Objective:Migrasomes,an emerging class of migration-facilitating membranous extracellular vesicles,remain largely uncharted in the intricate landscape of tumor metastasis.This study aimed to illuminate the roles and m...Objective:Migrasomes,an emerging class of migration-facilitating membranous extracellular vesicles,remain largely uncharted in the intricate landscape of tumor metastasis.This study aimed to illuminate the roles and mechanisms underlying cancer cell-derived migrasomes in breast cancer brain metastasis(BCBM).Methods:Migrasomes were isolated and purified from BCBM cells(231-BR)and non-specific organotropic parental counterparts(MDA-MB-231),specifically designated as Mig-BCBM and Mig-BC,respectively.The role of Mig-BCBM in BCBM was investigated using an in vitro endothelial cell layer permeability model and a BCBM mouse model.The regulatory mechanism underlying Mig-BCBM was assessed using RT-qPCR,western blotting,immunofluorescence,ex vivo fluorescence imaging,and a series of rescue experiments.Results:Mig-BCBM potently augmented the permeability of vascular endothelial layers,which facilitated the efficient migration of 231-BR cells across endothelial barriers in vitro.The administration of Mig-BCBM significantly disrupted the blood-brain barrier(BBB)and accelerated BCBM progression in vivo,as evidenced in mouse models,compared to the Mig-BC and control groups.Mechanistically,Mig-BCBM harbored ATF6,a critical transducer of endoplasmic reticulum(ER)stress.Upon internalization into hCMEC/D3 cells,ATF6 elicited robust ER stress responses,culminating in downregulation of ZO-1 and VE-cadherin.Digital PCR analysis disclosed significant upregulation of ATF6 in serum migrasomes derived from BCBM patients compared to migrasomes from breast cancer patients and healthy individuals.Conclusions:This study uncovered a pivotal role of cancer cell-derived in BCBM by harnessing ATF6-mediated ER stress to disrupt the BBB and promote metastasis,suggesting novel diagnostic and therapeutic strategies targeting migrasomes and migrasome cargo.展开更多
Mesenchymal stem cells(MSCs),which are mechanosensitive cells,mediate the cells crosstalk in response to mechanical force,thereby playing a crucial role in bone homeostasis.Migrasomes serve as an important mediator fo...Mesenchymal stem cells(MSCs),which are mechanosensitive cells,mediate the cells crosstalk in response to mechanical force,thereby playing a crucial role in bone homeostasis.Migrasomes serve as an important mediator for cellular communication.However,whether the mechanical stimulus regulates the biology and property of migrasomes on bone metabolism remains unknown.This study shows that mechanical stimulus could promote MSCs to synthesize and secrete migrasomes,which could significantly alleviate chronic infectious bone destruction in periodontal tissue by inhibiting osteoclastic differentiation of macrophage and reestablishing local immune microenvironment.Mechanistically,miR-29b-3p is more abundant in migrasomes from mechanical force stimulated MSCs than in control ones.MiR-29b-3p blocks the activation of pyrin domain containing protein 3(NLRP3)and mitochondrial DNA(mtDNA)release by directly targeting on Tet1.Thus,mechanical sensing migrasomes inhibit osteoclast differentiation to alleviate inflammation induced bone destruction.These findings reveal that the mechanical stimulus controls the formation and properties of migrasomes,which provides a new biotechnological strategy for chronic infectious bone destruction intervention.展开更多
Viruses have evolved diverse strategies to propagate between cells.Classical paradigms describe two primary transmission modes:cell-free diffusion,where virions navigate extracellular spaces to initiate new infections...Viruses have evolved diverse strategies to propagate between cells.Classical paradigms describe two primary transmission modes:cell-free diffusion,where virions navigate extracellular spaces to initiate new infections,and direct cell-to-cell spread that minimizes exposure to host immunity[1,2].In recent years,a third mechanism has emerged wherein viruses exploit extracellular vesicles(EVs)as intercellular transmission carriers.Diverse EV subtypes,including exosomes,secretory lysosomes,and apoptotic bodies,have been shown to encapsulate clusters of viral particles for intercellular transmission[3].However,the full repertoire of vesicle-mediated viral spread remains incompletely cataloged,particularly regarding heterogenous structures with specialized biogenesis pathways.展开更多
