Me Me Tab sis Mighty—Exosomes, Novel Intercellular Messengers in Neurodegeneration Part 2

Differential ultracentrifugation: Txoj kev ultracentrifugation tau ntev tau suav tias yog 'tus qauv kub' rau kev cais tawm ntawm exosome [10,78] thiab yog txoj kev siv ntau tshaj plaws. Johnston thiab cov npoj yaig thawj zaug tau tshaj tawm ultracentrifugation kom cais cov exosomes los ntawm kab lis kev cai nruab nrab ntawm reticulocytes [10].

Nws tsis zoo li qhov sib txuas ncaj qha ntawm qhov sib txawv ultracentrifugation thiab kev nco, tab sis muaj qee qhov kev sib txuas ncaj qha ntawm lawv.

Ua ntej, qhov sib txawv ultracentrifugation tuaj yeem pab peb tswj lub cev thiab lub hlwb noj qab haus huv, yog li ua kom peb lub cim xeeb. Cov kev tshawb fawb tau pom tias kev tawm dag zog lub cev tuaj yeem txhawb kev sib txuas ntawm cov neurons hauv lub hlwb thiab txhim kho lub hlwb ua haujlwm, nrog rau kev nco. Raws li txoj kev siv zog siv zog, qhov sib txawv ntawm ultracentrifugation tuaj yeem txhawb kev noj qab haus huv ntawm cov hlab plawv, cov leeg nqaij, thiab kev ua siab ntev, uas tuaj yeem txhawb peb lub cim xeeb ntxiv.

Qhov thib ob, kev sib txawv ntawm ultracentrifugation tuaj yeem pab peb txo qis kev ntxhov siab thiab txhim kho kev xav, uas kuj muaj txiaj ntsig zoo rau kev nco. Thaum peb xav tias ntshai, ntxhov siab, lossis ntxhov siab, peb lub hlwb tso tawm qee yam kev xav tsis zoo, uas tuaj yeem cuam tshuam rau peb lub cim xeeb thiab kev txawj ntse. Los ntawm kev tawm dag zog sib txawv ultracentrifugation, peb tuaj yeem tso tawm kev ntxhov siab hauv lub cev thiab txhawb kev tso tawm ntawm cov neurotransmitters hauv lub hlwb, yog li txhim kho peb lub siab thiab kev txawj ntse.

Tsis tas li ntawd, qhov sib txawv ultracentrifugation tuaj yeem pab peb ua kom peb tus kheej muaj kev ntseeg siab thiab ua haujlwm rau tus kheej, uas tuaj yeem cuam tshuam los ntawm kev txhim kho peb lub cim xeeb. Thaum peb muaj kev ntseeg siab thiab ua tiav, peb lub hlwb tso tawm qee yam kev xav zoo, uas tuaj yeem txhim kho peb lub peev xwm kev txawj ntse thiab kev nco. Los ntawm kev tawm dag zog xws li kev sib txawv ntawm ultracentrifugation, peb tuaj yeem txhim kho peb qib kis las thiab lub cev muaj peev xwm, txhim kho peb tus kheej kev ntseeg siab thiab kev ua tau zoo ntawm tus kheej, thiab yog li ua tau zoo dua hauv kev txhim kho kev nco.

Feem ntau, tsis muaj kev sib raug zoo ntawm qhov sib txawv ntawm qhov sib txawv ultracentrifugation ce thiab nco, tab sis muaj tseeb qee qhov kev sib txuas tsis ncaj ntawm lawv. Los ntawm kev tawm dag zog, txo kev ntxhov siab, txhim kho lub siab, thiab txhim kho kev ntseeg siab ntawm tus kheej, peb tuaj yeem txhim kho peb lub cim xeeb thiab kev txawj ntse, thaum nqa cov txiaj ntsig kev noj qab haus huv ntawm lub cev thiab lub hlwb. Yog li ntawd, kev sib txawv ntawm ultracentrifugation yog ib txoj hauv kev zoo ntawm kev tawm dag zog uas tuaj yeem nqa cov txiaj ntsig ntau ntxiv rau peb lub cev thiab lub hlwb kev noj qab haus huv thiab kev nco. Nws tuaj yeem pom tias peb yuav tsum txhim kho kev nco, thiab Cistanche tuaj yeem txhim kho kev nco zoo vim Cistanche muaj cov tshuaj tiv thaiv antioxidant, tiv thaiv kev laus, thiab tiv thaiv kev laus, uas tuaj yeem pab txo qis oxidative thiab inflammatory tshwm sim hauv lub hlwb, yog li tiv thaiv kev noj qab haus huv. paj hlwb. Tsis tas li ntawd, Cistanche tuaj yeem txhawb txoj kev loj hlob thiab kho cov paj hlwb, yog li txhim kho kev sib txuas thiab kev ua haujlwm ntawm neural networks. Cov teebmeem no tuaj yeem pab txhim kho kev nco, kev kawm muaj peev xwm, thiab kev xav nrawm, thiab tseem tuaj yeem tiv thaiv qhov tshwm sim ntawm kev paub tsis meej thiab cov kab mob neurodegenerative.

