelination model, suggesting that antagonizing GPR30 is a promising strategy to synchronize angiogenesis with myelination to promote myelinogenesis. These findings establish GPR30 antagonism as a promising approach to enhance myelin repair through synchronizing pericyte-mediated angiogenesis and OPC differentiation.

Peripheral nerve injury (PNI) poses significant challenges due to the complex structure and regenerative microenvironment of peripheral nerves, which limit self-repair capabilities. Artificial nerve conduits have been widely used for nerve repair. Here, a conductive-piezoelectric integrated microstructured conduit is designed, using poly(lactic glycolic acid) (PLGA) and poly(vinylidene fluoride) (PVDF) via electrostatic spinning to obtain an implantable, biodegradable piezoelectric nanofibrous membrane. This membrane is further enhanced with a reduced graphene oxide/methacrylated gelatin (rGO/GelMA) gel, which synergistically promotes peripheral nerve repair. In vitro assessments reveal that the microgroove surface pattern of the conduit effectively stimulated the directional migration of cells. Moreover, using a rat sciatic nerve injury model, rGO is demonstrated to significantly modulate cellular oxidative stress, thereby facilitating nerve repair. Additionally, mild electrical stimulation induced by low-intensity pulsed ultrasound (LIPUS) is found to enhance the recovery of motor function. These findings demonstrate the multifaceted benefits of the rGO/GelMA@PVGA composite conduit, which integrates physical guidance, oxidative stress inhibition, and ultrasound-activated electrical stimulation, providing an unprecedented multimodal synergistic strategy with great potential for clinical treatment of peripheral nerve injury.

Recurrent re-experiencing traumatic memory is known as a common symptom in post-traumatic stress disorder (PTSD) patients, and its severity is closely related to the progression and prognosis of PTSD. Notably, some individuals with PTSD exhibit white matter abnormalities. Myelin constitutes a critical structure within white matter, and myelination in the adult brain has been demonstrated to actively regulate the consolidation of remote memories. However, the dynamics of myelin after re-experiencing traumatic stressors and their functional significance remain largely unexplored. Here, we developed a repeated fear recall mouse model to mimic re-experiencing symptoms in PTSD patients, and found that repeated fear recall can reinforce remote fear memory while cause anxiety-like behaviors and social preference deficits. This coincides with region-specific oligodendrogenesis, heightened reactivation of fear recall-associated engram cells, and an increase in dendritic spine density, demonstrated through cell-lineage tracing and labeling. We hypothesize that oligodendrogenesis driven by repeated fear recall is sufficient to regulate remote fear memory and behavioral abnormalities. Loss-of-function experiments, either inducing apoptosis of new oligodendrocytes (OLs) or cell-type-specific knocking out (cKO) oligodendroglial transcription factor 2 (Olig2), significantly attenuated the abnormal reinforcement of remote fear memory and ameliorated social deficits induced by repeated fear recall. Moreover, inhibiting oligodendrogenesis through Olig2 cKO relieved anxiety-like behavior. Notably, diminished newly formed OLs also decreases fear recall-induced neuronal activation and dendritic spine density in fear-related brain regions. More importantly, administering rapamycin, a potent inhibitor of oligodendrogenesis, during repeated fear recalls phenocopies the effects of anti-myelination on fear memory-related behavioral defects. In summary, our findings demonstrate that oligodendrogenesis induced by repeated fear recall is sufficient to drive the progression of PTSD-like behaviors, likely by modulating neuronal activity and dendritic spine density within the adult fear circuitry. Pharmacological treatments that inhibiting oligodendrogenesis during the recall phase represent a promising therapeutic strategy for preventing the pathological reinforcement of long-term fear memories, thereby averting the emergence of anxiety-like behaviors and social preference deficits in individuals with PTSD. Schematic image summarizing the major findings of the present study.

