A large number of apoptotic vesicles(ApoVs)are released during apoptosis,and mesenchymal stem cells(MSCs)-derived ApoVs(MSC-ApoVs)have significant efficacy in the field of tissue regeneration.ApoVs extracted by densit...A large number of apoptotic vesicles(ApoVs)are released during apoptosis,and mesenchymal stem cells(MSCs)-derived ApoVs(MSC-ApoVs)have significant efficacy in the field of tissue regeneration.ApoVs extracted by density gradient centrifugation have a larger volume and wider diameter distribution,high yield and drug loading efficiency,and inherit the apoptotic traces of FasL,phosphatidylserine(PS),ICAM-3,and other parent cells and the ability to target cell membranes.MSC-ApoVs can significantly promote skin wound healing;however,whether they can promote wound healing in the early stages by playing an antibacterial role is unclear.In the present study,human umbilical cord MSC-derived ApoVs(hucMSC-ApoVs)were extracted and prepared.An in vitro antibacterial test confirmed that hucMSC-ApoVs effectively inhibited the growth of bacteria and sterilized bacteria.In vivo experiments revealed that hucMSC-ApoVs can accelerate the healing of infected wounds.Further exploration of the antibacterial mechanism revealed that hucMSC-ApoVs significantly interfered with bacterial catabolic processes.In gram-positive bacteria(MRSA),hucMSC-ApoVs affect the normal metabolic process of bacteria mainly by inhibiting the metabolism of purines,pyrimidines,and other nucleotides of MRSA and arginine biosynthesis,whereas in the gram-negative bacteria E.coli,they affect this process.HucMSC-ApoVs inhibit bacterial metabolic processes such as sulfur,fatty acid,arginine,and proline metabolism;in particular,hucMSC-ApoVs can interfere with the ethanolamine metabolic process in E.coli by regulating a series of ethanolamine genes(Eut)that encode ethanolamine degrading enzymes.These findings suggest that hucMSC-ApoVs are useful natural reagents for inhibiting wound bacterial infection and promoting wound healing.展开更多
Utilizing transplanted human umbilical cord mesenchymal stem cells(HUMSCs)for cartilage defects yielded advanced tissue regeneration,but the underlying mechanism remain elucidated.Early after HUMSCs delivery to the de...Utilizing transplanted human umbilical cord mesenchymal stem cells(HUMSCs)for cartilage defects yielded advanced tissue regeneration,but the underlying mechanism remain elucidated.Early after HUMSCs delivery to the defects,we observed substantial apoptosis.The released apoptotic vesicles(apoVs)of HUMSCs promoted cartilage regeneration by alleviating the chondro-immune microenvironment.ApoVs triggered M2 polarization in macrophages while simultaneously facilitating the chondrogenic differentiation of endogenous MSCs.Mechanistically,in macrophages,miR-100-5p delivered by apoVs activated the MAPK/ERK signaling pathway to promote M2 polarization.In MSCs,let-7i-5p delivered by apoVs promoted chondrogenic differentiation by targeting the eEF2K/p38 MAPK axis.Consequently,a cell-free cartilage regeneration strategy using apoVs combined with a decellularized cartilage extracellular matrix(DCM)scaffold effectively promoted the regeneration of osteochondral defects.Overall,new mechanisms of cartilage regeneration by transplanted MSCs were unconcealed in this study.Moreover,we provided a novel experimental basis for cell-free tissue engineering-based cartilage regeneration utilizing apoVs.Utilizing transplanted human umbilical cord mesenchymal stem cells(HUMSCs)for cartilage defects yielded advanced tissue regeneration,but the underlying mechanism remain elucidated.Early after HUMSCs delivery to the defects,we observed substantial apoptosis.The released apoptotic vesicles(apoVs)of HUMSCs promoted cartilage regeneration by alleviating the chondro-immune microenvironment.ApoVs triggered M2 polarization in macrophages while simultaneously facilitating the chondrogenic differentiation of endogenous MSCs.Mechanistically,in macrophages,miR-100-5p delivered by apoVs activated the MAPK/ERK signaling pathway to promote M2 polarization.In MSCs,let-7i-5p delivered by apoVs promoted chondrogenic differentiation by targeting the eEF2K/p38 MAPK axis.Consequently,a cell-free cartilage regeneration strategy using apoVs combined with a decellularized cartilage extracellular matrix(DCM)scaffold effectively promoted the regeneration of osteochondral defects.Overall,new mechanisms of cartilage regeneration by transplanted MSCs were unconcealed in this study.Moreover,we provided a novel experimental basis for cell-free tissue engineering-based cartilage regeneration utilizing apoVs.展开更多
