Adenomyosis remains a challenging gynecological disorder to investigate due to the absence of in vitro models that accurately replicate endometrial tissue dynamics across the menstrual cycle.To address this gap,we est...Adenomyosis remains a challenging gynecological disorder to investigate due to the absence of in vitro models that accurately replicate endometrial tissue dynamics across the menstrual cycle.To address this gap,we established an endometrial assembloid model that faithfully mimics cycle-dependent endometrial responses and captures key cellular and molecular hallmarks of adenomyosis,including ectopic lesionspecific epithelial and stromal heterogeneity.Single-cell transcriptomics revealed that ectopic epithelial cells shift toward a luminaldominant,glandular-deficient transcriptional profile during the secretory-like phase.This transition correlated with ectopic stromal reorganization—specifically,loss of BMP4^(+)stromal cells and an accumulation of CRYAB^(+)IL15^(+)stromal cells—which impaired BMP-mediated stromal-epithelial signaling while enhancing WNT activation.Additionally,ectopic epithelial and stromal cells demonstrated increased immunity and angiogenesis activities.Our assembloid platform not only provides a physiologically relevant model for investigating adenomyosis pathogenesis but also implicates aberrant WNT signaling as a potential therapeutic target,offering new opportunities for mechanism-driven treatment strategies.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
Brain diseases affect 1 in 6 people worldwide.These diseases range from acute neurological conditions such as stroke to chronic neurodegenerative disorders such as Alzheimer’s disease.Recent advancements in tissue-en...Brain diseases affect 1 in 6 people worldwide.These diseases range from acute neurological conditions such as stroke to chronic neurodegenerative disorders such as Alzheimer’s disease.Recent advancements in tissue-engineered brain disease models have overcome many of the different shortcomings associated with the various animal models,tissue culture models,and epidemiologic patient data that are commonly used to study brain disease.One innovative method by which to model human neurological disease is via the directed differentiation of human pluripotent stem cells(hPSCs)to neural lineages including neurons,astrocytes,and oligodendrocytes.Three-dimensional models such as brain organoids have also been derived from hPSCs,offering more physiological relevance due to their incorporation of various cell types.As such,brain organoids can better model the pathophysiology of neural diseases observed in patients.In this review,we will emphasize recent developments in hPSC-based tissue culture models of neurological disorders and how they are being used to create neural disease models.展开更多
背景:近年来,许多研究证实类装配体可弥补类器官无法完全重现细胞与细胞、细胞与基质间的互作关系的缺点,但处于发展初期的类装配体构建方式种类繁多,更无统一标准。目的:综述目前类装配体的构建方法、应用和优缺点,为促进体外细胞模型...背景:近年来,许多研究证实类装配体可弥补类器官无法完全重现细胞与细胞、细胞与基质间的互作关系的缺点,但处于发展初期的类装配体构建方式种类繁多,更无统一标准。目的:综述目前类装配体的构建方法、应用和优缺点,为促进体外细胞模型的发展和完善提供指导。方法:以“assembloids,organoids,tumor microenvironment,organoids AND assemble,organoids AND microenvironment”为英文检索词,以“类装配体、类器官、类组装体、肿瘤微环境、类器官重组、多细胞模型”为中文检索词,检索PubMed、中国知网及万方数据库,在排除无关文章及去重后筛选出94篇文章进行综述。结果与结论:①根据细胞来源的不同,可将类装配体的构建方法分为自体组装、直接组装及混合组装3种;根据细胞培养方式的差异,又可分为悬浮培养法、“基质”培养法、器官芯片培养法和3D生物打印法。②自体组装过程涵盖细胞和组织的发育等早期过程,因此,在器官发育和发育障碍等领域有广阔的前景,而分化成熟细胞的功能相对较完善,由它们直接组装成的类装配体在功能障碍及细胞损伤性疾病的研究中更具潜力;自体组装或在器官移植方面更胜一筹,直接组装将更适用于组织损伤的修复,混合组装综合了前两者的优势,多用于探索微环境中细胞的生理和病理机制以及药物筛选等领域。③虽然不同的类装配体各具优势,但都面临脉管系统不完善的难题;每种类装配体构建方法也存在各自的局限性,如自体组装形成的类装配体中细胞分化程度与体内的差异,直接组装模型的细胞种类固定、无法完全反映复杂的体内微环境等均是亟待解决的难题。④将来随着类装配体培养技术的不断完善,研究者们可以在体外组装出具有更复杂组织结构的仿生类器官,为研究人类组织和器官生理及病理过程提供无限趋近真实的模型。展开更多