ABSTRACT Bone healing is a tightly orchestrated, multiphase process that requires coordinated interactions between immune cells and skeletal cells. Sensory nerves act as intrinsic effectors of the inflammatory response, whose role in osteoimmunology during healing remains poorly defined. Using a bone healing model with sensory denervation, it's shown that sensory nerves protect bone repair by suppressing excessive osteoclastogenesis. During the acute inflammatory phase, sensory nerves are upstream regulators of macrophage activation. At the molecular level, calcitonin gene‐related peptide (CGRP), a sensory neuron–derived neuropeptide, is identified to modulate macrophage activation by restricting key functions such as migration, phagocytosis, and pro‐inflammatory cytokine production. Importantly, CGRP rapidly constrains adenosine triphosphate (ATP) synthesis and mitochondrial respiration in activating macrophages, accompanied by downregulation of genes associated with oxidative phosphorylation and mitochondrial complex components. Following the metabolic alterations, macrophages exposed to CGRP show attenuated osteoclastogenic capacity, with decreased secretion of multiple key factors that support osteoclast differentiation and survival. Together, these findings indicate a neuro–immune–metabolic axis in bone healing, where sensory nerve–derived CGRP influences macrophage bioenergetics and thereby contributes to osteoimmunoligical regulation. It emphasizes the potential of incorporating sensory signals into therapeutic strategies, particularly those targeting immunometabolism in bone regeneration.

Skin burns remain challenging in clinical treatment due to their complex wound morphology, high oxidative stress, hypoxic microenvironment, and severe inflammatory response. Developing strategies for highly effective biomaterials with precise biological functions has become an urgent priority in addressing clinical challenges. This study developed a fluffy fibrous scaffold loaded with a metal-polyphenol nanocomposite (CeLut). The scaffold possesses water-retaining capacity, three-dimensional fluffiness, and interlayer porosity, which promote cell spreading, migration, and proliferation. It is capable of sustained release of luteolin and Ce ions, efficiently scavenging ROS while modulating oxygen metabolism. These synergistic effects of physics and biomaterials science rebalance the oxidative and hypoxic microenvironment of burn wounds, significantly accelerating wound healing, promoting skin regeneration, and alleviating inflammatory responses in a mouse burn model. The results showed that within 14 days after a second-degree burn, the recovery rate of functional skin structure reached 96.3%. These findings demonstrate the therapeutic value of fluffy fibrous scaffold containing metal-polyphenol nanocomposites in promoting burn wound repair, thereby providing a new strategy for the preparation of customized multifunctional bioactive scaffolds.

Aging profoundly compromises immune homeostasis, leaving elderly individuals highly vulnerable to inflammatory diseases. Central to this process is macrophage dysfunction, as macrophages progressively shift toward a pro-inflammatory M1 phenotype with excessive inflammation and impaired phagocytosis. This diminished phagocytic capacity not only weakens host defense but also limits the therapeutic efficacy of nanoparticle (NP)-based antisenescence interventions due to the reduced cellular uptake. Therefore, reversing cellular inflammation and restoring the function of senescent macrophages are crucial in treating inflammatory diseases in the elderly. This article presents an M1-targeted NP to rejuvenate aged macrophages and restore their phagocytosis. Gold nanocages (AuNCs) were camouflaged with E. coli-derived outer membrane vesicles (OMVs) and loaded with dexmedetomidine (dex) to create AuNC-OM-dex. The OMV coating enhanced the uptake of NPs by M1-like aged macrophages through CD64 and CD14-mediated recognition of bacterial membrane components, significantly improving drug delivery efficiency. Once internalized, dex, an anti-inflammatory agent, not only reduced senescence-associated factors but also restored phagocytic function in vitro. Mechanistically, dex rescued phagocytosis in senescent macrophages by suppressing p38-MAPK signaling, a pathway which had not been implicated in age-related phagocytic decline in prior studies. Restoring macrophage phenotype and function enhanced their immunoregulatory capacity, thereby aiding in the control of inflammation in aged inflammatory diseases. Furthermore, AuNC-OM-dex effectively prevented lipopolysaccharide-induced inflammatory bone resorption in an aged mouse model, highlighting its therapeutic potential in vivo. These findings demonstrate a dual-action nanoplatform that both enhances delivery to and rejuvenates aged macrophages, offering a promising therapeutic approach for treating inflammatory diseases associated with aging.