Nyem paub ntxiv los txhim kho kev nco

Cov txheej txheem no yog raws li kev siv lub zog centrifugal los ua ntu ntu cais raws li lawv qhov loj thiab qhov ceev. Loj dua thiab ntom ntom cov party yuav tsum tau cov rog ntawm centrifugal rau sedimentfirst [44,84].

Nyob ntawm qhov xwm txheej ntawm tus qauv, thawj qhov qis centrifugation ntawm 300–2000 × gremoves floating hlwb, de, ad,, thiab apoptotic Higher-speeded centrifugation ntawm 10,000 × gremoves loj vesicles thiab cell debris.

Exosomes yog pelleted los ntawm ultracentrifugation ntawm 100, 000 × g. Kev ua tau zoo ntawm exosome cais nyob ntawm ntau yam xws li acceleration (g), hom rotor ua haujlwm thiab nws cov yam ntxwv (k yam, vojvoog ntawm kev sib hloov), thiab qhov kawg viscosity ntawm cov qauv pib. Exosome sedimentation efficiency txo nrog nce viscosity.

Yog li ntawd, e, kev cais tawm ntawm exosomes los ntawm cov ntshav / ntshav yuav tsum tau ceev ceev centrifugation cov kauj ruam rau lub sij hawm ntev dua li piv rau exosome cais tawm ntawm cell culture nruab nrab. Nyob ntawm cov rotor siv, kuj loj cov qauv ntim tuaj yeem ua tiav. Ultracentrifugation rau exosome cais yuav tsum tau tsawg reagents thiab consumables thiab muaj zoo reproducibility tab sis yuav tsum tau ntau lub sij hawm thiab kim khoom.

Lub peev xwm ntawm pelleting protein aggregates thiab lwm yam uas tsis yog-exosomal particleshas prompted siv gradient ultracentrifugation uas tso cai rau exosome cais raws li lawv buoyant ceev.

Sucrose, Iohex, ol, thiab iodixanol feem ntau yog ua haujlwm rau isopycnic centrifugation [85, 86]. Txoj kev no yog siv sijhawm ntev, yuav tsum tau siv lub ntim ntim me me raws li cov raj xa hluav taws xob tsis tuaj yeem ua rau overloaded, thiab yields me me ntawm purepreparation ntawm exosomes.

Ultrafiltration: Txoj kev no yog ua raws li kev siv hydrophilic ntxeem tau daim nyias nyias nrog lub pore-los yog molecular hnyav txiav tawm-loj rau ntxiab hais txog qhov loj me me. Cov qauv xws li kab lis kev cai nruab nrab lossis cov kua dej lom lom tau raug lim los ntawm daim nyias nyias nrog txo qhov pore loj. Qhov no tso cai rau khaws cia ntawm cov particles loj nyob rau txhua kauj ruam pom thiab cov retentate yog enriched nrog cov particle loj.

Exosomes tau rov qab los ntawm qhov kawg retentate los ntawm ultracentrifugation. Cov txheej txheem no tau nrawm thiab tau txais koob meej [69]. Ultrafiltration yog txuam nrog ib co shortcomings vim tomembrane clogging thiab exosome ntxiab, ua rau nruab nrab exosome tawm los. Lub sheererstress ntawm pom yuav ua rau exosomes.Size-exclusion chromatography: Lub hauv paus ntsiab lus ntawm txoj kev no yog raws li proteinpurification los ntawm chromatography.

Cov kab no tau ntim nrog cov pob zeb polymer porous orresin xws li Sephacryl S-1000, Sepharose 2B, thiab Sepharose CL-2B [71,83–89]. Thaum cov qauv yog loadeontoto rau kab, nws traverses los ntawm resin. Cov khoom loj dua hla ntawm kab vim tias lawv loj dhau los nkag rau hauv cov resin thiab yog thawj zaug rau beeluted (tseem hu ua aflow-drough).