Organoids have emerged as a powerful platform for studying complex biological processes and diseases in vitro.However,most studies have focused on individual organoids,overlooking the inter-organ interactions in vivo ...Organoids have emerged as a powerful platform for studying complex biological processes and diseases in vitro.However,most studies have focused on individual organoids,overlooking the inter-organ interactions in vivo and limiting the physiological relevance of the models.To address this limitation,the development of a multi-organoid system has gained considerable attention.This system aims to recapitulate inter-organ communication and enable the study of complex physiological processes.This review provides a comprehensive overview of the recent advancements in organoid engineering and the emerging strategies for constructing a multi-organoid system.First,we highlight the critical mechanical,structural,and biochemical factors involved in designing suitable materials for the growth of different organoids.Additionally,we discuss the incorporation of dynamic culture environments to enhance organoid culture and enable inter-organoid communication.Furthermore,we explore techniques for manipulating organoid morphogenesis and spatial positioning of organoids to establish effective inter-organoid communication networks.We summarize the achievements in utilizing organoids to recapitulate inter-organ communication in vitro,including assembloids and microfluidic multiorganoid platforms.Lastly,we discuss the existing challenges and opportunities in developing a multi-organoid system from its technical bottlenecks in scalability to its applications toward complex human diseases.展开更多
基金supported by the National Natural Science Foundation of China(82488101 to S.G)the National Natural Science Foundation of China(82471684 to X.C.,32330030 to S.G.,32270840 to L.W.,32270908 to X.X.)+3 种基金the National Key Research and Development Program of China(2023YFA1800300 to X.X.,2023YFA1801800 to L.W.,2022YFC2702200 to S.G.)Science and Technology Commission of Shanghai Municipality(23JC1403700)Shanghai Key Laboratory of Maternal-Fetal Medicine(mfmkf202201)the Natural Science Foundation of Zhejiang Province(LTGY24H040002)。
文摘Adenomyosis remains a challenging gynecological disorder to investigate due to the absence of in vitro models that accurately replicate endometrial tissue dynamics across the menstrual cycle.To address this gap,we established an endometrial assembloid model that faithfully mimics cycle-dependent endometrial responses and captures key cellular and molecular hallmarks of adenomyosis,including ectopic lesionspecific epithelial and stromal heterogeneity.Single-cell transcriptomics revealed that ectopic epithelial cells shift toward a luminaldominant,glandular-deficient transcriptional profile during the secretory-like phase.This transition correlated with ectopic stromal reorganization—specifically,loss of BMP4^(+)stromal cells and an accumulation of CRYAB^(+)IL15^(+)stromal cells—which impaired BMP-mediated stromal-epithelial signaling while enhancing WNT activation.Additionally,ectopic epithelial and stromal cells demonstrated increased immunity and angiogenesis activities.Our assembloid platform not only provides a physiologically relevant model for investigating adenomyosis pathogenesis but also implicates aberrant WNT signaling as a potential therapeutic target,offering new opportunities for mechanism-driven treatment strategies.
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CTSA Award from the National Center for Advancing Translational Sciences to the Vanderbilt Institute for Clinical and Translational Research,No.UL1 TR002243A Pilot and Feasibility Award from the NIDDK to the Vanderbilt Diabetes Research and Training Center,No.DK020593a VA MERIT Award,No.BX004845.