Oligodendrocyte (OL) myelination is essential for neurological function in the brain. During OL differentiation, rapid membrane synthesis is required for myelin formation, but the mechanisms driving this process remain poorly understood. Choline, a critical component of membrane phospholipids, is transported into cells via choline transporters (ChTs). Here, we identify SLC44A1 and SLC44A5 as the predominant ChTs selectively expressed in oligodendroglia. Conditional knockout (cKO) of either SLC44A1 or SLC44A5 in oligodendroglia impairs OL differentiation and myelination in neonatal brains, with shortened myelin segment lengths. SLC44A1-cKO mice show persistent hypomyelination into adulthood whereas SLC44A5-cKO mice do not, a divergence likely attributable to age-related decline in SLC44A5 expression in oligodendroglia. Metabolomics profiling indicates disrupted lipid metabolism by SLC44A1 deletion, specifically inhibiting plasmalogen synthesis, a pathway vital for myelin biogenesis. Our findings show that SLC44A1/5 support white matter integrity by fueling lipid metabolism, underscoring their potential as therapeutic targets for demyelinating diseases.

Background:Contemporary healthcare requires medical professionals with advanced scientific literacy. Current undergraduate medical curricula may not consistently develop this critical skillset. This study evaluates the effectiveness and challenges of an academic competition-based learning (ACBL) for enhancing scientific literacy in medical undergraduates. Methods:The International Genetically Engineered Machine (iGEM) Competition based program was developed using a two-round modified Delphi study. 30 students participated in an iGEM-based academic competition during 18 months. Scientific literacy domains were assessed through validated questionnaires during a five-year follow-up period. Results:iGEM participants demonstrated significantly greater improvement in literature review, experimental design, technical execution, presentation skills, and research management compared to controls (p < 0.01). Significant gains were observed in scientific knowledge acquisition and scientific reasoning (p < 0.01). Scores for active learning, critical thinking, and collaborative communication were significantly higher in the iGEM group (p < 0.05). Participants identified laboratory resources, space, equipment and funding as primary implementation constraints. Conclusion:ACBL is an innovative and effective strategies to develop students' scientific literacy for professional competitiveness, which highlights the potential of ACBL as a transformative approach in medical education.

Review Insights into Bioengineering Approaches for Aging Bone Regeneration: Strategies to Target Osteoimmunosenescence Lan Xiao 1,2,†, Wendong Gao 1,2,†, Jinfu Wu 3, Itsasne Erezuma 4, Alireza Dolatshahi-Pirouz 5, Joana Silva-Correia 6,7, Yinghong Zhou 2,8, Antonia Rujia Sun 2,9, Indira Prasadam 2,9, Ross Crawford 2,9, Joaquim Miguel Oliveira 6,7, Gorka Orive 5,10,11,12,13, Chengtie Wu 3 and Yin Xiao 1,2,* 1 School of Medicine and Dentistry, Griffith University (GU), Gold Coast, QLD 4222, Australia 2 The Australia-China Centre for Tissue Engineering and Regenerative Medicine (ACCTERM), Queensland University of Technology (QUT), Brisbane, QLD 4000, Australia 3 State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics Chinese Academy of Sciences, Shanghai 200050, China 4 NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad, 01006 Vitoria-Gasteiz, Spain 5 Department of Health Technology, Technical University of Denmark (DTU), 2800 Kongens Lyngby, Denmark 6 3B’s Research Group, I3Bs—Research Institute on Biomaterials, Biodegradables and Biomimetics, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, University of Minho, AvePark, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, 4805-017 Guimarães, Portugal 7 ICVS/3B’s—PT Government Associated Laboratory, 4805-017 Guimarães, Portugal 8 School of Dentistry, University of Queensland, Brisbane, QLD 4006, Australia 9 School of Mechanical, Medical and Process Engineering, Centre for Biomedical Technologies, Queensland University of Technology (QUT), Brisbane, QLD 4000, Australia 10 Biomedical Research Networking Centre in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 19-01007 Vitoria-Gasteiz, Spain 11 University Institute for Regenerative Medicine and Oral Implantology (UIRMI), UPV/EHU-Fundación Eduardo Anitua, 19-01007 Vitoria-Gasteiz, Spain 12 Bioaraba, NanoBioCel Research Group, 19-01007 Vitoria-Gasteiz, Spain 13 Singapore Eye Research Institute, The Academia, 20 College Road, Discovery Tower, Singapore 169856, Singapore * Correspondence: yin.xiao@griffith.edu.au † These authors contributed equally to this work. Received: 22 October 2024; Revised: 8 January 2025; Accepted: 15 January 2025; Published: 22 January 2025 Abstract: The global accumulation of ageing population is a serious problem causing significant health and social burdens. Especially, aging results in reduced bone regeneration potential and increased risk of morbidities and mortality, which calls the urgent need for advanced therapeutic approaches to improve bone regeneration in the aged patients. The aging associated poor bone regeneration capacity can be attributed to the low-grade, sterile chronic inflammation termed “inflammaging”, which result in detrimental environment for bone healing. The pathogenesis of inflammaging is mainly due to the senescence of immune cells. The senescent immune cells, especially senescent macrophages play a major role in inflammaging via an inflammatory secretome (senescence-associated secretory phenotype/SASP) which is due to ROS accumulation associated mitochondrial dysfunction, energy metabolism change, decline in oxidized nicotinamide adenine dinucleotide (NAD+) level and insufficient autophagy. In addition, the SASP can turn the local young cells into senescent cells, a paracrine senescence effect to facilitate senescent cell accumulation and inflammation, which can also be attributed to the insufficient clearance of senescent cells due to phagocytosis deficiency in senescent immune cells. Therefore, in aging bone environment, the interplay between immune and skeletal cells, termed “osteoimmunosenescence” in this review, not only generates a long-term chronical inflammatory environment to reduce osteogenesis, but also induces senescence in young skeletal progenitor cells to dampen their osteogenic differentiation potential, suggesting osteoimmunosenescence should be considered as a key modulatory target for bone regeneration biomaterials design for the aged patients. In this review, the pathogenesis of inflammaging and the potential impact of osteoimmunosenescence on bone regeneration have been discussed. In addition, to target osteoimmunosenescence, two potential strategies are considered, one is advanced immunomodulation to correct the inflammaging environment, the other is to target immunosenescence, and the current and potential material approaches regarding these two are summarized in this review. Furthermore, it proposes potential strategies to design osteoimmunosenescence-modulating materials by targeting the molecular intersection between senescence and inflammation and by flexibly correct the local environment and environmental responsively induce osteogenesis.