Chikungunya virus(CHIKV)infection induces the formation of migrasomes,yet their specific role in CHIKV pathogenesis remains unclear.This study explores the mechanisms underlying mitochondrial damage induced by CHIKV 1...Chikungunya virus(CHIKV)infection induces the formation of migrasomes,yet their specific role in CHIKV pathogenesis remains unclear.This study explores the mechanisms underlying mitochondrial damage induced by CHIKV 181 clone 25(CHIKV 181/25)and the role of migrasomes in mitigating this damage.Using cultured cell lines,we assessed the impact of CHIKV infection on mitochondrial integrity and function,with particular emphasis on the viroporin proteins transframe(TF)and 6K.We utilized fluorescence microscopy and transmission electron microscopy to visualize the interplay between migrasome formation and damaged mitochondria.Additionally,calcium imaging assays were conducted to evaluate intracellular calcium levels,and RNA sequencing was performed to examine gene expression.Our results demonstrated that CHIKV infection leads to mitochondrial damage,mediated by the action of TF and 6K.Notably,migrasomes induced by nonstructural protein 1(nsP1)effectively clearing impaired mitochondria through mitocytosis.Furthermore,we identified the arginine residue R37 within the viroporin proteins of CHIKV as crucial for inducing mitochondrial damage through elevated intracellular calcium levels.Importantly,R37 within TF from other alphaviruses is also critical for mitochondrial damage.In conclusion,our findings elucidate the complex interplay between CHIKV and mitochondrial dysfunction,positioning migrasomes as potential mediators in alleviating CHIKVinduced mitochondrial damage.展开更多
A recent study suggests that low-intensity pulsed ultrasound selectively eliminates damaged mitochondria by promoting migrasome formation during myocardial ischemia-reperfusion injury,thereby enhancing mitochondrial q...A recent study suggests that low-intensity pulsed ultrasound selectively eliminates damaged mitochondria by promoting migrasome formation during myocardial ischemia-reperfusion injury,thereby enhancing mitochondrial quality control and reducing cardiomyocyte damage.−This discovery first proposes the specific role and mechanism of migrasomes in the heart and provides preliminary evidence for their protective function against cardiomyocyte damage.展开更多
Mitochondria are essential for meeting cardiac metabolic demands and their dysfunction is associated with heart failure and is a key mediator of cardiac ischemia–reperfusion injury.Cardiomyocytes engage integrated me...Mitochondria are essential for meeting cardiac metabolic demands and their dysfunction is associated with heart failure and is a key mediator of cardiac ischemia–reperfusion injury.Cardiomyocytes engage integrated mechanisms to maintain mitochondrial function;however,chronic stress or disease can overwhelm this capacity.The removal of damaged mitochondria is mediated by a process known as mitophagy,which,together with mitochondrial biogenesis,plays a key role in maintaining mitochondrial quality control.Maintenance of mitochondrial quality control was initially thought to be autonomously regulated within each cellular population with little exchange between cells.However,recently the phenomenon of transmitophagy has been identified in which damaged mitochondria are transferred to neighboring cells for degradation.This review discusses the current understanding of transmitophagy in the context of heart injury,aging and disease,with particular emphasis on exophers,migrasomes,and tunneling nanotubes as pathways mediating cell–cell communication between cardiomyocytes,macrophages and fibroblasts.We further discuss the potential of targeting transmitophagy for cardioprotection and highlight key unanswered questions and challenges.Addressing these gaps may reveal novel strategies to preserve mitochondrial homeostasis and improve the outcomes of patients with cardiovascular disease.展开更多