Aging skeletons display decreased bone mass,increased marrow adiposity,and impaired bone marrow mesenchymal stem cells(MSCs).Apoptosis is a programmed cell death process that generates a large number of apoptotic vesi...Aging skeletons display decreased bone mass,increased marrow adiposity,and impaired bone marrow mesenchymal stem cells(MSCs).Apoptosis is a programmed cell death process that generates a large number of apoptotic vesicles(apoVs).Dysregulated apoptosis has been closely linked to senescence-associated diseases.However,whether apoVs mediate agingrelated bone loss is not clear.In this study,we showed that young MSC-derived apoVs effectively rejuvenated the nuclear abnormalities of aged bone marrow MSCs and restored their impaired self-renewal,osteo-/adipo-genic lineage differentiation capacities via activating autophagy.Mechanistically,apoptotic young MSCs generated and enriched a high level of Ras-related protein 7(Rab7)into apoVs.Subsequently,recipient aged MSCs reused apoV-derived Rab7 to restore autolysosomes formation,thereby contributing to autophagy flux activation and MSC rejuvenation.Moreover,systemic infusion of young MSC-derived apoVs enhanced bone mass,reduced marrow adiposity,and recused the impairment of recipient MSCs in aged mice.Our findings reveal the role of apoVs in rejuvenating aging-MSCs via restoring autolysosome formation and provide a potential approach for treating age-related bone loss.展开更多
Rheumatoid arthritis(RA)is a severe autoimmune disease with symptoms including synovial inflammation,cartilage erosion,and bone loss in RA lesions,which eventually lead to joint deformity and function loss.Most curren...Rheumatoid arthritis(RA)is a severe autoimmune disease with symptoms including synovial inflammation,cartilage erosion,and bone loss in RA lesions,which eventually lead to joint deformity and function loss.Most current treatments fail to achieve satisfying therapeutic outcomes with some adverse effects.Extracellular vesicles derived from apoptotic cells(apoEVs)have emerged as important mediators in intercellular communication regulating diverse physiological and pathological processes.In this study,we investigated the therapeutic efficacy of macrophage-derived and osteoclast-derived apoEVs(Mφ-apoEVs and OC-apoEVs)on RA.The in vitro results showed that both Mφ-apoEVs and OC-apoEVs induced macrophage repolarization toward the anti-inflammatory M2 phenotype,promoted chondrocyte functions and chondrogenesis,and inhibited osteoclast formation and maturation.In addition,OC-apoEVs promoted osteogenic differentiation.The in vivo study on the CIA mouse model further demonstrated that apoEVs could couple various functions and exert synergistic effects on the joint with RA,as evidenced by the regression of synovial inflammation,the reversal of cartilage damage and bone erosion,and the preservation of joint structure.These findings demonstrated that Mφ-apoEVs and OC-apoEVs contributed to restoring the homeostasis of the overall microenvironment in the RA joint and highlighted their potential application as a promising alternative to treat RA.展开更多
Apoptotic extracellular vesicles(ApoEVs)are membrane-bound vesicles released during apoptosis,crucial for intercellular communication by delivering bioactive molecules to recipient cells.These vesicles are increasingl...Apoptotic extracellular vesicles(ApoEVs)are membrane-bound vesicles released during apoptosis,crucial for intercellular communication by delivering bioactive molecules to recipient cells.These vesicles are increasingly recognized for their potential in tumor therapy,immune modulation,and tissue regeneration.Recent studies reveal that ApoEVs play diverse roles in the medical fields.In tumor therapy,they enhance targeted drug delivery and antitumor immunity.Immune modulation is achieved by presenting antigens to immune cells,fostering specific