The temporary transition of macrophages from a pro-inflammatory macrophages (M1) to an anti-inflammatory macrophages (M2) is crucial for tissue repair and regeneration processes. Selectively targeting M1 macrophages is preferred to modulate inflammatory responses. However, macrophage populations are inherently heterogeneous, and the competitive phagocytosis of nanoparticles (NPs) by these two subtypes has not been thoroughly investigated. This study establishes a 3D cell co-culture system to evaluate the competitive phagocytosis of M1-targeting NPs under dynamic fluidic flow conditions. Bacterial outer membrane vesicles (OMVs) are utilized as a "trojan horse" to decorate gold nanocage (AuNC), creating hybrid NPs (AuNC-OM) capable of selectively targeting M1 macrophages. It is noted that the selective uptake of AuNC-OM by M1 macrophages is mediated through phagocytosis-related receptors CD64 and CD14, which are highly expressed on the M1 macrophage surfaces. Furthermore, the study demonstrates that AuNC-OM selectively targets M1 macrophages without affecting the phagocytosis of M2 macrophages. Once internalized, the nanoparticles release anti-inflammatory drugs, effectively reversing the inflammation. The release of dexmedetomidine from AuNC-OM protects against lipopolysaccharide (LPS)-induced bone resorption in a mouse model. This study presents a novel system for accurately assessing the M1 macrophage-targeting capabilities and introduces an innovative strategy for M1 macrophage-targeted therapy.

Autism spectrum disorders (ASD) are neurodevelopmental disorders associated with synaptic deficits. Oligodendrocyte precursor cells (OPCs) are the only type of glial cells that establish direct synaptic connections with neurons within the central nervous system (CNS). However, the mechanism that results in the delicate construction of OPC-neuron synaptic connections remain poorly understood. Here we show in a mouse model that BAF155, a chromatin remodeling factor, is highly expressed in committed OPCs. BAF155 influences the OPC differentiation and myelination by coordinating the expression of multiple synapse-related genes that mediate OPC-neuron synaptic communication. The varying chromatin regulatory roles of BAF155 across brain regions give rise to local myelin deficits, contributing to the diverse clinical manifestations observed in individuals with ASD. Collectively, these results deepen our insight into OPC-neuron interactions under pathophysiological conditions and uncover a mechanism that integrates synaptic and ASD susceptibility genes, implying that abnormal OPC-neuron synaptogenesis could be an early instigator of ASD.