Cov khoom me me uas nkag mus rau hauv cov khoom ntxeem tau raug tshem tawm los ntawm passia ng tsis los ntawm kab. Qhov kev sib cais no nruj me ntsis raws li qhov loj lossis molecular loj thiab yog li tag nrho cov ws purification ntawm sub-populations ntawm exosomesSize exclusionchromatography yog ib txoj kev sai thiab rov tsim dua tshiab uas tsis cuam tshuam nrog kev ncaj ncees ntawm exosomes. Qhov tsuas yog caveat nrog txoj kev no yog tias ib feem me me ntawm cov roj lipoprotein ceev thiab cov proteins sib koom ua ke nrog exosomes [87].

Kev ua kom huv ntxiv los ntawm kev ceev gradient centrifugation yog yuav tsum tau tshem tawm cov protein aggregates thiab lipids kom tau txais cov tshuaj exosome ntshiab.Immunoaffinity capture: Txoj kev no yog raws li kev siv cov tshuaj tiv thaiv kab mob ntawm cov proteins ntawm exosomes xws li tetraspanin proteins [78,90,91]. Sib nqus beadscovalently coated nrog streptavidin yog incubated nrog biotinylated antibodies tiv thaiv saum npoo ntawm cov proteins ntawm exosomes, kuj hu ua 'capture antibodies'.

Magnetic hlaws-nrhiav antibody complexes yog incubated nrog cov qauv unbounded qauv tshem tawm los ntawm magnetizing cov hlaws dai. Cov hlaws ntxuav tau ua tiav ncaj qha rau cov ntawv thov qis qis yam tsis muaj exosomes. Qhov no yog ib qho yooj yim-rau-siv txoj kev thiab muab ntshiab kev npaj ntawm sub-populations ntawm exosomes. Txawm li cas los xij, txoj kev no yuav tsis raug siv niaj hnub asantibodies yog kim thiab txoj kev no yuav tsum muaj kev paub ua ntej ntawm exosome surfaceproteins thiab nyob ntawm qhov muaj cov tshuaj tiv thaiv tiv thaiv lawv.

Txoj kev no muaj teeb meem nrog kev tshem tawm ntawm cov exosomes tsis muaj zog. Txawm li cas los xij, ib zaug tsim, nws tuaj yeem ua haujlwm rau cov ntawv thov xws li kuaj qog exosomes hauv cov ntshav.

Ntxiv nrog rau magneticbeads, ob peb lwm platforms xws li porous monolithic silicmicrochipss, plasticplates, cellulose lim, membrane affinity lim, ib tug agarose sorbent, thiab microfluidicdevices ntiav affinity-based exosome purification.Microfluidics ntaus ntawv: Cov tshuaj lom neeg ntawm exosome thiab exosome. nanoscale.

Cov khoom siv microfluidics yuav tsum muaj cov qauv me me. Cov qauv no raug coj mus rau ntws los ntawm cov kab me me thiab cov exosomes raug ntes siv cov txheej txheem immunoaffinity los yog entrapment los ntawm cov qauv ntxeem tau [67], loj pom, nanowiretraping, lateral displacement, acoustic nanofiltration, thiab tsis ntev los no viscoelasticflow sorting [82].

Cov khoom siv no tau txais kev txaus siab ntau rau cov reagents xav tau yog nyob rau hauv microliter kom muaj nuj nqis, yog portable, thiab cov txheej txheem ntawm exosome cais tawm yog ceev heev thiab ua tau zoo. Yog li, cov khoom siv microfluidic muaj peev xwm tsim tau rau kev kuaj mob sai thiab kuaj mob. Tib qhov tsis zoo nrog txoj kev no yog lub peev xwm qis.

Flow cytometry, asymmetrical flow field-flow fractionation, gradient ultracentrifugation, thiab polymer nag lossis daus yog qee txoj hauv kev ntxiv uas tau tsim kho forexosome purification [92–94].

Nws pom tseeb los ntawm cov ntsiab lus ntawm kev cais tawm tam sim no uas tsis muaj txoj hauv kev tshwj xeeb yog tsim nyog rau txhua qhov kev cais tawm exosome.

Standardization ntawm txoj kev siv rau exosome isolation yog qhov tseem ceeb.

Txoj kev optimalisolation yuav nyob ntawm seb qhov xwm ntawm tus qauv, tus nqi pib samplevolume, thiab downstream daim ntawv thov. Ib txoj kev sib cais zoo tshaj plaws yuav zoo dua yog qhov yooj yim, thiab tsis xav tau cov cuab yeej nyuaj lossis kim. Hauv qhov chaw kho mob, exosomeisolation yuav tsum tau scalable, raug nqi, thiab sai.