responses.ApoEVs also aid in tissue regeneration,promoting wound healing and tissue repair.Advances in isolation and engineering techniques have improved the purity and functionality of ApoEVs,enabling their use as therapeutic delivery platforms.ApoEVs hold significant clinical potential by transferring genetic material,proteins,and other bioactive molecules.However,challenges such as standardizing production,ensuring safety,and addressing heterogeneity must be overcome.Future research should optimize isolation methods,elucidate ApoEV mechanisms,and develop strategies to enhance therapeutic efficacy.ApoEVs offer promising applications in cancer treatment,immune regulation,and tissue regeneration.This review summarizes the latest research and potential clinical applications of ApoEVs,highlighting their therapeutic promise and the challenges ahead.展开更多
Apoptosis has long been recognized as a significant mechanism for inhibiting tumor formation,and a plethora of stimuli can induce apoptosis during the progression and treatment of tumors.Moreover,tumor-derived apoptot...Apoptosis has long been recognized as a significant mechanism for inhibiting tumor formation,and a plethora of stimuli can induce apoptosis during the progression and treatment of tumors.Moreover,tumor-derived apoptotic extracellular vesicles(apoEVs)are inevitably phagocytosed by live tumor cells,promoting tumor heterogeneity.Understanding the mechanism by which apoEVs regulate tumor cells is imperative for enhancing our knowledge of tumor metastasis and recurrence.Herein,we conducted a series of in vivo and in vitro experiments,and we report that tumor-derived apoEVs promoted lung adenocarcinoma(LUAD)metastasis,self-renewal and chemoresistance.Mechanistically,we demonstrated that apoEVs facilitated tumor metastasis and stemness by initiating the epithelial-mesenchymal transition program and upregulating the transcription of the stem cell factor SOX2.In addition,we found that ALDH1A1,which was transported by apoEVs,activated the NF-κB signaling pathway by increasing aldehyde dehydrogenase enzyme activity in recipient tumor cells.Furthermore,targeting apoEVs-ALDH1A1 significantly abrogated these effects.Collectively,our findings elucidate a novel mechanism of apoEV-dependent intercellular communication between apoptotic tumor cells and live tumor cells that promotes the formation of cancer stem cell-like populations,and these findings reveal that apoEVs-ALDH1A1 may be a potential therapeutic target and biomarker for LUAD metastasis and recurrence.展开更多
Apoptotic vesicles(ApoVs)are membrane structures formed during cell apoptosis and play crucial roles in homeostasis maintenance,signal transduction,and immune regulation.Importantly,ApoVs inherit the properties and co...Apoptotic vesicles(ApoVs)are membrane structures formed during cell apoptosis and play crucial roles in homeostasis maintenance,signal transduction,and immune regulation.Importantly,ApoVs inherit the properties and contents of parental cells that show great potential in the diagnosis and treatment of diseases.Monitoring the formation process of ApoVs(such as quantity,morphological changes,release rules,etc.)can reveal the regulatory mechanism of apoptosis,and is also helpful for optimizing the preparation and application of ApoVs.However,due to the limitations of existing technologies,the formation processes of ApoVs have been challenging to precisely and entirely capture.Herein,we subtly constructed a versatile AIEgen(ADTP)that could induce ApoVs production and in situ monitor the formation process,and it was successfully applied to explore the formation mechanism of ApoVs.ADTP specifically targeted the plasma membrane,and it could effectively induce apoptosis under laser irradiation,so it was able to dynamically monitor the entire formation process of ApoVs and had validated ApoVs formation from membrane protrusions(including filopodia,tunneling nanotubes,and retraction fibers).Further investigation revealed that ApoVs derived from membrane protrusions with different components exhibited significant heterogeneity.Additionally,the nearinfrared emission characteristic of ADTP was compatible with the stimulated emission depletion(STED)microscopy equipped with a 775nmdepletion laser,enabling high-resolution visualization of detailed dynamic changes inmembrane protrusions during ApoVs formation.This work provided powerful tools for tracking the entire ApoVs formation process and also offered crucial scientific evidence for revealing the ApoVs formation mechanism.展开更多
