Progress in spinal cord organoid research:advancing understanding of neural development,disease modelling,and regenerative medicine

Stem cell-derived spinal cord organoids(SCOs)have revolutionised the study of spinal cord development and disease mechanisms,offering a three-dimensional model that recapitulates the complexity of native tissue.This review synthesises recent advancements in SCO technology,highlighting their role in modelling spinal cord morphogenesis and their application in neurodegenerative disease research.We discuss the methodological breakthroughs in inducing regional specification and cellular diversity within SCOs,which have enhanced their predictive ability for drug screening and their relevance in mimicking pathological conditions such as neurodegenerative diseases and neuromuscular disorders.Despite these strides,challenges in achieving vascularisation and mature neuronal integration persist.The future of SCOs lies in addressing these limitations,potentially leading to transformative impactions in regenerative medicine and therapeutic development.

Unresolved Excess Accumulation of Myelin-Derived Cholesterol Contributes to Scar Formation after Spinal Cord Injury

Spinal cord injury triggers complex pathological cascades,resulting in destructive tissue damage and incomplete tissue repair.Scar formation is generally considered a barrier for regeneration in the central nervous system.However,the intrinsic mechanism of scar formation after spinal cord injury has not been fully elucidated.Here,we report that excess cholesterol accumulates in phagocytes and is inefficiently removed from spinal cord lesions in young adult mice.Interestingly,we observed that excessive cholesterol also accumulates in injured peripheral nerves but is subsequently removed by reverse cholesteroltransport.Meanwhile,preventing reverse cholesterol transport leads to macrophage accumulation and fibrosis in injured peripheral nerves.Furthermore,the neonatal mouse spinal cord lesions are devoid of myelin-derived lipids and can heal without excess cholesterol accumulation.We found that transplantation of myelin into neonatal lesions disrupts healing with excessive cholesterol accumulation,persistent macrophage activation,and fibrosis.Myelin internalization suppresses macrophage apoptosis mediated by CD5L expression,indicating that myelin-derived cholesterol plays a critical role in impaired wound healing.Taken together,our data suggest that the central nervous system lacks an efficient approach for cholesterol clearance,resulting in excessive accumulation of myelin-derived cholesterol,thereby inducing scar formation after injury.

EVs-mediated delivery of CB2 receptor agonist for Alzheimer’s disease therapy

Alzheimer’s disease(AD)is a typical neurodegenerative disease that leads to irreversible neuronal degeneration,and effective treatment remains elusive due to the unclear mechanism.We utilized biocompatible mesenchymal stem cell-derived extracellular vesicles as carriers loaded with the CB2 target medicine AM1241(EVs-AM1241)to protect against neurodegenerative progression and neuronal function in AD model mice.According to the results,EVs-AM1241 were successfully constructed and exhibited better bioavailability and therapeutic effects than bare AM1241.The Morris water maze(MWM)and fear conditioning tests revealed that the learning and memory of EVs-AM1241-treated model mice were significantly improved.In vivo electrophysiological recording of CA1 neurons indicated enhanced response to an auditory conditioned stimulus following fear learning.Immunostaining and Western blot analysis showed that amyloid plaque deposition and amyloidβ(Aβ)-induced neuronal apoptosis were significantly suppressed by EVs-AM1241.Moreover,EVs-AM1241 increased the number of neurons and restored the neuronal cytoskeleton,indicating that they enhanced neuronal regeneration.RNA sequencing revealed that EVs-AM1241 facilitated Aβphagocytosis,promoted neurogenesis and ultimately improved learning and memory through the calcium-Erk signaling pathway.Our study showed that EVs-AM1241 efficiently reversed neurodegenerative pathology and enhanced neurogenesis in modelmice,indicating that they are very promising particles for treating AD.

Spinal cord injury:molecular mechanisms and therapeutic interventions

Spinal cord injury(SCI)remains a severe condition with an extremely high disability rate.The challenges of SCI repair include its complex pathological mechanisms and the difficulties of neural regeneration in the central nervous system.In the past few decades,researchers have attempted to completely elucidate the pathological mechanism of SCI and identify effective strategies to promote axon regeneration and neural circuit remodeling.