文摘Brain diseases affect 1 in 6 people worldwide.These diseases range from acute neurological conditions such as stroke to chronic neurodegenerative disorders such as Alzheimer’s disease.Recent advancements in tissue-engineered brain disease models have overcome many of the different shortcomings associated with the various animal models,tissue culture models,and epidemiologic patient data that are commonly used to study brain disease.One innovative method by which to model human neurological disease is via the directed differentiation of human pluripotent stem cells(hPSCs)to neural lineages including neurons,astrocytes,and oligodendrocytes.Three-dimensional models such as brain organoids have also been derived from hPSCs,offering more physiological relevance due to their incorporation of various cell types.As such,brain organoids can better model the pathophysiology of neural diseases observed in patients.In this review,we will emphasize recent developments in hPSC-based tissue culture models of neurological disorders and how they are being used to create neural disease models.
文摘背景:近年来,许多研究证实类装配体可弥补类器官无法完全重现细胞与细胞、细胞与基质间的互作关系的缺点,但处于发展初期的类装配体构建方式种类繁多,更无统一标准。目的:综述目前类装配体的构建方法、应用和优缺点,为促进体外细胞模型的发展和完善提供指导。方法:以“assembloids,organoids,tumor microenvironment,organoids AND assemble,organoids AND microenvironment”为英文检索词,以“类装配体、类器官、类组装体、肿瘤微环境、类器官重组、多细胞模型”为中文检索词,检索PubMed、中国知网及万方数据库,在排除无关文章及去重后筛选出94篇文章进行综述。结果与结论:①根据细胞来源的不同,可将类装配体的构建方法分为自体组装、直接组装及混合组装3种;根据细胞培养方式的差异,又可分为悬浮培养法、“基质”培养法、器官芯片培养法和3D生物打印法。②自体组装过程涵盖细胞和组织的发育等早期过程,因此,在器官发育和发育障碍等领域有广阔的前景,而分化成熟细胞的功能相对较完善,由它们直接组装成的类装配体在功能障碍及细胞损伤性疾病的研究中更具潜力;自体组装或在器官移植方面更胜一筹,直接组装将更适用于组织损伤的修复,混合组装综合了前两者的优势,多用于探索微环境中细胞的生理和病理机制以及药物筛选等领域。③虽然不同的类装配体各具优势,但都面临脉管系统不完善的难题;每种类装配体构建方法也存在各自的局限性,如自体组装形成的类装配体中细胞分化程度与体内的差异,直接组装模型的细胞种类固定、无法完全反映复杂的体内微环境等均是亟待解决的难题。④将来随着类装配体培养技术的不断完善,研究者们可以在体外组装出具有更复杂组织结构的仿生类器官,为研究人类组织和器官生理及病理过程提供无限趋近真实的模型。
基金Health and Medical Research Fund Scheme,Grant/Award Numbers:01150087,16172691Research Grants Council of Hong Kong ECS,Grant/Award Number:PolyU 251008/18 M+4 种基金GRF,Grant/Award Numbers:PolyU 151061/20 M,PolyU15100821MNFSC/RGC schemes,Grant/Award Number:N_PolyU 520/20ITF MHKJFS,Grant/Award Numbers:MHP/011/20,MHP/037/23,2023YFE0210500Hong Kong Polytechnic University Project of Strategic Importance,Grant/Award Number:ZE2CBrigham Research Institute。
文摘Organoids have emerged as a powerful platform for studying complex biological processes and diseases in vitro.However,most studies have focused on individual organoids,overlooking the inter-organ interactions in vivo and limiting the physiological relevance of the models.To address this limitation,the development of a multi-organoid system has gained considerable attention.This system aims to recapitulate inter-organ communication and enable the study of complex physiological processes.This review provides a comprehensive overview of the recent advancements in organoid engineering and the emerging strategies for constructing a multi-organoid system.First,we highlight the critical mechanical,structural,and biochemical factors involved in designing suitable materials for the growth of different organoids.Additionally,we discuss the incorporation of dynamic culture environments to enhance organoid culture and enable inter-organoid communication.Furthermore,we explore techniques for manipulating organoid morphogenesis and spatial positioning of organoids to establish effective inter-organoid communication networks.We summarize the achievements in utilizing organoids to recapitulate inter-organ communication in vitro,including assembloids and microfluidic multiorganoid platforms.Lastly,we discuss the existing challenges and opportunities in developing a multi-organoid system from its technical bottlenecks in scalability to its applications toward complex human diseases.