Chronic periodontitis(CP)is one of the most prevalent local inflammatory disorders and is associated with various systemic diseases.However,the relationship between local CP pathogenesis and systemic metabolic respons...Chronic periodontitis(CP)is one of the most prevalent local inflammatory disorders and is associated with various systemic diseases.However,the relationship between local CP pathogenesis and systemic metabolic responses is not fully elucidated.In this study,we show that CP causes systemic inflammation,leading to apoptotic resistance and senescent cell accumulation,which are crucial for maintaining local inflammation in a CP mouse model.Eliminating senescent cells through systemic senolytic therapy ameliorate local CP pathological changes.Proteomic analysis reveals that CP patient plasma extracellular vesicles show upregulation of immune response-related proteins and downregulation of metabolic and apoptosis-related proteins,among which pyru-vate kinase M2(PKM2)was significantly reduced.Moreover,CP mice show reduced circulating apoptotic ves-icles(apoVs),particularly those carrying PKM2.Systemic administration of PKM2+mesenchymal stem cellderived apoVs(MSC-apoVs)effectively rescues apoptotic resistance,eliminates senescent cells,and mitigates CP phenotypes.Mechanistically,we show that chronic inflammation reduces the level of nuclear PKM2 to promote apoptotic resistance.Systemic infusion of PKM2+MSC-apoVs facilitates the nuclear translocation of PKM2 to alleviate apoptotic resistance and eliminate senescent cells.Our findings suggest that elimination of senescent cells as a new strategy for CP treatment.In addition,we propose the concept that systemic metabolism may determine the maintenance of local inflammation pathogenesis in CP.展开更多
Estrogen deficiency is one of the most frequent causes of osteoporosis in postmenopausal women.Under chronic inflammatory conditions caused by estrogen deficiency,activated T cells contribute to elevated levels of pro...Estrogen deficiency is one of the most frequent causes of osteoporosis in postmenopausal women.Under chronic inflammatory conditions caused by estrogen deficiency,activated T cells contribute to elevated levels of proinflammatory cytokines,impaired osteogenic differentiation capabilities of bone marrow mesenchymal stem cells(BMMSCs),and disturbed regulatory T cell(Treg)/Th17 cell balance.However,therapeutic strategies that re-establish immune homeostasis in this disorder have not been well developed.Here,we produced T cell-depleting nanoparticles(TDNs)that ameliorated the osteopenia phenotype and rescued the osteogenic deficiency of BMMSCs in ovariectomized(OVX)mice.TDNs consist of monocyte chemotactic protein-1(MCP-1)-encapsulated mesoporous silica nanoparticles as the core and Fas-ligand(FasL)as the corona.We showed that the delicate design of the TDNs enables rapid release of MCP-1 to recruit activated T cells and then induces their apoptosis through the conjugated FasL both in vitro and in vivo.Apoptotic signals recognized by macrophages help skew the Treg/Th17 cell balance and create an immune tolerant state,further attenuating the osteogenic deficiency of BMMSCs and the osteopenia phenotype.Mechanistically,we found that the therapeutic effects of TDNs were partially mediated by apoptotic T cell-derived extracellular vesicles(ApoEVs),which promoted macrophage transformation towards the M2 phenotype.These findings demonstrate that TDNs may represent a promising strategy for treating osteoporosis and other immune disorders.展开更多
基金supported by the National Natural Science Foundation of China(Nos.82372552 and 82303775)the Excellent Youth of Natural Science Research Projects in Anhui Province Universities(No.2023AH030060)+2 种基金Anhui Provincial Natural Science Foundation(No.2408085Y016)Anhui Province Excellent Research and Innovation Team Project(No.2024AH010013)the Anhui Medical University Research Fund Youth Project(No.2023xkj018).