Melatonin enhances radiofrequency-induced NK antitumor immunity,causing cancer metabolism reprogramming and inhibition of multiple pulmonary tumor development

Surgery is the comm on treatme nt for early lung cancer with multiple pulm onary no dules,but it is often accompanied by the problem of significant malignancy of other nodules in non-therapeutic areas.In this study,we found that a combined treatment of local rad iofreq ue ncy ablati on(RFA)and melatonin(MLT)greatly improved clinical outcomes for early lung cancer patie nts with multiple pulmonary nodules by minimizing lung function injury and reducing the probability of malignant transformation or enlargement of nodules in non-ablated areas.Mechanically,as demonstrated in an associated mouse lung tumor model,RFA not only effectively remove treated tumors but also stimulate antitumor immunity,which could inhibit tumor growth in non-ablated areas.MLT enhanced RFA-stimulated NK activity and exerted synergistic antitumor effects with RFA.Transcriptomics and proteomics analyses of residual tumor tissues revealed enhanced oxidative phosphorylation and reduced acidification as well as hypoxia in the tumor microenvironment,which suggests reprogrammed tumor metabolism after combined treatment with RFA and MLT.Analysis of residual tumor further revealed the depressed activity of MAPK,NF-kappa B,Wnt,and Hedgehog pathways and upregulated P53 pathway in tumors,which was in line with the inhibited tumor growth.Combined RFA and MLT treatment also reversed the Warburg effect and decreased tumor malignancy.These findings thus demonstrated that combined treatment of RFA and MLT effectively inhibited the malignancy of non-ablated nodules and provided an innovative non-invasive strategy for treating early lung tumors with multiple pulmonary nodules.Trial registration:www.chictr.org.cn,identifier ChiCTR2100042695,http://www.chictr.org.cn/showproj.aspx?proj=120931.

Emerging phagocytosis checkpoints in cancer immunotherapy

Cancer immunotherapy,mainly including immune checkpoints-targeted therapy and the adoptive transfer of engineered immune cells,has revolutionized the oncology landscape as it utilizes patients’own immune systems in combating the cancer cells.Cancer cells escape immune surveillance by hijacking the corresponding inhibitory pathways via overexpressing checkpoint genes.Phagocytosis checkpoints,such as CD47,CD24,MHC-I,PD-L1,STC-1 and GD2,have emerged as essential checkpoints for cancer immunotherapy by functioning as“don’t eat me”signals or interacting with“eat me”signals to suppress immune responses.Phagocytosis checkpoints link innate immunity and adaptive immunity in cancer immunotherapy.Genetic ablation of these phagocytosis checkpoints,as well as blockade of their signaling pathways,robustly augments phagocytosis and reduces tumor size.Among all phagocytosis checkpoints,CD47 is the most thoroughly studied and has emerged as a rising star among targets for cancer treatment.CD47-targeting antibodies and inhibitors have been investigated in various preclinical and clinical trials.However,anemia and thrombocytopenia appear to be formidable challenges since CD47 is ubiquitously expressed on erythrocytes.Here,we review the reported phagocytosis checkpoints by discussing their mechanisms and functions in cancer immunotherapy,highlight clinical progress in targeting these checkpoints and discuss challenges and potential solutions to smooth the way for combination immunotherapeutic strategies that involve both innate and adaptive immune responses.

Baicalein inhibits SARS-CoV-2/VSV replication with interfering mitochondrial oxidative phosphorylation in a mPTP dependent manner

Dear Editor,The ongoing outbreak of pneumonia(coronavirus disease 2019,COVID-19)caused by severe acute respiratory syndrome coronavirus-2(SARS-CoV-2)has become a global health emergency.Scutellaria Baicalensis Georgi extract,a Traditional Chinese Medicine(TCM)widely used for treating infection of multiple different viruses,1 also shows beneficial effects when treating COVID-19.However,underline mechanism for broad antiviral activity of Scutellaria B.extract remains elusive,which limits its further application.