Current treatments for cerebral amyloid angiopathy are mainly symptomatic and have limited efficacy,and there is a lack of targeted therapies.Mesenchymal stem cell transplantation improves cognitive and motor function...Current treatments for cerebral amyloid angiopathy are mainly symptomatic and have limited efficacy,and there is a lack of targeted therapies.Mesenchymal stem cell transplantation improves cognitive and motor function in conditions such as Alzheimer’s disease,acute ischemic stroke,and Parkinson’s disease.In addition,mesenchymal stem cell therapy modulates the immune system,reduces neuroinflammation,and improves resolution of brain lesions by cells of the macrophage lineage.Cerebral amyloid angiopathy and Alzheimer’s disease share similar pathologic changes involving amyloid-beta deposition,which contributes to the progression of both diseases and exacerbates cognitive deficits through impaired vascular integrity and neuroinflammation.Therefore,we hypothesized that mesenchymal stem cell therapy could also ameliorate the pathological changes seen in cerebral amyloid angiopathy by modulating the immune response.In this study,we show that bone marrow mesenchymal stem cells have a protective effect in a mouse model of cerebral amyloid angiopathy(Tg-SwDI/B).Bone marrow mesenchymal stem cell treatment improved cognitive function,reduced neuroinflammation,and maintained blood-brain barrier integrity in Tg-SwDI/B mice.Mechanistically,bone marrow mesenchymal stem cell treatment enhanced the expulsion of damaged mitochondria from neutrophils via migrasomes,in a process known as mitocytosis,thereby preserving mitochondrial quality within the neutrophils.Mitochondrial damage in neutrophils leads to cellular injury,including the generation of reactive oxygen species and the formation of neutrophil extracellular traps.Neutrophils activate mitocytosis to promote mitochondrial renewal,which further enhances their own clearance by macrophage lineage cells.Our findings demonstrate that bone marrow mesenchymal stem cells are a promising therapeutic candidate for cerebral amyloid angiopathy,as they play a significant role in migrasome-dependent mitochondrial quality control in neutrophils.展开更多
基金supported by the National Natural Science Foundation of China(Grant No.81702884)Natural Science Foundation of Shandong Province(Grant Nos.ZR2022MH272,ZR2020QH216,and ZR2023QH115)Medicine and Health Science and Technology Foundation of Shandong Province(Grant Nos.202402060623 and 202202080721).
文摘Objective:Migrasomes,an emerging class of migration-facilitating membranous extracellular vesicles,remain largely uncharted in the intricate landscape of tumor metastasis.This study aimed to illuminate the roles and mechanisms underlying cancer cell-derived migrasomes in breast cancer brain metastasis(BCBM).Methods:Migrasomes were isolated and purified from BCBM cells(231-BR)and non-specific organotropic parental counterparts(MDA-MB-231),specifically designated as Mig-BCBM and Mig-BC,respectively.The role of Mig-BCBM in BCBM was investigated using an in vitro endothelial cell layer permeability model and a BCBM mouse model.The regulatory mechanism underlying Mig-BCBM was assessed using RT-qPCR,western blotting,immunofluorescence,ex vivo fluorescence imaging,and a series of rescue experiments.Results:Mig-BCBM potently augmented the permeability of vascular endothelial layers,which facilitated the efficient migration of 231-BR cells across endothelial barriers in vitro.The administration of Mig-BCBM significantly disrupted the blood-brain barrier(BBB)and accelerated BCBM progression in vivo,as evidenced in mouse models,compared to the Mig-BC and control groups.Mechanistically,Mig-BCBM harbored ATF6,a critical transducer of endoplasmic reticulum(ER)stress.Upon internalization into hCMEC/D3 cells,ATF6 elicited robust ER stress responses,culminating in downregulation of ZO-1 and VE-cadherin.Digital PCR analysis disclosed significant upregulation of ATF6 in serum migrasomes derived from BCBM patients compared to migrasomes from breast cancer patients and healthy individuals.Conclusions:This study uncovered a pivotal role of cancer cell-derived in BCBM by harnessing ATF6-mediated ER stress to disrupt the BBB and promote metastasis,suggesting novel diagnostic and therapeutic strategies targeting migrasomes and migrasome cargo.
基金supported by the National Key Research and Development Program of China(No.2022YFA1105800(R.L.Y.))Clinical Medicine Plus X-Young Scholars Project of Peking University(No.2025PKULCXQ015(R.L.Y.))+2 种基金Research Foundation of Peking University School and Hospital of Stomatology(No.PKUSS20230103)the Fundamental Research Funds for the Central Universities-Peking University Clinical Scientist Training Program(No.L232107(R.L.Y.))Beijing Municipal Natural Science Foundation-Haidian Original Innovation Joint Fund(Nos.L222001(Xiaomo Liu)and L232107(Jie Shi)).