文摘A large number of apoptotic vesicles(ApoVs)are released during apoptosis,and mesenchymal stem cells(MSCs)-derived ApoVs(MSC-ApoVs)have significant efficacy in the field of tissue regeneration.ApoVs extracted by density gradient centrifugation have a larger volume and wider diameter distribution,high yield and drug loading efficiency,and inherit the apoptotic traces of FasL,phosphatidylserine(PS),ICAM-3,and other parent cells and the ability to target cell membranes.MSC-ApoVs can significantly promote skin wound healing;however,whether they can promote wound healing in the early stages by playing an antibacterial role is unclear.In the present study,human umbilical cord MSC-derived ApoVs(hucMSC-ApoVs)were extracted and prepared.An in vitro antibacterial test confirmed that hucMSC-ApoVs effectively inhibited the growth of bacteria and sterilized bacteria.In vivo experiments revealed that hucMSC-ApoVs can accelerate the healing of infected wounds.Further exploration of the antibacterial mechanism revealed that hucMSC-ApoVs significantly interfered with bacterial catabolic processes.In gram-positive bacteria(MRSA),hucMSC-ApoVs affect the normal metabolic process of bacteria mainly by inhibiting the metabolism of purines,pyrimidines,and other nucleotides of MRSA and arginine biosynthesis,whereas in the gram-negative bacteria E.coli,they affect this process.HucMSC-ApoVs inhibit bacterial metabolic processes such as sulfur,fatty acid,arginine,and proline metabolism;in particular,hucMSC-ApoVs can interfere with the ethanolamine metabolic process in E.coli by regulating a series of ethanolamine genes(Eut)that encode ethanolamine degrading enzymes.These findings suggest that hucMSC-ApoVs are useful natural reagents for inhibiting wound bacterial infection and promoting wound healing.
基金Natural Science Foundation of Beijing Municipality(L234024)National Natural Science Foundation of China(82102552)Natural Science Foundation of Guangdong Province(2024A1515030295).
文摘Utilizing transplanted human umbilical cord mesenchymal stem cells(HUMSCs)for cartilage defects yielded advanced tissue regeneration,but the underlying mechanism remain elucidated.Early after HUMSCs delivery to the defects,we observed substantial apoptosis.The released apoptotic vesicles(apoVs)of HUMSCs promoted cartilage regeneration by alleviating the chondro-immune microenvironment.ApoVs triggered M2 polarization in macrophages while simultaneously facilitating the chondrogenic differentiation of endogenous MSCs.Mechanistically,in macrophages,miR-100-5p delivered by apoVs activated the MAPK/ERK signaling pathway to promote M2 polarization.In MSCs,let-7i-5p delivered by apoVs promoted chondrogenic differentiation by targeting the eEF2K/p38 MAPK axis.Consequently,a cell-free cartilage regeneration strategy using apoVs combined with a decellularized cartilage extracellular matrix(DCM)scaffold effectively promoted the regeneration of osteochondral defects.Overall,new mechanisms of cartilage regeneration by transplanted MSCs were unconcealed in this study.Moreover,we provided a novel experimental basis for cell-free tissue engineering-based cartilage regeneration utilizing apoVs.Utilizing transplanted human umbilical cord mesenchymal stem cells(HUMSCs)for cartilage defects yielded advanced tissue regeneration,but the underlying mechanism remain elucidated.Early after HUMSCs delivery to the defects,we observed substantial apoptosis.The released apoptotic vesicles(apoVs)of HUMSCs promoted cartilage regeneration by alleviating the chondro-immune microenvironment.ApoVs triggered M2 polarization in macrophages while simultaneously facilitating the chondrogenic differentiation of endogenous MSCs.Mechanistically,in macrophages,miR-100-5p delivered by apoVs activated the MAPK/ERK signaling pathway to promote M2 polarization.In MSCs,let-7i-5p delivered by apoVs promoted chondrogenic differentiation by targeting the eEF2K/p38 MAPK axis.Consequently,a cell-free cartilage regeneration strategy using apoVs combined with a decellularized cartilage extracellular matrix(DCM)scaffold effectively promoted the regeneration of osteochondral defects.Overall,new mechanisms of cartilage regeneration by transplanted MSCs were unconcealed in this study.Moreover,we provided a novel experimental basis for cell-free tissue engineering-based cartilage regeneration utilizing apoVs.