Exosome purification frthe om hlwb: Exosomes muaj cov lus cog tseg zoo li kev kuaj mob rau cov kab mob thiab raws li prognostic biomarkers. Tam sim no exosome kev cais tawm los ntawm cov kua roj ntsha nrog rau cov ntshav, zis, thiab cov kua cerebrospinal, thaum tsis muaj kev sib tw, tau ua tas li. Txawm li cas los xij, txhawm rau txhawm rau txhawm rau muaj peev xwm ntawm exosomes, txoj hauv kev rau rho tawm exosomes los ntawm cov ntaub so ntswg yuav tsum tau tsim.rau cov kab mob neurodegenerative, thawj pathology feem ntau nyob rau thaj tsam aspecific paj hlwb tab sis cov proteins lom tom qab kis mus rau lwm lub hlwb. Cov txheej txheem tam sim no ntawm cov protein muaj kuab lom kis mus rau lwm thaj chaw hauv lub hlwb tsis to taub tag nrho.Exosomes yuav yog cov neeg sib tw vim lawv koom nrog kev sib txuas lus hauv hlwb. Thescenario uas exosomal cargo txawv nyob rau hauv sib txawv cheeb tsam ntawm lub paj hlwb yog heev yuav.

Yog li ntawd, kev cais tawm exosomes los ntawm brairegionson ntawm kev txaus siab tuaj yeem ua tau zoo heev.Ib qho ntawm cov ntawv tshaj tawm ntxov tshaj plaws ntawm kev cais tawm ntawm lub hlwb los ntawm Perez Gonzalezlez thiab cov npoj yaig [95]. Lawv ntxuav cov exosomes ntawm nws tus kheej los ntawm cov tshiab thiab khov nas lub hlwb, thiab khov tib neeg lub hlwb cov ntaub so ntswg.

Txoj kev cais tawm tau ua rau kev kho mob pib papain ntawm cov ntaub so ntswg ua raws li kev pom kom tshem tawm cov hlwb thiab cov khib nyiab. Tom qab ntawd, cov homogenates tau raug mus rau ib qho ntawm cov centrifugations uas tsis tshua muaj siab ua raws li cov aseries ntawm high-speed centrifugations. Exosomes tau ua kom huv ntxiv los ntawm kev faib tawm ntawm sucrose gradient. Siv cov txheej txheem no, cov kws sau ntawv tshaj tawm txog kev sib cais ntawm cov exosomes los ntawm lub hlwb [95].

Ib txoj kev zoo sib xws tau siv los ntawm Vella thiab cov npoj yaig tshwj tsis yog tias cov qauv no tsis raug pom [96]. Cov txheej txheem ua haujlwm los ntawm pawg tshawb fawb no ua rau muaj kev sib cais ntawm exosomes uas tau ntsib tag nrho cov txheej txheem exosome uas muab cov cuab yeej tseem ceeb rau cov kws tshawb fawb neuroscientists. Ib qho nthuav thiab sib txawv mus kom ze toexosome cais tau los ntawm lwm pab pawg tshawb fawb.

Sib cav hais tias ultracentrifugationpellets cia "tsis xav soluble proteins thiab aggregates", Gallart-Palau thiab cov npoj yaig sib koom ua ke tshiab nas hlwb thiab khov tib neeg frontal lobe hauv 0.1M ammonium acetatebuffer supplemented nrog anti-proteases.

Pooled supernatants tau sib xyaw nrog plaub ntu ntawm chilled acetone los ua kom cov protein ntau hydrophilic thiab cov ntaub so ntswg zoo sib xws macromoleculesleaving hydrophobic exosomes hauv kev daws [97]. Hauv peb lub tswv yim, muaj ob peb drawbactoith txoj kev no. Ua ntej, nws tsis zoo li tias ammonium acetate tuaj yeem tswj tau qhov nruab nrab pHas pKa ntawm acetic acid nyob ib ncig ntawm pH 4.75 thiab pKa ntawm ammonium nyob ib ncig ntawm pH 9.25.

Yog li, cov ntaub so ntswg ntawm lub hlwb yog homogenized siv qhov tsis muaj pH tsis ruaj khov thiab qhov no yuav cuam tshuam rau tus nqi ntawm macromolecules [98].

Qhov thib ob, txawm hais tias acetone tuaj yeem cais cov hydrophilicproteins thiab lwm cov hydrophilic molecules los ntawm supernatants nws tuaj yeem hloov cov phospholipidbilayer li peb, peb yuav ua rau peb cov plasma membrane fluidity nce ntxiv uas qhia txog qhov tsis sib xws ntawm cov ntsiab lus exosome [99].

