Investigating the mechanisms underlying central nervous system disorders is a major scientific issue in the 21st century.However,the inaccessibility and complexity of the human brain have always represented a challeng...Investigating the mechanisms underlying central nervous system disorders is a major scientific issue in the 21st century.However,the inaccessibility and complexity of the human brain have always represented a challenge in understanding the pathophysiology of the central nervous system.Brain organoids are self-assembled threedimensional aggregates derived from pluripotent stem cells with cell types and structures similar to the embryonic human brain,giving them potential for investigating the atypical cellular,molecular,and genetic characteristics characteristic of central nervous system disorders.Brain organoids also provide a platform for drug screening and serve as a potential source for transplantation therapy for brain injuries.However,the broad application of brain organoids is hampered by several limitations,such as the lack of high-fidelity cell types,insufficient maturation,and considerable heterogeneity,undermining their reliability in specific applications.This review summarizes brain organoid evolution,discusses recent technological and methodological innovations,and reviews their applications in drug screening,transplantation therapy,and disease modeling,as well as clinical research progress.Additionally,we emphasize the limitations of current brain organoid research and explore the potential for advancing the technology to enhance its applicability.展开更多
Human spinal cord organoids(hSCOs)offer a promising platform to study neurotrauma by addressing many limitations of traditional research models.These organoids provide access to human-specific physiological and geneti...Human spinal cord organoids(hSCOs)offer a promising platform to study neurotrauma by addressing many limitations of traditional research models.These organoids provide access to human-specific physiological and genetic mechanisms and can be derived from an individual's somatic cells(e.g.,blood or skin).This enables patient-specific paradigms for precision neurotrauma research,pa rticula rly relevant to the over 300,000 people in the United States living with chronic effects of spinal cord injury(SCI).展开更多
Human cardiac organoids have revolutionized the study of cardiac development,disease modeling, drug discovery, and regenerative therapies. This review systematically discusses strategies and progress in the constructi...Human cardiac organoids have revolutionized the study of cardiac development,disease modeling, drug discovery, and regenerative therapies. This review systematically discusses strategies and progress in the construction of cardiac organoids, categorizing them into three main types:cardiac spheroids, self-organizing/assembloid organoids, and organoid-on-a-chip systems. This review uniquely integrates the advances in vascularization, organ-on-chip design, and environmental cardiotoxicity modeling within cardiac organoid platforms, offering a critical synthesis that is absent in the literature. In the context of escalating environmental threats to cardiovascular health, there is an urgent need for physiologically relevant models to accurately identify cardiac toxicants and elucidate their underlying mechanisms of action. This review highlights advances in cardiac organoid applications for disease modeling-including congenital heart defects and acquired cardiovascular diseases-drug development, toxicity screening, and the study of environmentally induced cardiovascular pathogenesis. In addition, it critically examines ongoing challenges and underscores opportunities brought by bioengineering approaches. Finally, we propose future directions for developing standardized cardiac organoid platforms with clinical predictability, aiming to expand the utility of this technology across broader research applications.展开更多
The brain is the most complex human organ,and commonly used models,such as two-dimensional-cell cultures and animal brains,often lack the sophistication needed to accurately use in research.In this context,human cereb...The brain is the most complex human organ,and commonly used models,such as two-dimensional-cell cultures and animal brains,often lack the sophistication needed to accurately use in research.In this context,human cerebral organoids have emerged as valuable tools offering a more complex,versatile,and human-relevant system than traditional animal models,which are often unable to replicate the intricate architecture and functionality of the human brain.Since human cerebral organoids are a state-of-the-art model for the study of neurodevelopment and different pathologies affecting the brain,this field is currently under constant development,and work in this area is abundant.In this review,we give a complete overview of human cerebral organoids technology,starting from the different types of protocols that exist to generate different human cerebral organoids.We continue with the use of brain organoids for the study of brain pathologies,highlighting neurodevelopmental,psychiatric,neurodegenerative,brain tumor,and infectious diseases.Because of the potential value of human cerebral organoids,we describe their use in transplantation,drug screening,and toxicology assays.We also discuss the technologies available to study cell diversity and physiological characteristics of organoids.Finally,we summarize the limitations that currently exist in the field,such as the development of vasculature and microglia,and highlight some of the novel approaches being pursued through bioengineering.展开更多
This review highlights advances in inner ear organoids(IEOs)as a novel platform for drug screening and disease modeling,particularly for hearing loss.IEOs,derived from embryonic stem cells,induced pluripotent stem cel...This review highlights advances in inner ear organoids(IEOs)as a novel platform for drug screening and disease modeling,particularly for hearing loss.IEOs,derived from embryonic stem cells,induced pluripotent stem cells,or tissue-specific progenitors,provide a physiologically relevant alternative to traditional animal models.Significant progress has been made in utilizing various cell sources,extracellular matrix materials such as Matrigel and hydrogels,and methods for controlling microenvironments through biochemical and biophysical signals.Applications of IEOs in drug screening,disease modeling,and personalized medicine enable exploration of hearing loss mechanisms and therapeutic testing.However,challenges remain,including the incomplete maturation of cochlear cells and difficulty replicating in vivo environments.Future research should focus on optimizing IEO generation,incorporating microfluidic technologies,and advancing high-throughput screening to enhance drug discovery and clinical translation.展开更多
Brain organoids are artificial neural tissues derived in vitro,containing a variety of cell types,as well as structural and/or functional brain regions.They can partially mimic brain physiological activities and disea...Brain organoids are artificial neural tissues derived in vitro,containing a variety of cell types,as well as structural and/or functional brain regions.They can partially mimic brain physiological activities and diseased processes.Owing to their operability and sample accessibility,brain organoids serve as a bridge between in vitro monolayer cell culture models and in vivo animal models.An increasing number of induction protocols for brain organoids have been developed over the preceding decade.A key future research direction will focus on ensuring the complexity and quality of brain organoids.The integration of powerful technologies,such as the CRISP R/Cas9 genome editing and lineage tra cing systems,shall precipitate practical and broad applications of brain organoids.In this review,we discuss the generation and application of brain organoids,as well as their integration with genome editing technologies,in the study of neural development,disease modeling,and mechanistic investigations.The innovative combination of these two technologies may offer a fresh perspective for exploring the fundamental aspects of the human nervous system and related diseases.展开更多