基金This work was supported by grants from the National Natural Science Foundation of China(No.82170924)the National Key R&D Program of China(No.2021YFA1100600)+2 种基金the Pearl River Talent Recruitment Program(Nos.2019ZT08Y485 and 2019JC01Y138)the Guangdong Financial Fund for High-Caliber Hospital Construction(174-2018-XMZC-0001-03-0125,C-03 and D-11)the Sun Yat-sen University Young Teacher Key Cultivation Project(No.18ykzd05).
文摘Aging skeletons display decreased bone mass,increased marrow adiposity,and impaired bone marrow mesenchymal stem cells(MSCs).Apoptosis is a programmed cell death process that generates a large number of apoptotic vesicles(apoVs).Dysregulated apoptosis has been closely linked to senescence-associated diseases.However,whether apoVs mediate agingrelated bone loss is not clear.In this study,we showed that young MSC-derived apoVs effectively rejuvenated the nuclear abnormalities of aged bone marrow MSCs and restored their impaired self-renewal,osteo-/adipo-genic lineage differentiation capacities via activating autophagy.Mechanistically,apoptotic young MSCs generated and enriched a high level of Ras-related protein 7(Rab7)into apoVs.Subsequently,recipient aged MSCs reused apoV-derived Rab7 to restore autolysosomes formation,thereby contributing to autophagy flux activation and MSC rejuvenation.Moreover,systemic infusion of young MSC-derived apoVs enhanced bone mass,reduced marrow adiposity,and recused the impairment of recipient MSCs in aged mice.Our findings reveal the role of apoVs in rejuvenating aging-MSCs via restoring autolysosome formation and provide a potential approach for treating age-related bone loss.
基金supported by the National Natural Science Foundation of China(T2288101,31971266,82272152,U1801252)Guangdong Basic and Applied Basic Research Foundation(2022A1515011925)+1 种基金Science and Technology Program of Guangzhou(202206040001)the Key Research and Development Program of Guangzhou(202007020002).
文摘Rheumatoid arthritis(RA)is a severe autoimmune disease with symptoms including synovial inflammation,cartilage erosion,and bone loss in RA lesions,which eventually lead to joint deformity and function loss.Most current treatments fail to achieve satisfying therapeutic outcomes with some adverse effects.Extracellular vesicles derived from apoptotic cells(apoEVs)have emerged as important mediators in intercellular communication regulating diverse physiological and pathological processes.In this study,we investigated the therapeutic efficacy of macrophage-derived and osteoclast-derived apoEVs(Mφ-apoEVs and OC-apoEVs)on RA.The in vitro results showed that both Mφ-apoEVs and OC-apoEVs induced macrophage repolarization toward the anti-inflammatory M2 phenotype,promoted chondrocyte functions and chondrogenesis,and inhibited osteoclast formation and maturation.In addition,OC-apoEVs promoted osteogenic differentiation.The in vivo study on the CIA mouse model further demonstrated that apoEVs could couple various functions and exert synergistic effects on the joint with RA,as evidenced by the regression of synovial inflammation,the reversal of cartilage damage and bone erosion,and the preservation of joint structure.These findings demonstrated that Mφ-apoEVs and OC-apoEVs contributed to restoring the homeostasis of the overall microenvironment in the RA joint and highlighted their potential application as a promising alternative to treat RA.
基金supported by the National Natural Science Foundation of China(Grant Nos.82170271 to D.S.)Henan Key Research and Development Projects(Grant Nos.2411131160 to D.S.).