3. Lub luag haujlwm ntawm Exosomes hauv Central Nervous System (CNS)

Kev sib cuam tshuam ntawm cov neurons thiab glia yog qhov yuav tsum tau ua ua ntej rau kev ua haujlwm ntawm lub paj hlwb (Daim duab 4) [100]. Kev sib txuas lus hauv CNS tau piav qhia ntau yam thiab tau faib ua cov xaim xaim (ntawm-ib kis) thiab ntim kis-rau-ntau kis) [101].

Cov xaim xaim muaj xws li neurotransmission ntawm hluav taws xob thiab tshuaj synapses koom nrog kev hloov pauv ntawm me me moleculesand ions los ntawm qhov sib txawv junctions. Volume kis tau tus mob, ntawm qhov tod tes, yog yooj yim los ntawm paracrine kis tau tus mob ntawm cov teeb liab los ntawm qhov chaw interstitial los yog cerebrospinalfluid. Xyoo tsis ntev los no, txawm li cas los xij, nws tau pom meej tias exosomes pab txhawb kev sib txuas lus hauv CNS [102].

Exosomes ua tiav lawv lub luag haujlwm ua cell-cell communicatorsby exerting lawv cov teebmeem los ntawm ntau yam mechanisms. Exosomes tuaj yeem pib signaltransduction cascades los ntawm kev ua kom lub ntsej muag receptors lossis xa lawv cov khoom thauj ntawm nucleic acids, proteins, lipids, thiab lwm yam me me molecules uas ua rau muaj txiaj ntsig zoo hauv cov neeg tau txais txiaj ntsig.

Exosome tso tawm thiab uptake yog bidirectional, tso cai rau kev sib koom tes ntawm cov xwm txheej lom neeg. Exosomes raug tso tawm los ntawm txhua lub hlwb hauv CNS, suav nrog microglia, oligodendrocytes, astrocytes,tes thiab neurons [103Kev tso tawm ntawm exosomes feem ntau tswj los ntawm neurotransmitter signaling hauv lub hlwb.

Tawm mus rau excitatory neurotransmitter glutamate txhawb kev tso tawm ntawm exosomes los ntawm paub tab cortical thiab hippocampal neurons culturedin vitro. Hloov pauv, AMPA receptor lossis NMDA receptor antagonists thim rov qab cov excitatoryactivity nrog txo qis exosome tso zis. Cov ntaub ntawv no qhia tias exosome tso tawm yog hloov kho los ntawm excitatory synaptic kev ua si.

Tsis tas li ntawd, exosome tso tawm tau yooj yim los ntawm neuronaldepolarization thiab calcium influx tom qab kho nrog calcium ionophore, ionomycin [49]. Adenosine triphosphate (ATP) tso tawm ntawm synapses ua ib co-transmitteractivating glial purinergic receptors.

ATP txhawb nqa exosome tso tawm los ntawm astrocytes thiab microglial hlwb. Associating exosome tso tawm nrog cov neurotransmitter tso tawm qhia tias cov kab mob nanoparticles yuav nyiam nyob rau hauv cheeb tsam ntawm lub hlwb nrog cov kev ua haujlwm siab siab tej zaum vim muaj ntau dua demanforof intercellular kev sib txuas lus thiab kev sib koom tes ntawm cellular kev ua ub no hauv cheeb tsam [100] Ntau qhov kev tshuaj xyuas ntawm cov ncauj lus no muabde kom ntxaws account cell-cellular kev sib txuas lus los ntawm exosomes [52,53,104–108].Table 2 luv luv piav qhia txog exosomes 'lub luag hauj lwm hauv intercellular kev sib txuas lus hauv hlwb. Hauv qab no, peb piav qhia luv luv ntawm exosome-mediated intercellular kev sib txuas lus ntawm hlwb hlwb.

Daim duab 4. Exosome-mediated intercellular kev sib txuas lus ntawm cov hlwb hlwb. Exosomes los ntawm ib tug niam txiv yuav muaj ntau lub hom phiaj (los yog cov neeg tau txais) cov hlwb nyob rau hauv lub hlwb los xyuas kom meej kev saib xyuas ntawm homeostasis.(A) Exosome tso tawm nyob rau hauv lub CNS tshwm sim nyob rau hauv teb rau neurotransmitter signaling thiab yog li tswj los ntawm hluav taws xob kev ua si.

Piv txwv li, raug rau poov tshuaj chloride depolarizes neurons, feem ntau hu ua hluav taws xob nquag neurons. Depolarized neurons tso glutamate uas khi rau thiab txhawb nqa AMPA thiab NMDA receptors ntawm oligodendrocytes. Ua kom cov glutamate receptorsincreases intracellular calcium ntau ntau hauv oligodendrocytes. Kev nce hauv calcium intracellular induces tso tawm ntawm exosomes los ntawm oligodendrocytes [109].