Background:Cartilage repair remains a considerable challenge in regenerative medicine.Despite extensive research on biomaterials for cartilage repair in recent years,issues such as prolonged repair cycles and suboptim...Background:Cartilage repair remains a considerable challenge in regenerative medicine.Despite extensive research on biomaterials for cartilage repair in recent years,issues such as prolonged repair cycles and suboptimal outcomes persist.Organoids,miniature three-dimensional(3D)tissue structures derived from the directed differentiation of stem or progenitor cells,mimic the structure and function of natural organs.Therefore,the construction of cartilage organoids(COs)holds great promise as a novel strategy for cartilage repair.Methods:This study employed a digital light processing system to perform 3D bioprinting of a DNA-silk fibroin(DNA-SF)hydrogel sustained-release system(DSRGT)with bone-marrow mesenchymal stem cells(BMSCs)to construct millimeter-scale CO.COs at different developmental stages were characterized,and the COs with the best cartilage phenotype were selected for in vivo cartilage repair in a rat articular cartilage defect model.Results:This study developed a DSRGT by covalently grafting glucosamine(which promotes cartilage matrix synthesis)and TD-198946(which promotes chondrogenic differentiation)onto a hydrogel using acrylic acid-polyethylene glycolN-hydroxysuccinimide(AC-PEG-NHS).In vitro,4-week COs exhibited higher SRY-box transcription factor 9(SOX9),typeⅡcollagen(ColⅡ),and aggrecan(ACAN)expression and lower typeⅠcollagen(ColⅠ)and typeⅩcollagen(ColⅩ)expression,indicating that 4 weeks is the optimal culture duration for hyaline cartilage development.In vivo,the mitogen-activated protein kinase(MAPK)signaling pathway was upregulated in 4-week COs,enabling cartilage repair within 8 weeks.Transcriptomic analysis revealed that cartilage regenerated with 4-week COs presented gene expression profiles resembling those of healthy cartilage.Conclusion:This study employs DSRGT to construct COs,providing an innovative strategy for the regeneration of cartilage defects.展开更多
Brain organoids encompass a large collection of in vitro stem cell–derived 3D culture systems that aim to recapitulate multiple aspects of in vivo brain development and function.First,this review provides a brief int...Brain organoids encompass a large collection of in vitro stem cell–derived 3D culture systems that aim to recapitulate multiple aspects of in vivo brain development and function.First,this review provides a brief introduction to the current state-of-the-art for neuroectoderm brain organoid development,emphasizing their biggest advantages in comparison with classical two-dimensional cell cultures and animal models.However,despite their usefulness for developmental studies,a major limitation for most brain organoid models is the absence of contributing cell types from endodermal and mesodermal origin.As such,current research is highly investing towards the incorporation of a functional vasculature and the microglial immune component.In this review,we will specifically focus on the development of immune-competent brain organoids.By summarizing the different approaches applied to incorporate microglia,it is highlighted that immune-competent brain organoids are not only important for studying neuronal network formation,but also offer a clear future as a new tool to study inflammatory responses in vitro in 3D in a brainlike environment.Therefore,our main focus here is to provide a comprehensive overview of assays to measure microglial phenotype and function within brain organoids,with an outlook on how these findings could better understand neuronal network development or restoration,as well as the influence of physical stress on microglia-containing brain organoids.Finally,we would like to stress that even though the development of immune-competent brain organoids has largely evolved over the past decade,their full potential as a pre-clinical tool to study novel therapeutic approaches to halt or reduce inflammation-mediated neurodegeneration still needs to be explored and validated.展开更多
Current organoid-generation strategies rely predominantly on intricate in vitro manipulations of dissociated stem cells,including isolation,expansion,and genetic modification.However,these approaches present significa...Current organoid-generation strategies rely predominantly on intricate in vitro manipulations of dissociated stem cells,including isolation,expansion,and genetic modification.However,these approaches present significant challenges in terms of safety and scalability for clinical applications.An alternative strategy involves the direct generation of organoids from readily available tissues.Herein,we report the generation of functional organoids representing all three germ layers from human adult adipose tissue without single-cell processing steps.Specifically,by employing a specialized suspension culture system,we have developed reaggregated microfat(RMF)tissues,which differentiated into mesodermal bone marrow organoids capable of reconstituting human normal hematopoiesis in immunodeficient mice,endodermal insulin-producing organoids that reversed hyperglycemia in streptozotocin(STZ)-induced diabetic mice,and ectodermal nervous-like tissues resembling neurons and neuroglial cells.These findings therefore highlight the potential of human adipose tissue as a safe,scalable,and clinically viable source for organoid-based regenerative therapies.展开更多
The structure of intestinal tissue is complex.In vitro simulation of intestinal structure and function is important for studying intestinal development and diseases.Recently,organoids have been successfully constructe...The structure of intestinal tissue is complex.In vitro simulation of intestinal structure and function is important for studying intestinal development and diseases.Recently,organoids have been successfully constructed and they have come to play an important role in biomedical research.Organoids are miniaturized three-dimensional(3D)organs,derived from stem cells,which mimic the structure,cell types,and physiological functions of an organ,making them robust models for biomedical research.Intestinal organoids are 3D micro-organs derived from intestinal stem cells or pluripotent stem cells that can successfully simulate the complex structure and function of the intestine,thereby providing a valuable platform for intestinal development and disease research.In this article,we review the latest progress in the construction and application of intestinal organoids.展开更多
Brain organoid-on-chip platforms have emerged as groundbreaking tools in neural disease modeling and drug discovery,offering a unique and highly accurate simulation of human organ physiology and func-tion compared wit...Brain organoid-on-chip platforms have emerged as groundbreaking tools in neural disease modeling and drug discovery,offering a unique and highly accurate simulation of human organ physiology and func-tion compared with traditional cell culture systems.This technology is a harmonious fusion of organ-on-a-chip and organoid culture technologies,leveraging their strengths to provide the most realistic in vitro replication of the in vivo environment,both physically and biologically.As both technologies continue to advance rapidly,this platform is highly promising in vitro platform for disease modeling.In this review,we summarize the historical developments,recent advancements,limitations,and future prospects of brain organoid-on-chip technology,aiming to illuminate the transformative potential of this platform in advancing our understanding and treatment of neural diseases.展开更多
Coronavirus disease 2019(COVID-19),caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),not only affects the lungs but also damages various non-pulmonary organs,resulting in tissue injury and potentia...Coronavirus disease 2019(COVID-19),caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),not only affects the lungs but also damages various non-pulmonary organs,resulting in tissue injury and potential long-term sequelae in infected individuals.COVID-19 is likely to persist as a public health concern,given the frequent emergence of new mutations and viral strains.Multiple clinical lines of evidence indicate the efficacy of traditional Chinese medicine(TCM)in the prevention and treatment of COVID-19.However,the exact mechanism underlying these effects remains unclear.In this perspective review,we summarize the utility of in vitro three-dimensional(3D)cultured organoid models and organ-on-a-chip(OoC)technology for studying COVID-19 pathogenesis,viral tropism,and infectious mechanisms across different tissues.We highlight the successful application of these platforms in aiding drug development and discuss their advantages and limitations.We also review how such organotypic models can be employed to study TCMs.Finally,we discuss the opportunities for integrated microphysiological multi-tissue models to rapidly discover active components and potential targets in the context of COVID-19.The utilization of these emerging technologies could accelerate drug discovery and the modernization of TCM.展开更多