文摘Mesenchymal stem cells(MSCs),which are mechanosensitive cells,mediate the cells crosstalk in response to mechanical force,thereby playing a crucial role in bone homeostasis.Migrasomes serve as an important mediator for cellular communication.However,whether the mechanical stimulus regulates the biology and property of migrasomes on bone metabolism remains unknown.This study shows that mechanical stimulus could promote MSCs to synthesize and secrete migrasomes,which could significantly alleviate chronic infectious bone destruction in periodontal tissue by inhibiting osteoclastic differentiation of macrophage and reestablishing local immune microenvironment.Mechanistically,miR-29b-3p is more abundant in migrasomes from mechanical force stimulated MSCs than in control ones.MiR-29b-3p blocks the activation of pyrin domain containing protein 3(NLRP3)and mitochondrial DNA(mtDNA)release by directly targeting on Tet1.Thus,mechanical sensing migrasomes inhibit osteoclast differentiation to alleviate inflammation induced bone destruction.These findings reveal that the mechanical stimulus controls the formation and properties of migrasomes,which provides a new biotechnological strategy for chronic infectious bone destruction intervention.
基金supported by the Ministry of Science and Technology of the People’s Republic of China(2022ZD0212900)the National Natural Science Foundation of China(32300570)+3 种基金the Beijing Natural Science Foundation(5244036)the National Key Research and Development Program of China(2023YFF0613402)the Clinical Medicine Plus X-Young Scholars Project of Peking University(PKU2025PKULCXQ013)the Research Funds from Health@InnoHK Program launched by Innovation Technology Commission of the Hong Kong Special Administrative Region.
文摘Viruses have evolved diverse strategies to propagate between cells.Classical paradigms describe two primary transmission modes:cell-free diffusion,where virions navigate extracellular spaces to initiate new infections,and direct cell-to-cell spread that minimizes exposure to host immunity[1,2].In recent years,a third mechanism has emerged wherein viruses exploit extracellular vesicles(EVs)as intercellular transmission carriers.Diverse EV subtypes,including exosomes,secretory lysosomes,and apoptotic bodies,have been shown to encapsulate clusters of viral particles for intercellular transmission[3].However,the full repertoire of vesicle-mediated viral spread remains incompletely cataloged,particularly regarding heterogenous structures with specialized biogenesis pathways.
基金supported by grants from Prevention and Control of Emerging and Major Infectious Diseases-National Science and Technology Major Project(grant number 2025ZD01903602 to L.Z.)Shandong Provincial Natural Science Foundation(grant number ZR2024MH017 to L.Z.)+2 种基金National Natural Science Foundation of China(grant numbers 82272306 and 82072270 to L.Z.)Taishan Scholars Program(grant number tstp20221142 to L.Z.)Joint Innovation Team for Clinical&Basic Research(grant number 202409 to L.Z.)。
文摘Chikungunya virus(CHIKV)infection induces the formation of migrasomes,yet their specific role in CHIKV pathogenesis remains unclear.This study explores the mechanisms underlying mitochondrial damage induced by CHIKV 181 clone 25(CHIKV 181/25)and the role of migrasomes in mitigating this damage.Using cultured cell lines,we assessed the impact of CHIKV infection on mitochondrial integrity and function,with particular emphasis on the viroporin proteins transframe(TF)and 6K.We utilized fluorescence microscopy and transmission electron microscopy to visualize the interplay between migrasome formation and damaged mitochondria.Additionally,calcium imaging assays were conducted to evaluate intracellular calcium levels,and RNA sequencing was performed to examine gene expression.Our results demonstrated that CHIKV infection leads to mitochondrial damage,mediated by the action of TF and 6K.Notably,migrasomes induced by nonstructural protein 1(nsP1)effectively clearing impaired mitochondria through mitocytosis.Furthermore,we identified the arginine residue R37 within the viroporin proteins of CHIKV as crucial for inducing mitochondrial damage through elevated intracellular calcium levels.Importantly,R37 within TF from other alphaviruses is also critical for mitochondrial damage.In conclusion,our findings elucidate the complex interplay between CHIKV and mitochondrial dysfunction,positioning migrasomes as potential mediators in alleviating CHIKVinduced mitochondrial damage.