文摘Apoptotic extracellular vesicles(ApoEVs)are membrane-bound vesicles released during apoptosis,crucial for intercellular communication by delivering bioactive molecules to recipient cells.These vesicles are increasingly recognized for their potential in tumor therapy,immune modulation,and tissue regeneration.Recent studies reveal that ApoEVs play diverse roles in the medical fields.In tumor therapy,they enhance targeted drug delivery and antitumor immunity.Immune modulation is achieved by presenting antigens to immune cells,fostering specific responses.ApoEVs also aid in tissue regeneration,promoting wound healing and tissue repair.Advances in isolation and engineering techniques have improved the purity and functionality of ApoEVs,enabling their use as therapeutic delivery platforms.ApoEVs hold significant clinical potential by transferring genetic material,proteins,and other bioactive molecules.However,challenges such as standardizing production,ensuring safety,and addressing heterogeneity must be overcome.Future research should optimize isolation methods,elucidate ApoEV mechanisms,and develop strategies to enhance therapeutic efficacy.ApoEVs offer promising applications in cancer treatment,immune regulation,and tissue regeneration.This review summarizes the latest research and potential clinical applications of ApoEVs,highlighting their therapeutic promise and the challenges ahead.
基金supported by grants from the Director Foundation of Sun Yat-sen university Cancer Center(PT12020401)the National Key Research and Development Program of China(No.2021YFC2500905)+1 种基金the National Natural Science Foundation of China(No.82073121)Guangdong Basic and Applied Basic Research Foundation(No.2020A1515010041).
文摘Apoptosis has long been recognized as a significant mechanism for inhibiting tumor formation,and a plethora of stimuli can induce apoptosis during the progression and treatment of tumors.Moreover,tumor-derived apoptotic extracellular vesicles(apoEVs)are inevitably phagocytosed by live tumor cells,promoting tumor heterogeneity.Understanding the mechanism by which apoEVs regulate tumor cells is imperative for enhancing our knowledge of tumor metastasis and recurrence.Herein,we conducted a series of in vivo and in vitro experiments,and we report that tumor-derived apoEVs promoted lung adenocarcinoma(LUAD)metastasis,self-renewal and chemoresistance.Mechanistically,we demonstrated that apoEVs facilitated tumor metastasis and stemness by initiating the epithelial-mesenchymal transition program and upregulating the transcription of the stem cell factor SOX2.In addition,we found that ALDH1A1,which was transported by apoEVs,activated the NF-κB signaling pathway by increasing aldehyde dehydrogenase enzyme activity in recipient tumor cells.Furthermore,targeting apoEVs-ALDH1A1 significantly abrogated these effects.Collectively,our findings elucidate a novel mechanism of apoEV-dependent intercellular communication between apoptotic tumor cells and live tumor cells that promotes the formation of cancer stem cell-like populations,and these findings reveal that apoEVs-ALDH1A1 may be a potential therapeutic target and biomarker for LUAD metastasis and recurrence.
基金supported by the National Natural Science Foundation of China(52350002,52150222,U2330106,and 52073163)the Special Fund of Taishan Scholars Project of Shandong Province(tsqnz20231253)+1 种基金Natural Science Foundation of Shandong Province(ZR2024QB200,ZR2023ZD41)Fundamental Research Funds for the Central Universities(2022JC003).
文摘Apoptotic vesicles(ApoVs)are membrane structures formed during cell apoptosis and play crucial roles in homeostasis maintenance,signal transduction,and immune regulation.Importantly,ApoVs inherit the properties and contents of parental cells that show great potential in the diagnosis and treatment of diseases.Monitoring the formation process of ApoVs(such as quantity,morphological changes,release rules,etc.)can reveal the regulatory mechanism of apoptosis,and is also helpful for optimizing the preparation and application of ApoVs.However,due to the limitations of existing technologies,the formation processes of ApoVs have been challenging to precisely and entirely capture.Herein,we subtly constructed a versatile AIEgen(ADTP)that could induce ApoVs production and in situ monitor the formation process,and it was successfully applied to explore the formation mechanism of ApoVs.ADTP specifically targeted the plasma membrane,and it could effectively induce apoptosis under laser irradiation,so it was able to dynamically monitor the entire formation process of ApoVs and had validated ApoVs formation from membrane protrusions(including filopodia,tunneling nanotubes,and retraction fibers).Further investigation revealed that ApoVs derived from membrane protrusions with different components exhibited significant heterogeneity.Additionally,the nearinfrared emission characteristic of ADTP was compatible with the stimulated emission depletion(STED)microscopy equipped with a 775nmdepletion laser,enabling high-resolution visualization of detailed dynamic changes inmembrane protrusions during ApoVs formation.This work provided powerful tools for tracking the entire ApoVs formation process and also offered crucial scientific evidence for revealing the ApoVs formation mechanism.