ATP-mediated stimulation ntawm P2 purinoceptor subtype, P2X7 stimulates exosome tso tawm los ntawm microglia [110] thiab astrocytes [111]. Serotonin kuj txhawb xosomemes tso tawm los ntawm microglia [112]. (B) Neurons tswj qee lub luag haujlwm ntawm neurons, astrocytes, thiab endothelial hlwb los ntawm gh tso tawm ntawm exosomes [113].

Hauv particular, neuronal exosomes tshem tawm synapses thiab txhawb phagocytosis los ntawm microglial hlwb [114]. Neuronal exosomes tso tawm inresponse rau synaptic activation, tswj lub luag hauj lwm qhia ntawm glutamate transportersastrocytescyte rau regulateextracellular glutamate theem [115]. (C) Astrocyte-derived exosomes modulate neuronal functionand exert lub luag hauj lwm neuroprotective.

Astrocyte exosomes qhib microglia thiab ua si tseem ceeb hauv kev sib txawv ntawm oligodendrocytes. (D) Microglial exosomes modulate noj synaptic muaj nuj nqi ntawm neurons thiab sib txuas lus nrog astrocytes kom induce neuroinflammation.

Microglial exosomes tuaj yeem kho ob qho tib si neuroprotective thiab neurodegenerative lub luag haujlwm cuam tshuam nrog microglia. (E) Matureoligodendrocyte exosomes txhawb nqa kev thauj mus los ntawm axonal thiab pab tswj kev huv microenvironmentthrough kev sib txuas lus ntawm microglia thiab astrocytes. (F) Oligodendrocyte precursor cell-derivedexosomes pab hauv neuroregeneration [116].

Kho nrog kev tso cai los ntawm Schnatz, A., Müller, C., Brahmer, A., thiab Krämer-Albers, E.-M. (2021), Extracellular Vesicles hauv neural cell sib cuam tshuam thiab CNS homeostasis. FASEB BioAdvances, 3: 577–592 [100]. doi:10.1096/fba.2021-00035; Copyright © 2022 Tus Sau.

FASEB BioAdvances luam tawm los ntawm Federation of American Societies for Experimental Biology. Tsab xov xwm qhib kev nkag mus no raws li cov ntsiab lus ntawm http://creativecommons.org/licenses/by-nc/4.0/License (3 Lub Peb Hlis 2022), uas tso cai siv, faib, thiab luam tawm hauv nruab nrab, yog tias thawj cov haujlwm tau raug suav hais tias raug thiab tsis siv rau kev lag luam.

Neuron-Derived Exosomes: Cultured neurons ntawm nas thiab tib neeg keeb kwm, thiab neuralstem hlwb tso tawm exosomes [92,117,118].

Ib qho kev soj ntsuam nthuav tau ua los ntawm Chivetand cov npoj yaig thaum kawm exosomes tso tawm los ntawm cov hlwb neuroblastoma. Lawv pom cov cell tshwj xeeb internalization ntawm exosomes.

Exosomes los ntawm cov hlwb neuroblastoma tau nkag tau yooj yim endocytosed los ntawm astrocytes thiab oligodendrocytes tab sis kom tsawg dua los ntawm hippocampal neurons. Exosomes tso tawm los ntawm cov neurons nyob rau hauv cov lus teb rau synaptic kev ua si, ntawm qhov tod tes, tsuas yog coj los ntawm cov neurons qhia qhov tshwj xeeb ntawm exosome-mediated kev sib txuas lus ntawm cov hlwb hlwb [119].

Neuron-derived exosomes tau xav tias yuav koom nrog hauv synaptic plasticity los ntawm kev tshem tawm cov protein uas tsis siv lawm thiab RNA. Qhov no yog ua tiav los ntawm kev ua kom lub phagocytic muaj nuj nqi ntawm microglia [120]. Potassium-induced depolarization ofcultured human neuroblastoma hlwb tso tawm exosomes enriched nyob rau hauv ib pawg ntawm kev ua si-relatedmiRNAs thiab synaptic protein MAP1b.

MAP1b protein ntau tam sim no inaxon loj hlob cones thiab dendritic spin thiab yog txuam nrog synaptic plasticity [121] .Depolarization stimulates s uptake ntawm soma-dendritic exosomes los ntawm cov neeg nyob sib ze synapses.

Internalized exosomes pab txhawb lub zog synaptic los ntawm kev txhais lus sai sai ntawm mRNAs cuam tshuam rau kev ua haujlwm synaptic hauv cheeb tsam tom qab synaptic [121]. Kev txhawb ntxiv rau lub luag haujlwm ntawm exosomes hauv kev hloov pauv neurotransmission yog muab los ntawm cov kev tshawb fawb siv thawj embryonic cortical neurons uas tso tawm exosomes uas muaj ob microRNAs, Cia -7c thiab miR-21.