The neurotransmitter 5-hydroxytryptamine(5-HT),primarily produced by intestinal enterochromaffin(EC)cells,relies on tryptophan hydroxylase 1(TPH1)for synthesis.Research suggested Bifidobacterium breve CCFM1025’s pote...The neurotransmitter 5-hydroxytryptamine(5-HT),primarily produced by intestinal enterochromaffin(EC)cells,relies on tryptophan hydroxylase 1(TPH1)for synthesis.Research suggested Bifidobacterium breve CCFM1025’s potential in regulating Tph1 gene expression,maintaining 5-HT levels in stressed mice,but its precise mechanisms were unclear.This study used metabolomic techniques to assess probiotic fermentation products,revealing acetate as the crucial element in Bb-CCFM1025’s regulation of gut 5-HT synthesis.Further exploration correlated acetate with Tph1 transcription in intestinal organoids.Transcriptomic methods and quantitative reverse transcription polymerase chain reaction validation demonstrated how acetate facilitated 5-HT synthesis and secretion.It unveiled that acetate orchestrates signaling pathways(phosphoinositide 3-kinase-protein kinase B(PI3K-AKT),phospholipase C-phosphorylated extracellular signal-regulated kinase(PLC-pERK),and PLC-1,4,5-trisphosphate(IP3)-Ca^(2+))within EC,enabling 5-HT production.These findings elucidate the biochemical mechanisms behind specific probiotics’effects,aiding in the targeted selection of similar beneficial strains.This study offers theoretical support for choosing probiotics with analogous functionalities based on their physiological impacts.展开更多
In this letter,we discuss the highlights of the paper by Hu et al,including how patient-derived organoids may be beneficial to hepatobiliary pancreatic research.The article provides a review of how organoids can be us...In this letter,we discuss the highlights of the paper by Hu et al,including how patient-derived organoids may be beneficial to hepatobiliary pancreatic research.The article provides a review of how organoids can be used in drug sensitivity testing;looking at ways in which successful organoids are created.The literature included in the review revealed heterogeneity in organoid establishment inclu-ding some differences between organoids from resected tumours compared with liquid biopsies.Additional research is required in creating organoids from liquid biopsies and optimizing these techniques for widespread clinical practice.The article raises awareness of limitations of organoids with suggestions of how co-culture or microfluid platforms may help to simulate the tumour microenvir-onment for better model fidelity.The article provides a comprehensive review of how organoids are being used in drug testing and ideas about how to harvest or produce these in future.展开更多
Current experimental models struggle to simulate the complex process of the transformation from atrophic gastritis to gastric cancer,while gastric organoid technology,especially region-specific modeling,provides a mor...Current experimental models struggle to simulate the complex process of the transformation from atrophic gastritis to gastric cancer,while gastric organoid technology,especially region-specific modeling,provides a more precise in vitro platform for studying this carcinogenic mechanism.Helicobacter pylori activates carcinogenic signaling pathways through virulence factors,inducing DNA damage,epigenetic dysregulation,and immune microenvironment imbalance,driving inflammation-cancer conversion.Intestinal metaplasia and spasmolytic polypeptide-expressing metaplasia serve as critical precursor lesions,gradually developing into dysplasia and adenocarcinoma under the influence of chronic inflammation and genetic instability through intestinal cell transformation and high trefoil factor 2-expressing cell expansion.The immune suppression,metabolic reprogramming,and matrix remodeling within the tumor microenvironment collaboratively create a pro-cancer ecosystem that accelerates inflammationcarcinogenesis transformation.The gastric organoid model successfully simulates the spatiotemporal dynamics of the carcinogenesis process in atrophic gastritis,and its future integration with single-cell omics,real-time imaging technologies,and artificial intelligence technologies could provide a more precise platform for elucidating molecular mechanisms and screening intervention strategies.These advances position gastric organoids as pivotal tools for clinical translation,enabling personalized risk stratification,early intervention targeting precancerous transitions,and ex vivo prediction of patient-specific therapeutic responses to guide precision management of gastric cancer.展开更多
BACKGROUND Liver metastases are very common in pancreatic neuroendocrine tumors(pNETs).When surgical resection is possible,it is typically associated with survival benefits in patients with pNET and liver metastases.P...BACKGROUND Liver metastases are very common in pancreatic neuroendocrine tumors(pNETs).When surgical resection is possible,it is typically associated with survival benefits in patients with pNET and liver metastases.Patient-derived organoids are a powerful preclinical platform that show great potential for predicting treatment response,and they have been increasingly applied in precision medicine and cancer research.CASE SUMMARY A 51-year-old man was admitted to the hospital with the chief complaint of in-termittent dull pain in the upper abdomen for over 3 years.Computerized to-mography showed multiple space-occupying lesions in the liver and a neoplasm in the pancreatic body.Pathological results suggested a grade 3 pancreas-derived hepatic neuroendocrine tumor.In combination with relevant examinations,the patient was diagnosed with pNET with liver metastases(grade 3).Transarterial chemoembolization was initially performed with oxaliplatin and 5-fluorouracil,after which the chemotherapy regimen was switched to liposomal irinotecan and cisplatin for a subsequent perfusion,guided by organoid-based drug sensitivity testing.Following interventional treatment,the tumor had decreased in size.However,due to poor treatment compliance and the patient’s preference for sur-INTRODUCTION Pancreatic neuroendocrine tumors(pNETs)are a rare and heterogeneous group of neoplasms arising from pancreatic islet cells,with variations in histology,clinical characteristics,and prognosis[1].They may present as non-infiltrative,slow-growing tumors,locally invasive tumors,or even rapidly metastasizing tumors[2].Most metastases localize to the liver,and approximately 28%-77%of patients with pNETs will experience liver metastases in their lifetime[3].Patients with liver metastases may be subjected to local complications such as biliary obstruction,liver insufficiency,and carcinoid syndrome.Additionally,liver metastases are a major risk factor for the prognosis of patients with pNETs[4].When feasible,surgical resection is significantly associated with the best long-term survival outcomes[5].Therefore,for patients with pNET liver metastases,comprehensive assessment and multidisciplinary approaches are required to determine the feasibility of surgical resection and the optimal treatment to improve the prognosis.Over the past decade,the advent of in vitro three-dimensional technologies including organoids has revolutionized the development of human cancer models.Patient-derived organoids(PDOs),an in vitro three-dimensional microstructure,can faithfully recapitulate the intricate spatial architecture and cell heterogeneity of the tissue,and simulate the biological behaviors and functions of parental tumors while preserving biological,genetic and molecular features[6,7].As a po-werful preclinical platform,PDOs have been increasingly applied in precision medicine and cancer research.Importantly,there is a significant association between the use of PDO-based drug sensitivity testing and clinical responses to chemotherapy,radiotherapy and targeted therapy in multiple cancer types[8-10].Although gastroenteropancreatic neuroendocrine neoplasm organoids have been confirmed to retain the pathohistological and functional phenotypes of parental tumors[7],their roles in the prediction of clinical outcomes have not been presented.Here,we report a case of pNET with liver metastases who successfully received surgical resection after personalized treatment guided by PDO-based drug sensitivity testing,resulting in a favorable prognosis.展开更多