Objective: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a complex, progressive disorder involving multiple cell types, ranging from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH), characterized by pro-inflammatory macrophage activation, and can eventually advance to fibrosis, initiated by hepatic stellate cells (HSCs). In vitro multi-cell coculture models are vital tools for elucidating the mechanisms underlying MASLD. Impact Statement: Existing in vitro models for MASLD, including traditional 2-dimensional (2D) cultures and advanced organ-on-a-chip and organoid systems, face challenges in representing multiple cell types and analyzing them individually. Here, utilizing a cell carrier developed in our laboratory, we introduce a series of 3D dynamic coculture models that simulate different stages of MASLD progression and enable individual cell type analysis. Introduction: Currently, no single system provides an optimal balance of control, reproducibility, and analytical convenience. Most in vitro models lack the ability to isolate and analyze individual cell types post-culture, making it difficult to study cell-specific responses in MASLD progression. Methods: The 3D hollow porous sphere cell carrier allows cells to grow on its surface, while the culture device (mini-bioreactor) creates a dynamic environment. The 3 distinct MASLD models were established based on cocultured cell types: steatosis (hepatocytes only), MASH (hepatocytes and macrophages in a 4:1 ratio), and fibrosis (hepatocytes, macrophages, and HSCs in an 8:2:1 ratio). Well-established MASLD mouse models were employed to validate our in vitro 3D dynamic MASLD models, using 7-week-old male C57BL/6J mice fed a high-fat diet. Results: Our models demonstrate a progressive decline in hepatocyte viability and increased lipid accumulation, mirroring in vivo pathology. Additionally, gene expression profiles of our models align with those observed in MASLD-affected mouse livers. Notably, comparative analysis highlights the role of pro-inflammatory macrophages in disrupting hepatocyte lipid metabolism. Conclusion: These models offer a robust platform for investigating MASLD mechanisms and show potential for screening anti-MASLD therapeutics.

Major psychiatric disorders like schizophrenia, depression and anxiety disorders, etc have serious impact on patients' health, but the pathogenesis remains unknown. With an extensive study on glial cells, their functions in psychiatric disorders have attracted much attention in recent years. Oligodendrocyte lineage cells (OLGs), as major myelination cells in the CNS, not only exhibit dynamic changes compatible with alterations in neurologic function but also regulate synaptic development and brain function from multiple aspects by interacting with neurons, astrocytes, and microglia. Concurrently, a growing number of studies have found extensive myelin loss and abnormal alterations of OLGs in the brains of patients with different types of psychiatric disorders. Moreover, impaired development and/or dysfunction of OLGs can lead to neuropsychiatric symptoms such as anxiety, depression, and social disorders by disrupting synaptic transmission or the glial network in animal models. Thus, targeting OLGs may represent a promising strategy for the treatment of psychiatric disorders.

The recurrent re-experiencing of traumatic memories is a core symptom of post-traumatic stress disorder (PTSD), and the severity of this symptom has been consistently associated with the clinical course and long-term prognosis of the disorder. Notably, some patients exhibit white matter abnormalities. Myelin, a crucial white matter component, has been shown to regulate the consolidation of remote memory in the adult brain. However, the dynamics of myelin following re-experienced traumatic stressors and their potential significance remain elusive. Here, we developed a repeated fear recall mouse model simulating PTSD re-experiencing symptoms, revealing that fear recalls profoundly reinforce remote fear memory and induce psychotic and social deficits. This pathological reinforcement coincides with region-specific oligodendrogenesis, heightened reactivation of fear recall-associated engram cells, and increased dendritic spine density, as demonstrated by cell-lineage tracing and labeling. We hypothesize that repeated recall-induced oligodendrogenesis may critically reinforce remote fear memories and contribute to these functional impairments. Strikingly, loss-of-function experiments, either inducing apoptosis of new oligodendrocytes or cell-specific Olig2 knockout, effectively relieve the abnormal reinforcement of long-term fear memory and the accompanying social impairments caused by repeated recall. Furthermore, diminished oligodendrogenesis also reduces fear recall-induced neuronal activation and attenuates dendritic spine changes within fear-related brain regions. Crucially, administering rapamycin, a potent oligodendrogenesis inhibitor, during repeated fear recalls phenocopies the beneficial effects of anti-myelination interventions on fear memory-related behavioral defects. In summary, our findings demonstrate that oligodendrogenesis triggered by repeated fear recall is sufficient to drive PTSD-like behavioral progression, likely by modulating neuronal circuits underlying remote fear memories in adults. Medications targeting oligodendrogenesis during recall may prevent pathological reinforcement of long-term fear memories and mitigate psychotic and social deficits in PTSD patients.