Cov microRNAs no yog ligands rau tus xov tooj hu-zoo li receptor 7 (Tlr7). Ua kom tus xov tooj-likereceptor 7 ua lub luag haujlwm tsis zoo hauv kev loj hlob ntawm axonal thiab dendritic. Incubation ntawm neurons nrogLet-7c thiab miRhurtt ntawm dendritic kev loj hlob nyob rau hauv ib txwm neurons thiab cov nyhuv no tau obliterated nyob rau hauv neurons los ntawm Tlr7(−/−) knockout nas [122].

Nws yog li tsim nyog xav tias neuronal exosomes tuaj yeem hloov kho neurotransmission los ntawm kev tswj cov neuritegrowth thaum lub sij hawm neurodevelopment. Synaptogenesis thiab kev kho synapse kuj cuam tshuam los ntawm exosomes.

Proline-nplua nuj transmembrane protein, PRR7 yog tso tawm los ntawm neuronsin ib qho kev ua si-dependent yam ntawm exosomes. Internalization ntawm PRR7-muaj cov exosomes los ntawm cov neeg nyob sib ze neurons txo lawv cov naj npawb ntawm excitatory synapses.

Kev txo qis ntawm excitatory synapses yog ua tiav los ntawm kev ua kom GSk3, stimulating proteasomal degradation ntawm PSD proteins, thiab ib txhij inhibiting exosomal secretion ntawm Wnts [123]. Exosomesare yog li muaj kev cuam tshuam hauv kev ua si rs neuron-neuron thiab neuron-glial kev sib txuas lus.Astrocyte-Derived Exosomes: Astrocytes sawv cev rau ntau hom glial cell hauv lub hlwb.

Lawv yog qhov tseem ceeb rau kev saib xyuas ntawm lub hlwb homeostasis thiab muab cov haujlwm tseem ceeb xws li kev txhawb nqa neurotrophic, kev hloov pauv ntawm kev ua haujlwm synaptic, thiab plasticity [124,125].

Cov txheej txheem Astrocytic tswj kev sib cuag nrog cov ntshav capillaries hauv lub hlwb uas ua rau kev kho mob ntawm thblood-brainin barrier [126]. Ntxiv nrog rau kev ua cov luag haujlwm tseem ceeb no, astrocytes ua haujlwm li cov hlwb immunocompetent hauv CNS.

Nyob ntawm cov ntsiab lus, kev ua astrocyte tuaj yeem ua rau muaj kev cuam tshuam inflammatory lossis txhawb kev tiv thaiv kab mob thiab kho cov ntaub so ntswg. Ntawm qhov chaw ntawm CNS cov ntaub so ntswg puas, reactive astrocytes tsim cov caws pliav uas ua haujlwm zoo rau cov kab mob inflammatory, yog li tswj CNSinflammation [127]. Reactive astrocytes tso tawm cov tshuaj neurotoxic thiab inflammatory molecules xws li cytokines thiab chemokines.

Qee qhov haujlwm ntawm astrocytes no yog ib feem los ntawm kev tso tawm exosomes. Tsis tas li ntawd, accumulating pov thawj lends credence rau lub tswv yim hais tias nws t neuroprotective luag hauj lwm ntawm astrocytes yog kho los ntawm exosomes. Rat astrocytescultured nyob rau hauv vitro tso tawm exosomes uas muaj neuroprotective thiab neurotrophic yam.

Tshwj xeeb, astrocytic exosomes tau enriched nrog fibroblast kev loj hlob yam 2 thiab vascularendothelial kev loj hlob factor [128]. Ob leeg yog angiogenic molecules thiab mediate proliferation, axonal regeneration, neurogenesis, thiab synaptic plasticity [129,130]. Kev ntxhov siab ua rau muaj kev suav nrog glycolytic enzyme aldolase C hauv astrocytic exosomes [131].

Kev nce qib ntawm aldolaseC tsis tsuas yog ua rau muaj kev qhia ntawm miR-26a-5p hauv astrocytes, tab sis kev ntim cov qib siab ntawm miR-26a-5p hauv exosomes. Internalization ntawm astrocytic exosomes nrog nce qib ntawm miR-26a-5p txo MAP2 thiab GSk3 protein ntau hauv hippocampalneurons, ua rau txo dendritic complexity [132].

Kev nthuav tawm ntawm thawj nas corticalastrocyte kab lis kev cai rau pro-inflammatory cytokines, I, L1, thiab TNF ua rau tso tawm ntawm exosomes enriched nrog miRNAs uas tsom cov proteins koom nrog hauv neurotropin signaling.