Major depressive disorder(MDD)is a debilitating psychiatric condition associated with substantial personal,societal,and economic costs.Despite considerable advances in research,most conventional antidepressant therapi...Major depressive disorder(MDD)is a debilitating psychiatric condition associated with substantial personal,societal,and economic costs.Despite considerable advances in research,most conventional antidepressant therapies fail to achieve adequate response in a significant proportion of patients,underscoring the need for novel,mechanism-based interventions.Lycium barbarum glycopeptide(LbGp),a bioactive compound with emerging neuroprotective properties,has been proposed as a candidate for antidepressant development;however,its therapeutic efficacy and underlying mechanisms remain largely uncharacterized.In this study,ventral forebrain organoids were generated from patients with MDD to investigate disease-related neurophysiological abnormalities.These organoids exhibited disrupted neuronal morphology,diminished calcium signaling,and impaired electrophysiological activity.Administration of LbGp effectively restored structural and functional deficits in MDD-derived organoids.Transcriptomic profiling revealed that LbGp ameliorated endoplasmic reticulum(ER)stress responses.To investigate the causative role of ER stress,control organoids were treated with the ER stress agonist CCT020312,which elicited neural activity impairments resembling those observed in MDD organoids.Notably,LbGp reversed the phenotypic consequences of CCT020312 exposure in control organoids.In conclusion,ventral forebrain organoids derived from individuals with MDD demonstrated that LbGp ameliorates disease-associated phenotypes by modulating ER stress.展开更多
AIM:To explore the changes in early retinal development after the occurrence of ischemia.METHODS:Human retinal organoids(hROs)of day 18 or day 30 were treated with oxygen-glucose deprivation and reperfusion(OGD/R)to s...AIM:To explore the changes in early retinal development after the occurrence of ischemia.METHODS:Human retinal organoids(hROs)of day 18 or day 30 were treated with oxygen-glucose deprivation and reperfusion(OGD/R)to simulate the retinal ischemia.All hROs were maintained normally until day 60 to evaluate changes in ischemic injuries during retinal development.Paraffin section staining was used for detecting changes in organoid structure and cell number.Real-time quantitative polymerase chain reaction(RT-qPCR)and Western blot(WB)analyses were used to observe the change in the expression of retinal cell markers.RESULTS:In hROs,OGD/R induced the decrease of proliferating cells,inhibited the expression of proliferated marker Ki67 and promoted early apoptosis of retinal cells(P<0.05).Under OGD/R condition,the progenitor cell layer and ganglion cell layer of hROs lost normal structure,and the number of neural stem cells(SOX2^(+)),retinal progenitor cells(CHX10^(+))and retinal ganglion cells(TUJ1^(+)/BRN3^(+)/ATOH7^(+))decreased(P<0.05).The expression of corresponding retinal cell markers also decreased(P<0.05).Organoids treated with OGD/R on day 30 had similar injuries in retinal structure and retinal cell markers to those on day 18.Long-term observations revealed that day 18-treated organoids remained disorganized progenitor and ganglion cell layers by day 60,with no recovery in proliferating cell nuclear antigen(PCNA)protein expression.RT-qPCR showed persistently low Ki67 transcription levels(P<0.001),while other retinal cell markers recovered or exceeded normal levels,indicating a limited self-repair happened in the development of hROs.In contrast,day 30-treated organoids exhibited normal structure and marker expression by day 60,with transcription levels of retinal cell markers returning to normal(P>0.05),demonstrating complete recovery from OGD/R damage.CONCLUSION:Retinal ischemia damage the retinal development in the short-term.After the restoration of retinal blood supply,the retinal ischemic damage can be recovered during subsequent development.However,retinal ischemic injuries at different developmental stages exhibit varying degrees of reversibility.The earlier ischemic injury occurs,the more difficult it is to repair retinal cell and structure damage.展开更多
Hepatobiliary and pancreatic(HBP)cancers are among the most aggressive malig-nancies,with recurrence and metastasis driven by tumor heterogeneity and drug resistance,presenting considerable challenges to effective tre...Hepatobiliary and pancreatic(HBP)cancers are among the most aggressive malig-nancies,with recurrence and metastasis driven by tumor heterogeneity and drug resistance,presenting considerable challenges to effective treatment.Currently,personalized and accurate treatment prediction models for these cancers are lacking.Patient-derived organoids(PDOs)tumor are three-dimensional in vitro models created from the tumor tissues of individual patients.Recent reports and our cultivation data indicate that the success rate of cultivating organoids for HBP cancers consistently exceeds 70%.The predictive accuracy of these tumor orga-noids has been shown to surpass 90%.However,PDOs still face notable limita-tions,especially in simulating the tumor microenvironment,including tumor angiogenesis and the surrounding cellular context,which require further refi-nement.While co-culture techniques and microfluidic platforms have been deve-loped to mimic multi-cellular environments and functional vascular perfusion,they remain insufficient in accurately recapitulating the complexities of the in vivo environment.Additionally,PDOs are needed to fully assess their potential in predicting the efficacy of multi-drug combination therapies.This review provides an overview of the applications,challenges,and prospects for organoid models in the study of HBP cancer.展开更多
Organoids are three-dimensional structures derived from stem cells that recapitulate the gene expression profiles and functional characteristics of their tissue of origin,rendering them invaluable tools for disease mo...Organoids are three-dimensional structures derived from stem cells that recapitulate the gene expression profiles and functional characteristics of their tissue of origin,rendering them invaluable tools for disease modeling,drug screening,and precision medicine.Despite their promise,the widespread application of organoids is limited by extended culture durations and technical complexity.Cryopreservation has emerged as a critical strategy to overcome challenges related to the long-term storage and application of organoids,offering a range of preservation approaches tailored to organoid development.Nevertheless,conventional cryopreservation techniques encounter significant limitations when applied to organoids.To address these issues,the development of naturally derived,low-toxicity Cryoprotectants(CPAs),along with the optimization of CPA loading methods and refinement of cooling and warming protocols,is essential to mitigate cryoinjury.Looking forward,the comprehensive enhancement of cryopreservation technologies may facilitate the transformation of organoids into“off-the-shelf”products,enabling scalable production,batch standardization,and centralized distribution.Such advancements will lay the foundation for the establishment of Next-Generation Living Biobanks(NGLB).展开更多
基金supported by Guizhou Provincial Higher Education Science and Technological Innovation Team,No.[2023]072 (to LX)Graduate Education and Teaching Innovation Program of Zunyi Medical University,No.ZYK262 (to QW)the Guizhou Graduate Research Fund,No.2024YJSKYJJ333 (to QW)
文摘Investigating the mechanisms underlying central nervous system disorders is a major scientific issue in the 21st century.However,the inaccessibility and complexity of the human brain have always represented a challenge in understanding the pathophysiology of the central nervous system.Brain organoids are self-assembled threedimensional aggregates derived from pluripotent stem cells with cell types and structures similar to the embryonic human brain,giving them potential for investigating the atypical cellular,molecular,and genetic characteristics characteristic of central nervous system disorders.Brain organoids also provide a platform for drug screening and serve as a potential source for transplantation therapy for brain injuries.However,the broad application of brain organoids is hampered by several limitations,such as the lack of high-fidelity cell types,insufficient maturation,and considerable heterogeneity,undermining their reliability in specific applications.This review summarizes brain organoid evolution,discusses recent technological and methodological innovations,and reviews their applications in drug screening,transplantation therapy,and disease modeling,as well as clinical research progress.Additionally,we emphasize the limitations of current brain organoid research and explore the potential for advancing the technology to enhance its applicability.