基金supported by grants from the Pearl River Talent Recruitment Program(2019ZT08Y485,2019JC01Y182to S.S)the National Key R&D Program of China(2021YFA1100600 to S.S.)the Guangdong Financial Fund for High-Caliber Hospital Construction(174-2018-XMZC-0001-03-0125,D-07 to S.S.).
文摘Chronic periodontitis(CP)is one of the most prevalent local inflammatory disorders and is associated with various systemic diseases.However,the relationship between local CP pathogenesis and systemic metabolic responses is not fully elucidated.In this study,we show that CP causes systemic inflammation,leading to apoptotic resistance and senescent cell accumulation,which are crucial for maintaining local inflammation in a CP mouse model.Eliminating senescent cells through systemic senolytic therapy ameliorate local CP pathological changes.Proteomic analysis reveals that CP patient plasma extracellular vesicles show upregulation of immune response-related proteins and downregulation of metabolic and apoptosis-related proteins,among which pyru-vate kinase M2(PKM2)was significantly reduced.Moreover,CP mice show reduced circulating apoptotic ves-icles(apoVs),particularly those carrying PKM2.Systemic administration of PKM2+mesenchymal stem cellderived apoVs(MSC-apoVs)effectively rescues apoptotic resistance,eliminates senescent cells,and mitigates CP phenotypes.Mechanistically,we show that chronic inflammation reduces the level of nuclear PKM2 to promote apoptotic resistance.Systemic infusion of PKM2+MSC-apoVs facilitates the nuclear translocation of PKM2 to alleviate apoptotic resistance and eliminate senescent cells.Our findings suggest that elimination of senescent cells as a new strategy for CP treatment.In addition,we propose the concept that systemic metabolism may determine the maintenance of local inflammation pathogenesis in CP.
基金This work was supported by the National Natural Science Foundation of China(81930025,31800817,81670915,and 31870970)Innovative Talent Project of Shaanxi province(2020KJXX-057)Key Research and Development Program of Shaanxi Province(2019SF-073).
文摘Estrogen deficiency is one of the most frequent causes of osteoporosis in postmenopausal women.Under chronic inflammatory conditions caused by estrogen deficiency,activated T cells contribute to elevated levels of proinflammatory cytokines,impaired osteogenic differentiation capabilities of bone marrow mesenchymal stem cells(BMMSCs),and disturbed regulatory T cell(Treg)/Th17 cell balance.However,therapeutic strategies that re-establish immune homeostasis in this disorder have not been well developed.Here,we produced T cell-depleting nanoparticles(TDNs)that ameliorated the osteopenia phenotype and rescued the osteogenic deficiency of BMMSCs in ovariectomized(OVX)mice.TDNs consist of monocyte chemotactic protein-1(MCP-1)-encapsulated mesoporous silica nanoparticles as the core and Fas-ligand(FasL)as the corona.We showed that the delicate design of the TDNs enables rapid release of MCP-1 to recruit activated T cells and then induces their apoptosis through the conjugated FasL both in vitro and in vivo.Apoptotic signals recognized by macrophages help skew the Treg/Th17 cell balance and create an immune tolerant state,further attenuating the osteogenic deficiency of BMMSCs and the osteopenia phenotype.Mechanistically,we found that the therapeutic effects of TDNs were partially mediated by apoptotic T cell-derived extracellular vesicles(ApoEVs),which promoted macrophage transformation towards the M2 phenotype.These findings demonstrate that TDNs may represent a promising strategy for treating osteoporosis and other immune disorders.