基金supported by the National Natural Science Foundation of China(No.82400362)the National Natural Science Foundation of China(No.82200095).
文摘A recent study suggests that low-intensity pulsed ultrasound selectively eliminates damaged mitochondria by promoting migrasome formation during myocardial ischemia-reperfusion injury,thereby enhancing mitochondrial quality control and reducing cardiomyocyte damage.−This discovery first proposes the specific role and mechanism of migrasomes in the heart and provides preliminary evidence for their protective function against cardiomyocyte damage.
文摘Mitochondria are essential for meeting cardiac metabolic demands and their dysfunction is associated with heart failure and is a key mediator of cardiac ischemia–reperfusion injury.Cardiomyocytes engage integrated mechanisms to maintain mitochondrial function;however,chronic stress or disease can overwhelm this capacity.The removal of damaged mitochondria is mediated by a process known as mitophagy,which,together with mitochondrial biogenesis,plays a key role in maintaining mitochondrial quality control.Maintenance of mitochondrial quality control was initially thought to be autonomously regulated within each cellular population with little exchange between cells.However,recently the phenomenon of transmitophagy has been identified in which damaged mitochondria are transferred to neighboring cells for degradation.This review discusses the current understanding of transmitophagy in the context of heart injury,aging and disease,with particular emphasis on exophers,migrasomes,and tunneling nanotubes as pathways mediating cell–cell communication between cardiomyocytes,macrophages and fibroblasts.We further discuss the potential of targeting transmitophagy for cardioprotection and highlight key unanswered questions and challenges.Addressing these gaps may reveal novel strategies to preserve mitochondrial homeostasis and improve the outcomes of patients with cardiovascular disease.
基金Guangdong Basic and Applied Basic Research Foundation,No.2023A1515110543(to XK)National Natural Science Foundation of China,Nos.82471335 and 82171307(to ZL)+3 种基金Noncommunicable Chronic Diseases-National Science and Technology Major Project,No.2023ZD0504803(to ZL)Science and Technology Program of Guangzhou,No.202201020588(to ZL)China Postdoctoral Science Foundation,No.2023M744023(to MH)Guangzhou Municipal School(Hospital)Joint Funding(Dengfeng Hospital)Municipal Key Laboratory Construction Project,No.202102010009(to ZL).
文摘Current treatments for cerebral amyloid angiopathy are mainly symptomatic and have limited efficacy,and there is a lack of targeted therapies.Mesenchymal stem cell transplantation improves cognitive and motor function in conditions such as Alzheimer’s disease,acute ischemic stroke,and Parkinson’s disease.In addition,mesenchymal stem cell therapy modulates the immune system,reduces neuroinflammation,and improves resolution of brain lesions by cells of the macrophage lineage.Cerebral amyloid angiopathy and Alzheimer’s disease share similar pathologic changes involving amyloid-beta deposition,which contributes to the progression of both diseases and exacerbates cognitive deficits through impaired vascular integrity and neuroinflammation.Therefore,we hypothesized that mesenchymal stem cell therapy could also ameliorate the pathological changes seen in cerebral amyloid angiopathy by modulating the immune response.In this study,we show that bone marrow mesenchymal stem cells have a protective effect in a mouse model of cerebral amyloid angiopathy(Tg-SwDI/B).Bone marrow mesenchymal stem cell treatment improved cognitive function,reduced neuroinflammation,and maintained blood-brain barrier integrity in Tg-SwDI/B mice.Mechanistically,bone marrow mesenchymal stem cell treatment enhanced the expulsion of damaged mitochondria from neutrophils via migrasomes,in a process known as mitocytosis,thereby preserving mitochondrial quality within the neutrophils.Mitochondrial damage in neutrophils leads to cellular injury,including the generation of reactive oxygen species and the formation of neutrophil extracellular traps.Neutrophils activate mitocytosis to promote mitochondrial renewal,which further enhances their own clearance by macrophage lineage cells.Our findings demonstrate that bone marrow mesenchymal stem cells are a promising therapeutic candidate for cerebral amyloid angiopathy,as they play a significant role in migrasome-dependent mitochondrial quality control in neutrophils.