基金supported by the Belle Carnell Regenerative Neurorehabilitation Fundthe National Institutes of Health(R01NS113935 to CKF)。
文摘Human spinal cord organoids(hSCOs)offer a promising platform to study neurotrauma by addressing many limitations of traditional research models.These organoids provide access to human-specific physiological and genetic mechanisms and can be derived from an individual's somatic cells(e.g.,blood or skin).This enables patient-specific paradigms for precision neurotrauma research,pa rticula rly relevant to the over 300,000 people in the United States living with chronic effects of spinal cord injury(SCI).
基金supported by the Innovation Promotion Program of NHC and Shanghai Key Labs,SIBPT(grant number PT2025-01)。
文摘Human cardiac organoids have revolutionized the study of cardiac development,disease modeling, drug discovery, and regenerative therapies. This review systematically discusses strategies and progress in the construction of cardiac organoids, categorizing them into three main types:cardiac spheroids, self-organizing/assembloid organoids, and organoid-on-a-chip systems. This review uniquely integrates the advances in vascularization, organ-on-chip design, and environmental cardiotoxicity modeling within cardiac organoid platforms, offering a critical synthesis that is absent in the literature. In the context of escalating environmental threats to cardiovascular health, there is an urgent need for physiologically relevant models to accurately identify cardiac toxicants and elucidate their underlying mechanisms of action. This review highlights advances in cardiac organoid applications for disease modeling-including congenital heart defects and acquired cardiovascular diseases-drug development, toxicity screening, and the study of environmentally induced cardiovascular pathogenesis. In addition, it critically examines ongoing challenges and underscores opportunities brought by bioengineering approaches. Finally, we propose future directions for developing standardized cardiac organoid platforms with clinical predictability, aiming to expand the utility of this technology across broader research applications.
基金supported by the Grant PID2021-126715OB-IOO financed by MCIN/AEI/10.13039/501100011033 and"ERDFA way of making Europe"by the Grant PI22CⅢ/00055 funded by Instituto de Salud CarlosⅢ(ISCⅢ)+6 种基金the UFIECPY 398/19(PEJ2018-004965) grant to RGS funded by AEI(Spain)the UFIECPY-396/19(PEJ2018-004961)grant financed by MCIN (Spain)FI23CⅢ/00003 grant funded by ISCⅢ-PFIS Spain) to PMMthe UFIECPY 328/22 (PEJ-2021-TL/BMD-21001) grant to LM financed by CAM (Spain)the grant by CAPES (Coordination for the Improvement of Higher Education Personnel)through the PDSE program (Programa de Doutorado Sanduiche no Exterior)to VSCG financed by MEC (Brazil)
文摘The brain is the most complex human organ,and commonly used models,such as two-dimensional-cell cultures and animal brains,often lack the sophistication needed to accurately use in research.In this context,human cerebral organoids have emerged as valuable tools offering a more complex,versatile,and human-relevant system than traditional animal models,which are often unable to replicate the intricate architecture and functionality of the human brain.Since human cerebral organoids are a state-of-the-art model for the study of neurodevelopment and different pathologies affecting the brain,this field is currently under constant development,and work in this area is abundant.In this review,we give a complete overview of human cerebral organoids technology,starting from the different types of protocols that exist to generate different human cerebral organoids.We continue with the use of brain organoids for the study of brain pathologies,highlighting neurodevelopmental,psychiatric,neurodegenerative,brain tumor,and infectious diseases.Because of the potential value of human cerebral organoids,we describe their use in transplantation,drug screening,and toxicology assays.We also discuss the technologies available to study cell diversity and physiological characteristics of organoids.Finally,we summarize the limitations that currently exist in the field,such as the development of vasculature and microglia,and highlight some of the novel approaches being pursued through bioengineering.
基金supported by the National Natural Science Foundation of China(82222017 and 82271183)Hubei Province’s Key Research and Development Program(2022BCA046)the Start-up Research Fund of Southeast University(RF1028623028).
文摘This review highlights advances in inner ear organoids(IEOs)as a novel platform for drug screening and disease modeling,particularly for hearing loss.IEOs,derived from embryonic stem cells,induced pluripotent stem cells,or tissue-specific progenitors,provide a physiologically relevant alternative to traditional animal models.Significant progress has been made in utilizing various cell sources,extracellular matrix materials such as Matrigel and hydrogels,and methods for controlling microenvironments through biochemical and biophysical signals.Applications of IEOs in drug screening,disease modeling,and personalized medicine enable exploration of hearing loss mechanisms and therapeutic testing.However,challenges remain,including the incomplete maturation of cochlear cells and difficulty replicating in vivo environments.Future research should focus on optimizing IEO generation,incorporating microfluidic technologies,and advancing high-throughput screening to enhance drug discovery and clinical translation.
基金Special Projectfor Clinical Research of Shanghai Municipal Health Commission,No.202140403Key Disciplines Group Construction Project of Pudong Health Bureau of Shanghai,No.PWZxq2022-05+2 种基金Natural Science Foundation of Ningxia Hui Autonomous Region,No.2024AAC05084Ningxia Hui Autonomous Region Key Research and Development Program,No.2021BEG03084National Natural Science Foundation of China,Nos.32370895,32070862。
文摘Brain organoids are artificial neural tissues derived in vitro,containing a variety of cell types,as well as structural and/or functional brain regions.They can partially mimic brain physiological activities and diseased processes.Owing to their operability and sample accessibility,brain organoids serve as a bridge between in vitro monolayer cell culture models and in vivo animal models.An increasing number of induction protocols for brain organoids have been developed over the preceding decade.A key future research direction will focus on ensuring the complexity and quality of brain organoids.The integration of powerful technologies,such as the CRISP R/Cas9 genome editing and lineage tra cing systems,shall precipitate practical and broad applications of brain organoids.In this review,we discuss the generation and application of brain organoids,as well as their integration with genome editing technologies,in the study of neural development,disease modeling,and mechanistic investigations.The innovative combination of these two technologies may offer a fresh perspective for exploring the fundamental aspects of the human nervous system and related diseases.
基金supported by the National Key Research and Development Program of China(2022YFB3804300)the National Natural Science Foundation of China(82230071,32471395,82427809,82472479)+2 种基金the Shanghai Science and Technology Innovation Action Plan(23141900600)the Research Physician Training Program of Shanghai Hospital Development Center(SHDC2023CRT013)the Shanghai Municipal Demonstration Project for Innovative Medical Device Applications(23SHS05700)。
文摘Background:Cartilage repair remains a considerable challenge in regenerative medicine.Despite extensive research on biomaterials for cartilage repair in recent years,issues such as prolonged repair cycles and suboptimal outcomes persist.Organoids,miniature three-dimensional(3D)tissue structures derived from the directed differentiation of stem or progenitor cells,mimic the structure and function of natural organs.Therefore,the construction of cartilage organoids(COs)holds great promise as a novel strategy for cartilage repair.Methods:This study employed a digital light processing system to perform 3D bioprinting of a DNA-silk fibroin(DNA-SF)hydrogel sustained-release system(DSRGT)with bone-marrow mesenchymal stem cells(BMSCs)to construct millimeter-scale CO.COs at different developmental stages were characterized,and the COs with the best cartilage phenotype were selected for in vivo cartilage repair in a rat articular cartilage defect model.Results:This study developed a DSRGT by covalently grafting glucosamine(which promotes cartilage matrix synthesis)and TD-198946(which promotes chondrogenic differentiation)onto a hydrogel using acrylic acid-polyethylene glycolN-hydroxysuccinimide(AC-PEG-NHS).In vitro,4-week COs exhibited higher SRY-box transcription factor 9(SOX9),typeⅡcollagen(ColⅡ),and aggrecan(ACAN)expression and lower typeⅠcollagen(ColⅠ)and typeⅩcollagen(ColⅩ)expression,indicating that 4 weeks is the optimal culture duration for hyaline cartilage development.In vivo,the mitogen-activated protein kinase(MAPK)signaling pathway was upregulated in 4-week COs,enabling cartilage repair within 8 weeks.Transcriptomic analysis revealed that cartilage regenerated with 4-week COs presented gene expression profiles resembling those of healthy cartilage.Conclusion:This study employs DSRGT to construct COs,providing an innovative strategy for the regeneration of cartilage defects.