Tshwj xeeb tshaj yog, miR-125a-5p thiab miR-16-5p tau tsom rau NTKR3 thiab nws cov dej ntws qis effectorBcl2. Downregulation ntawm Bcl2 hauv neurons ua rau txo qis ntawm dendritic kev loj hlob thiab complexity [133]. Yog li, astrocytes teb rau cov teeb meem inflammatory los ntawm modulating theexpression ntawm cov proteins koom nrog hauv synaptic stability thiab neuronal excitability.

Kev txo qis hauv kev ua haujlwm neuronal tuaj yeem cuam tshuam zoo rau kev muaj sia nyob tom qab kev thuam. Exosomes tso tawm los ntawm astrocytes nyob rau hauv cov lus teb rau intracerebral txhaj ntawm IL-1 imicese nkag mus rau hauv lub peripheral ncig thiab txhawb kev recruitment ntawm peripheral leukocytes. Yog li, cov ntaub ntawv no pom zoo tias exosomes txuas kev sib txuas lus ntawm lawv thiab lub antheperiphery [134].

Oligodendrocyte-Derived Exosomes: Kev nthuav tawm sai thiab txhim khu kev qha ntawm kev ua haujlwm muaj peev xwm ntawm axons nyob ntawm lub myelination ntawm neurons. Oligodendrocytes ensheath ntau axons Encanto txuas ntxiv myelin sheaths peb zaug hauv 2hours h hour135].Myelin tshwj xeeb yog enriched hauv lipids tab sis suav ntau cov proteins ib qho tseem ceeb rau kev tsim myelin.

Cov protein ntau ntawm myelin suav nrog cov protein ntau ntawm cov protein (PLP), myelinbasic protein (MBP), myelin-associated glycoprotein (MAG), thiab, 30-cyclic nucleotide30- phosphodiesterase (CNP) [136]. Ob lub proteins, PLP thiab MBP, tau muab faib rau hauv myelin sheath thiab yog cov cuab yeej siv rau hauv cov txheej txheem ntawm kev sib cog lus uas ua rau muaj cov qauv tsim ntau yam ntawm myelin.

Ntxiv rau lawv cov haujlwm tseem ceeb hauv kev tsim cov myelin, oligodendrocytes muab kev txhawb nqa trophic rau axons thiab yog li tseem ceeb rau kev ncaj ncees axonal [137]. Kev sib txuas lus ntawm oligodendrocytes thiab neuronsis tseem ceeb kom ua tiav txoj haujlwm tseem ceeb no. Cov kev tshawb fawb tsis ntev los no qhia tau hais tias oligodendrocyteexosomes yog sab hauv los ntawm cov neurons kom pab txhawb trophic rau axons.

Zoo ib yam li cov neurons, exosome tso tawm los ntawm oligodendrocytes iactivity-dependentnt. Cov neurotransmitterglutamate tso tawm los ntawm cov neurons nquag txhawb kev nce hauv cov cellular calcium inoligodendroglia ntawm NMDA thiab AMPA receptors.

Nce cytosolic Ca2+ ua rau lub zais zis ntawm CN-P thiab PLP-enriched exosomes los ntawm oligodendrocytes. Thaum tso tawm, exosomes yog internalized los ntawm neurons ua tiav ob txoj kev ncaj qha kev sib cuam tshuam ntawm oligodendrocytes thiab neurons [109,138].

Nyob rau hauv vitro kev tshawb fawb siv kab lis kev cai neurons ntxiv qhia tau tias exosomes tso tawm los ntawm oligodendrocytes nce neuronal ciaj sia nyob rau hauv tej yam kev mob ntawm cell stress [109]. Hauv kev txuas ntxiv ntawm cov kev tshawb fawb no, Frühbeis thiab cov npoj yaig tau pom tias CNP- thiab PLP-cov nas tsis muaj peev xwm nthuav tawm cov exosome tso tawm los ntawm oligodendrocytes [139].

Qhov tseem ceeb, oligodendrocytes cais thiab coj los ntawm CNP mutant nas lossis PLP mutant nas pom qhov txo qis hauv exosome tso tawm yog li cuam tshuam kev sib txuas lus oligodendrocytesneuron.

Tsis muaj kev sib txuas lus ntawm oligodendrocytes thiab neuronsvia exosomes ua rau axonal degeneration thiab txo cov metabolite txhawb rau neurons [139]. Cov kev soj ntsuam no qhia tias oligodendrocyte exosomes ua qhov tseem ceeb ntawm kev saib xyuas ntawm neuronal homeostasis.

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