Large bone defect healing remains a challenge in current clinical treatment, which suggests the need for functional bone repair materials. Piezoelectric materials can generate electrical stimulation under mechanical stress to improve the tissue healing environment, which are emerging candidates for tissue engineering. We created a self-powered piezoelectric hydrogel by simply blending the zinc oxide (ZnO) nanoparticles and regenerating silk fibroin (RSF). Our piezoelectric hydrogel showed controllable and suitable mechanical and piezoelectric properties which could generate electrical stimulation to promote bone tissue healing. Incorporating ZnO into RSF hydrogels not only enhanced their mechanical properties by 1.7 times and increased piezoelectric output by 2.8 times, but also mitigated the degradation rate. In vitro experiments showed that piezoelectric hydrogels significantly promoted osteogenesis differentiation of bone marrow mesenchymal stem cells (BMSCs) and enhanced vascular network reconstitution. In vivo experiments verified the osteogenic and angiogenic potential of ZnO/RSF piezoelectric hydrogels. ZnO/RSF piezoelectric hydrogel, a simple but universal strategy of RSF-based material to generate electric currents by body movement, provides novel insights into the applications of piezoelectric hydrogel. STATEMENT OF SIGNIFICANCE: ZnO/RSF hydrogels with stable piezoelectric properties were prepared by doping ZnO, which can generate stable and continuous electrical signals under pressure. After implantation into the bone defect site, it can promote the osteogenic differentiation of bone marrow mesenchymal stem cells and improve the vasculogenic ability of human umbilical vein endothelial cells, thus promoting the healing of bone tissue.

As one of the top causes of blindness worldwide, glaucoma leads to diverse optic neuropathies such as degeneration of retinal ganglion cells (RGCs). It is widely accepted that the level of intraocular pressure (IOP) is a major risk factor in human glaucoma, and reduction of IOP level is the principally most well-known method to prevent cell death of RGCs. However, clinical studies show that lowering IOP fails to prevent RGC degeneration in the progression of glaucoma. Thus, a comprehensive understanding of glaucoma pathological process is required for developing new therapeutic strategies. In this study, we provide functional and histological evidence showing that optic nerve defects occurred before retina damage in an ocular hypertension glaucoma mouse model, in which oligodendroglial lineage cells were responsible for the subsequent neuropathology. By treatment with clemastine, an Food and Drug Administration (FDA)-approved first-generation antihistamine medicine, we demonstrate that the optic nerve and retina damages were attenuated via promoting oligodendrocyte precursor cell (OPC) differentiation and enhancing remyelination. Taken together, our results reveal the timeline of the optic neuropathies in glaucoma and highlight the potential role of oligodendroglial lineage cells playing in its treatment. Clemastine may be used in future clinical applications for demyelination-associated glaucoma.

AbstractTissue engineering has demonstrated its efficacy in promoting tissue regeneration, and extensive research has explored its application in rotator cuff (RC) tears. However, there remains a paucity of research translating from bench to clinic. A key challenge in RC repair is the healing of tendon–bone interface (TBI), for which bioactive materials suitable for interface repair are still lacking. The umbilical cord (UC), which serves as a vital repository of bioactive components in nature, is emerging as an important source of tissue engineering materials. A minimally manipulated approach is used to fabricate UC scaffolds that retain a wealth of bioactive components and cytokines. The scaffold demonstrates the ability to modulate the TBI healing microenvironment by facilitating cell proliferation, migration, suppressing inflammation, and inducing chondrogenic differentiation. This foundation sets the stage for in vivo validation and clinical translation. Following implantation of UC scaffolds in the canine model, comprehensive assessments, including MRI and histological analysis confirm their efficacy in inducing TBI reconstruction. Encouraging short‐term clinical results further suggest the ability of UC scaffolds to effectively enhance RC repair. This investigation explores the mechanisms underlying the promotion of TBI repair by UC scaffolds, providing key insights for clinical application and translational research.