基金funded by the European Union’s Horizon 2020 research and innovation programme under the Marie Skodowska-Curie grant agreement No.813263(PMSMat Train,granted to UF,PP,MV,and DP)provided by the Fund for Scientific Research Flanders(FWO-Vlaanderen)of the Flemish Government(FWO sabbatical bench fee K800224N granted to PP)and ERA-NET Re Park(granted to PP)。
文摘Brain organoids encompass a large collection of in vitro stem cell–derived 3D culture systems that aim to recapitulate multiple aspects of in vivo brain development and function.First,this review provides a brief introduction to the current state-of-the-art for neuroectoderm brain organoid development,emphasizing their biggest advantages in comparison with classical two-dimensional cell cultures and animal models.However,despite their usefulness for developmental studies,a major limitation for most brain organoid models is the absence of contributing cell types from endodermal and mesodermal origin.As such,current research is highly investing towards the incorporation of a functional vasculature and the microglial immune component.In this review,we will specifically focus on the development of immune-competent brain organoids.By summarizing the different approaches applied to incorporate microglia,it is highlighted that immune-competent brain organoids are not only important for studying neuronal network formation,but also offer a clear future as a new tool to study inflammatory responses in vitro in 3D in a brainlike environment.Therefore,our main focus here is to provide a comprehensive overview of assays to measure microglial phenotype and function within brain organoids,with an outlook on how these findings could better understand neuronal network development or restoration,as well as the influence of physical stress on microglia-containing brain organoids.Finally,we would like to stress that even though the development of immune-competent brain organoids has largely evolved over the past decade,their full potential as a pre-clinical tool to study novel therapeutic approaches to halt or reduce inflammation-mediated neurodegeneration still needs to be explored and validated.
基金supported by the National Natural Science Foundation of China(82372535 to Ru-Lin Huang and 82361138568 to Qingfeng Li)the Shanghai Clinical Research Center of Plastic and Reconstructive Surgery supported by Science and Technology Commission of Shanghai Municipality(22MC1940300)the Shanghai Plastic Surgery Research Center of Shanghai Priority Research Center(2023ZZ02023)。
文摘Current organoid-generation strategies rely predominantly on intricate in vitro manipulations of dissociated stem cells,including isolation,expansion,and genetic modification.However,these approaches present significant challenges in terms of safety and scalability for clinical applications.An alternative strategy involves the direct generation of organoids from readily available tissues.Herein,we report the generation of functional organoids representing all three germ layers from human adult adipose tissue without single-cell processing steps.Specifically,by employing a specialized suspension culture system,we have developed reaggregated microfat(RMF)tissues,which differentiated into mesodermal bone marrow organoids capable of reconstituting human normal hematopoiesis in immunodeficient mice,endodermal insulin-producing organoids that reversed hyperglycemia in streptozotocin(STZ)-induced diabetic mice,and ectodermal nervous-like tissues resembling neurons and neuroglial cells.These findings therefore highlight the potential of human adipose tissue as a safe,scalable,and clinically viable source for organoid-based regenerative therapies.
基金funded by the National Natural Science Foundation of China(No.32300659)Shenzhen Science and Technology Innovation Commission Project(No.JCYJ20230807143302004)+6 种基金Zhangjiakou City Key R&D Plan Project(No.2421118D),Zhangjiakou City Key R&D Plan Project(No.2322088D)The Natural Science Project of Hebei North University(No.XJ2024034 and XJ2024035)Medical Science Research Subject Plan Project of Hebei Provincial Health Commission(No.20240782)Project of Administration of Traditional Chinese Medicine of Hebei Province(No.2025392)The 2025 Government-funded Training Project for Outstanding Clinical Medicine Talents(No.ZF2025264)Research Project of Medical Innovation for Chinese Youth(Project Leader:Jun Xue).g Project for Outstanding Clinical Medicine Talents(No.ZF2025264)Research Project of Medical Innovation for Chinese Youth(Project Leader:Jun Xue)。
文摘The structure of intestinal tissue is complex.In vitro simulation of intestinal structure and function is important for studying intestinal development and diseases.Recently,organoids have been successfully constructed and they have come to play an important role in biomedical research.Organoids are miniaturized three-dimensional(3D)organs,derived from stem cells,which mimic the structure,cell types,and physiological functions of an organ,making them robust models for biomedical research.Intestinal organoids are 3D micro-organs derived from intestinal stem cells or pluripotent stem cells that can successfully simulate the complex structure and function of the intestine,thereby providing a valuable platform for intestinal development and disease research.In this article,we review the latest progress in the construction and application of intestinal organoids.
基金Westlake University and the Research Center for Industries of the Future of Westlake University,China(Grant No.:WU2022C040)authors acknowledge BioRender.com for the assistance of drawing Figs.1 and 4 and Graphical abstract.
文摘Brain organoid-on-chip platforms have emerged as groundbreaking tools in neural disease modeling and drug discovery,offering a unique and highly accurate simulation of human organ physiology and func-tion compared with traditional cell culture systems.This technology is a harmonious fusion of organ-on-a-chip and organoid culture technologies,leveraging their strengths to provide the most realistic in vitro replication of the in vivo environment,both physically and biologically.As both technologies continue to advance rapidly,this platform is highly promising in vitro platform for disease modeling.In this review,we summarize the historical developments,recent advancements,limitations,and future prospects of brain organoid-on-chip technology,aiming to illuminate the transformative potential of this platform in advancing our understanding and treatment of neural diseases.
基金supported by the Zhejiang Provincial Natural Science Foundation of China(LDT23H19012H19)the National Key R&D Program of China(2021YFC1712905)+5 种基金supported by the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(ZYYCXTD-D-202002)the Fundamental Research Funds for the Central Universities(226-2024-00001)Volker M.Lauschke was supported by the Swedish Research Council(2019-01837 and 2021-02801)Ruth och Richard Julins Foundation for Gastroenterology(2021-00158)the Knut and Alice Wallenberg Foundation(VC-2021-0026)Robert Bosch Foundation,Stuttgart,Germany.
文摘Coronavirus disease 2019(COVID-19),caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),not only affects the lungs but also damages various non-pulmonary organs,resulting in tissue injury and potential long-term sequelae in infected individuals.COVID-19 is likely to persist as a public health concern,given the frequent emergence of new mutations and viral strains.Multiple clinical lines of evidence indicate the efficacy of traditional Chinese medicine(TCM)in the prevention and treatment of COVID-19.However,the exact mechanism underlying these effects remains unclear.In this perspective review,we summarize the utility of in vitro three-dimensional(3D)cultured organoid models and organ-on-a-chip(OoC)technology for studying COVID-19 pathogenesis,viral tropism,and infectious mechanisms across different tissues.We highlight the successful application of these platforms in aiding drug development and discuss their advantages and limitations.We also review how such organotypic models can be employed to study TCMs.Finally,we discuss the opportunities for integrated microphysiological multi-tissue models to rapidly discover active components and potential targets in the context of COVID-19.The utilization of these emerging technologies could accelerate drug discovery and the modernization of TCM.
基金supported by the National Natural Science Foundation of China(32201988)Natural Science Foundation of Jiangsu Province(BK20210456)+3 种基金Special Fund for Science and Technology Program of Jiangsu Province(BM2022019)the National Key R&D Program of China(2023YFC2506004)the Fundamental Research Funds for the Central Universities(JUSRP123047)the Program of Collaborative Innovation Centre of Food Safety and Quality Control in Jiangsu Province.
文摘The neurotransmitter 5-hydroxytryptamine(5-HT),primarily produced by intestinal enterochromaffin(EC)cells,relies on tryptophan hydroxylase 1(TPH1)for synthesis.Research suggested Bifidobacterium breve CCFM1025’s potential in regulating Tph1 gene expression,maintaining 5-HT levels in stressed mice,but its precise mechanisms were unclear.This study used metabolomic techniques to assess probiotic fermentation products,revealing acetate as the crucial element in Bb-CCFM1025’s regulation of gut 5-HT synthesis.Further exploration correlated acetate with Tph1 transcription in intestinal organoids.Transcriptomic methods and quantitative reverse transcription polymerase chain reaction validation demonstrated how acetate facilitated 5-HT synthesis and secretion.It unveiled that acetate orchestrates signaling pathways(phosphoinositide 3-kinase-protein kinase B(PI3K-AKT),phospholipase C-phosphorylated extracellular signal-regulated kinase(PLC-pERK),and PLC-1,4,5-trisphosphate(IP3)-Ca^(2+))within EC,enabling 5-HT production.These findings elucidate the biochemical mechanisms behind specific probiotics’effects,aiding in the targeted selection of similar beneficial strains.This study offers theoretical support for choosing probiotics with analogous functionalities based on their physiological impacts.
文摘In this letter,we discuss the highlights of the paper by Hu et al,including how patient-derived organoids may be beneficial to hepatobiliary pancreatic research.The article provides a review of how organoids can be used in drug sensitivity testing;looking at ways in which successful organoids are created.The literature included in the review revealed heterogeneity in organoid establishment inclu-ding some differences between organoids from resected tumours compared with liquid biopsies.Additional research is required in creating organoids from liquid biopsies and optimizing these techniques for widespread clinical practice.The article raises awareness of limitations of organoids with suggestions of how co-culture or microfluid platforms may help to simulate the tumour microenvir-onment for better model fidelity.The article provides a comprehensive review of how organoids are being used in drug testing and ideas about how to harvest or produce these in future.
基金Supported by National Traditional Chinese Medicine Advantageous Specialty Project of National Administration of Traditional Chinese MedicineShuguang Hospital Siming Foundation Research Special Project,No.SGKJ-202304.
文摘Current experimental models struggle to simulate the complex process of the transformation from atrophic gastritis to gastric cancer,while gastric organoid technology,especially region-specific modeling,provides a more precise in vitro platform for studying this carcinogenic mechanism.Helicobacter pylori activates carcinogenic signaling pathways through virulence factors,inducing DNA damage,epigenetic dysregulation,and immune microenvironment imbalance,driving inflammation-cancer conversion.Intestinal metaplasia and spasmolytic polypeptide-expressing metaplasia serve as critical precursor lesions,gradually developing into dysplasia and adenocarcinoma under the influence of chronic inflammation and genetic instability through intestinal cell transformation and high trefoil factor 2-expressing cell expansion.The immune suppression,metabolic reprogramming,and matrix remodeling within the tumor microenvironment collaboratively create a pro-cancer ecosystem that accelerates inflammationcarcinogenesis transformation.The gastric organoid model successfully simulates the spatiotemporal dynamics of the carcinogenesis process in atrophic gastritis,and its future integration with single-cell omics,real-time imaging technologies,and artificial intelligence technologies could provide a more precise platform for elucidating molecular mechanisms and screening intervention strategies.These advances position gastric organoids as pivotal tools for clinical translation,enabling personalized risk stratification,early intervention targeting precancerous transitions,and ex vivo prediction of patient-specific therapeutic responses to guide precision management of gastric cancer.
基金Supported by Chongqing Natural Science Foundation General Project,No.CSTB2023NSCQ-MSX0182 and No.CSTB2023NSCQMSX0252Clinical Research Special Project of The Second Affiliated Hospital of Army Medical University,No.2024 F022.
文摘BACKGROUND Liver metastases are very common in pancreatic neuroendocrine tumors(pNETs).When surgical resection is possible,it is typically associated with survival benefits in patients with pNET and liver metastases.Patient-derived organoids are a powerful preclinical platform that show great potential for predicting treatment response,and they have been increasingly applied in precision medicine and cancer research.CASE SUMMARY A 51-year-old man was admitted to the hospital with the chief complaint of in-termittent dull pain in the upper abdomen for over 3 years.Computerized to-mography showed multiple space-occupying lesions in the liver and a neoplasm in the pancreatic body.Pathological results suggested a grade 3 pancreas-derived hepatic neuroendocrine tumor.In combination with relevant examinations,the patient was diagnosed with pNET with liver metastases(grade 3).Transarterial chemoembolization was initially performed with oxaliplatin and 5-fluorouracil,after which the chemotherapy regimen was switched to liposomal irinotecan and cisplatin for a subsequent perfusion,guided by organoid-based drug sensitivity testing.Following interventional treatment,the tumor had decreased in size.However,due to poor treatment compliance and the patient’s preference for sur-INTRODUCTION Pancreatic neuroendocrine tumors(pNETs)are a rare and heterogeneous group of neoplasms arising from pancreatic islet cells,with variations in histology,clinical characteristics,and prognosis[1].They may present as non-infiltrative,slow-growing tumors,locally invasive tumors,or even rapidly metastasizing tumors[2].Most metastases localize to the liver,and approximately 28%-77%of patients with pNETs will experience liver metastases in their lifetime[3].Patients with liver metastases may be subjected to local complications such as biliary obstruction,liver insufficiency,and carcinoid syndrome.Additionally,liver metastases are a major risk factor for the prognosis of patients with pNETs[4].When feasible,surgical resection is significantly associated with the best long-term survival outcomes[5].Therefore,for patients with pNET liver metastases,comprehensive assessment and multidisciplinary approaches are required to determine the feasibility of surgical resection and the optimal treatment to improve the prognosis.Over the past decade,the advent of in vitro three-dimensional technologies including organoids has revolutionized the development of human cancer models.Patient-derived organoids(PDOs),an in vitro three-dimensional microstructure,can faithfully recapitulate the intricate spatial architecture and cell heterogeneity of the tissue,and simulate the biological behaviors and functions of parental tumors while preserving biological,genetic and molecular features[6,7].As a po-werful preclinical platform,PDOs have been increasingly applied in precision medicine and cancer research.Importantly,there is a significant association between the use of PDO-based drug sensitivity testing and clinical responses to chemotherapy,radiotherapy and targeted therapy in multiple cancer types[8-10].Although gastroenteropancreatic neuroendocrine neoplasm organoids have been confirmed to retain the pathohistological and functional phenotypes of parental tumors[7],their roles in the prediction of clinical outcomes have not been presented.Here,we report a case of pNET with liver metastases who successfully received surgical resection after personalized treatment guided by PDO-based drug sensitivity testing,resulting in a favorable prognosis.
基金supported by the National Key Research and Development Program of China(2021YFA1101800,2022YFA1104800,2023YFF1203600)National Natural Science Foundation of China(82325015,82171528,U23A20429,82371260,21904069,22274079,82401794)+2 种基金Jiangsu Provincial Natural Science Fund for Excellent Young Scholars(BK20240131)Natural Science Foundation of Jiangsu Province(BK20200677)Joint Project of the Yangtze River Delta Science and Technology Innovation Community(2024CSJZN0600)。
文摘Major depressive disorder(MDD)is a debilitating psychiatric condition associated with substantial personal,societal,and economic costs.Despite considerable advances in research,most conventional antidepressant therapies fail to achieve adequate response in a significant proportion of patients,underscoring the need for novel,mechanism-based interventions.Lycium barbarum glycopeptide(LbGp),a bioactive compound with emerging neuroprotective properties,has been proposed as a candidate for antidepressant development;however,its therapeutic efficacy and underlying mechanisms remain largely uncharacterized.In this study,ventral forebrain organoids were generated from patients with MDD to investigate disease-related neurophysiological abnormalities.These organoids exhibited disrupted neuronal morphology,diminished calcium signaling,and impaired electrophysiological activity.Administration of LbGp effectively restored structural and functional deficits in MDD-derived organoids.Transcriptomic profiling revealed that LbGp ameliorated endoplasmic reticulum(ER)stress responses.To investigate the causative role of ER stress,control organoids were treated with the ER stress agonist CCT020312,which elicited neural activity impairments resembling those observed in MDD organoids.Notably,LbGp reversed the phenotypic consequences of CCT020312 exposure in control organoids.In conclusion,ventral forebrain organoids derived from individuals with MDD demonstrated that LbGp ameliorates disease-associated phenotypes by modulating ER stress.
基金Supported by the National Natural Science Foundation of China(No.82070937).
文摘AIM:To explore the changes in early retinal development after the occurrence of ischemia.METHODS:Human retinal organoids(hROs)of day 18 or day 30 were treated with oxygen-glucose deprivation and reperfusion(OGD/R)to simulate the retinal ischemia.All hROs were maintained normally until day 60 to evaluate changes in ischemic injuries during retinal development.Paraffin section staining was used for detecting changes in organoid structure and cell number.Real-time quantitative polymerase chain reaction(RT-qPCR)and Western blot(WB)analyses were used to observe the change in the expression of retinal cell markers.RESULTS:In hROs,OGD/R induced the decrease of proliferating cells,inhibited the expression of proliferated marker Ki67 and promoted early apoptosis of retinal cells(P<0.05).Under OGD/R condition,the progenitor cell layer and ganglion cell layer of hROs lost normal structure,and the number of neural stem cells(SOX2^(+)),retinal progenitor cells(CHX10^(+))and retinal ganglion cells(TUJ1^(+)/BRN3^(+)/ATOH7^(+))decreased(P<0.05).The expression of corresponding retinal cell markers also decreased(P<0.05).Organoids treated with OGD/R on day 30 had similar injuries in retinal structure and retinal cell markers to those on day 18.Long-term observations revealed that day 18-treated organoids remained disorganized progenitor and ganglion cell layers by day 60,with no recovery in proliferating cell nuclear antigen(PCNA)protein expression.RT-qPCR showed persistently low Ki67 transcription levels(P<0.001),while other retinal cell markers recovered or exceeded normal levels,indicating a limited self-repair happened in the development of hROs.In contrast,day 30-treated organoids exhibited normal structure and marker expression by day 60,with transcription levels of retinal cell markers returning to normal(P>0.05),demonstrating complete recovery from OGD/R damage.CONCLUSION:Retinal ischemia damage the retinal development in the short-term.After the restoration of retinal blood supply,the retinal ischemic damage can be recovered during subsequent development.However,retinal ischemic injuries at different developmental stages exhibit varying degrees of reversibility.The earlier ischemic injury occurs,the more difficult it is to repair retinal cell and structure damage.
基金Supported by Key Research and Development Program of Zhejiang Province,No.2024C03172Clinical Medical Research Special Fund Project of Zhejiang Medical Association,No.2024ZYC-Z50.
文摘Hepatobiliary and pancreatic(HBP)cancers are among the most aggressive malig-nancies,with recurrence and metastasis driven by tumor heterogeneity and drug resistance,presenting considerable challenges to effective treatment.Currently,personalized and accurate treatment prediction models for these cancers are lacking.Patient-derived organoids(PDOs)tumor are three-dimensional in vitro models created from the tumor tissues of individual patients.Recent reports and our cultivation data indicate that the success rate of cultivating organoids for HBP cancers consistently exceeds 70%.The predictive accuracy of these tumor orga-noids has been shown to surpass 90%.However,PDOs still face notable limita-tions,especially in simulating the tumor microenvironment,including tumor angiogenesis and the surrounding cellular context,which require further refi-nement.While co-culture techniques and microfluidic platforms have been deve-loped to mimic multi-cellular environments and functional vascular perfusion,they remain insufficient in accurately recapitulating the complexities of the in vivo environment.Additionally,PDOs are needed to fully assess their potential in predicting the efficacy of multi-drug combination therapies.This review provides an overview of the applications,challenges,and prospects for organoid models in the study of HBP cancer.
基金supported by the National Natural Science Foundation of China(52076140).
文摘Organoids are three-dimensional structures derived from stem cells that recapitulate the gene expression profiles and functional characteristics of their tissue of origin,rendering them invaluable tools for disease modeling,drug screening,and precision medicine.Despite their promise,the widespread application of organoids is limited by extended culture durations and technical complexity.Cryopreservation has emerged as a critical strategy to overcome challenges related to the long-term storage and application of organoids,offering a range of preservation approaches tailored to organoid development.Nevertheless,conventional cryopreservation techniques encounter significant limitations when applied to organoids.To address these issues,the development of naturally derived,low-toxicity Cryoprotectants(CPAs),along with the optimization of CPA loading methods and refinement of cooling and warming protocols,is essential to mitigate cryoinjury.Looking forward,the comprehensive enhancement of cryopreservation technologies may facilitate the transformation of organoids into“off-the-shelf”products,enabling scalable production,batch standardization,and centralized distribution.Such advancements will lay the foundation for the establishment of Next-Generation Living Biobanks(NGLB).
