Kev Kho Hniav Mesenchymal Stem Cell Secretome: Ib Txoj Kev Zoo Rau Neuroprotection Thiab Neuroregeneration Part 2

Nws yog ib qho tseem ceeb uas yuav tsum nco ntsoov tias lub hnub nyoog pub dawb thiab microenvironmental tej yam kev mob hauv vitromay kuj cuam tshuam rau secretome muaj pes tsawg leeg. DPSC-CM tau txais nyob rau hauv cov xwm txheej normoxic tau tshaj tawm tias yuav ua kom muaj txiaj ntsig hauv cov molecules nrog kev tiv thaiv kab mob, kho cov ntaub so ntswg, thiab cov khoom tsim dua qub piv rau CM tau txais hauv cov mob hypoxic [44].

Hauv tib neeg kev kawm, kev nco, thiab kev paub, hauv vitro microenvironment plays lub luag haujlwm tseem ceeb. Kev ua neej nyob hauv ib puag ncig zoo hauv vitro microenvironment tuaj yeem pab peb tswj kev nco zoo, txhim kho kev kawm, thiab txhawb kev noj qab haus huv tag nrho.

Ua ntej, qhov zoo hauv vitro microenvironment tuaj yeem txhawb kev tsim thiab kev saib xyuas ntawm kev sib txuas neuronal. Neurons yog ib hom ntawm tes hauv lub hlwb uas muaj lub luag haujlwm rau kev xa cov cim thiab tsim kev nco. Thaum peb kawm tej yam tshiab, kev sib txuas ntawm cov neurons yuav ntxiv dag zog ntxiv, uas pab tsim cov cim tshiab. Ib puag ncig zoo tuaj yeem pab kev sib txuas neuronal nyob ruaj khov yam tsis muaj kev cuam tshuam.

Qhov thib ob, nyob rau hauv vitro microenvironment tuaj yeem cuam tshuam cov metabolism thiab kev ua haujlwm ntawm lub hlwb hlwb. Cov pa oxygen txaus, khoom noj khoom haus, thiab dej tuaj yeem txhim kho cov qib metabolic ntawm lub hlwb ntawm lub hlwb, zam lub hlwb kev tuag thiab kev laus, thiab yog li muaj txiaj ntsig zoo rau kev txhim kho kev nco thiab kev txawj ntse. Nyob rau tib lub sijhawm, qhov chaw nyob ntsiag to lossis ib puag ncig zoo tuaj yeem pab tib neeg kom mloog zoo thiab txhawb kev txhim kho kev kawm thiab kev ua haujlwm zoo.

Tsis tas li ntawd, ib puag ncig noj qab haus huv hauv vitro kuj muaj qhov cuam tshuam zoo rau lwm yam ntawm kev noj qab haus huv ntawm lub cev. Kev siv zog ua haujlwm xws li pw tsaug zog txaus, tso siab rau kev noj zaub mov zoo, thiab kev tawm dag zog me ntsis tuaj yeem txhim kho kev nco thiab kev txawj ntse. Txoj kev ua neej noj qab nyob zoo uas koom nrog lub cev thiab lub siab tuaj yeem txo cov kev xav tsis zoo xws li kev ntxhov siab, kev nyuaj siab, thiab kev ntxhov siab, yog li pab txhim kho lub hlwb kev ua haujlwm thiab kev xav tseem ceeb.

Hauv cov ntsiab lus, muaj qhov sib cais tsis sib xws ntawm qhov nyob hauv vitro microenvironment thiab nco. Ib puag ncig zoo tuaj yeem pab ntxiv dag zog rau kev sib txuas ntawm cov neurons thiab txhim kho cov metabolism hauv lub hlwb, yog li txhawb kev tsim thiab tswj kev nco, thiab nws kuj yog ib qho kev lees paub ntawm lub cev thiab lub hlwb. Cia peb ua haujlwm ua ke los tsim kom muaj kev noj qab haus huv thiab zoo hauv vitro ib puag ncig los ua kom muaj txiaj ntsig zoo rau peb txoj kev noj qab haus huv thiab kev vam meej. Txiv Neej Txiv Neej:

Nws tuaj yeem pom tias peb yuav tsum txhim kho kev nco, thiab Cistanche tuaj yeem txhim kho kev nco, vim

Cistanche yog cov khoom siv tshuaj suav tshuaj suav nrog ntau yam tshwj xeeb, ib qho ntawm kev txhim kho kev nco. Kev ua tau zoo ntawm Cistanche los ntawm ntau yam khoom xyaw uas nws muaj, suav nrog tannic acid, polysaccharides, flavonoid glycosides, thiab lwm yam. Cov khoom xyaw no tuaj yeem txhawb lub hlwb kev noj qab haus huv ntau txoj hauv kev.

Nyem paub 10 txoj hauv kev los txhim kho kev nco

Ntxiv mus, secretomecollected los ntawm 5% O2 kab lis kev cai DPSCs pom muaj zog stimulatory ntau dua ntawm kev loj hlob thiab tsiv teb tsaws ntawm nas embryonic fibroblast NIH3T3 hlwb thiab neuronal sib txawv ntawm SH-SY5Y hlwb [45].
Qhov ntau thiab qhov loj ntawm EXOs thiab lawv cov lus qhia tetraspanin kuj txawv nyob ntawm qhov nruab nrab siv rau kab lis kev cai [46]. Cov secretome ntawm SHEDs thiab cov tub ntxhais hluasDPSCs muaj ntau yam kev loj hlob thiab qis qis ntawm cov pro-inflammatory cytokines piv rau DPSCs tau los ntawm cov kev kawm qub.

Qhov sib txawv muaj peev xwm kuj tseem siab dua hauv SHEDs thiab cov tub ntxhais hluas DPSCs [47].

CM tuaj yeem tau txais los ntawm PDLSCs noj qab haus huv tab sis kuj yog los ntawm PDLSCs. CM tau los ntawm cov kab mob ua rau muaj kev loj hlob ntawm ob qho tib si noj qab haus huv thiab o PDLSCs tab sis txo qhov sib txawv rau osteoblasts. Noj qab nyob zoo CM cawm tau qhov tsis taus osteogenicdifferentiation [48].

Kev kho mob nrog cov tshuaj sib txawv kuj tuaj yeem cuam tshuam cov cell secretome. Kev kho mob ntawm DPSCs nrog 2,3,5,40-tetrahydroxystilbene-2-O- -D-glucoside (THSG), bioactive tivthaiv ntawm Polygonum multiflorum Thunb., induced hloov nyob rau hauv lub secretion. ofgrowth-associated proteins hauv CM, nce ib co ntawm lawv xws li AKT2 thiab NGF receptor [49].

Hloov chaw, CM los ntawm FGF-2- hloov GMSCs muaj ntau VEGF-A, FGF-2, thiab TGF- [50]. Ascorbic acid kev kho mob ntawm SHEDs tau nce qhov kev tso tawm ntawm kev loj hlob yam tsim nyog rau cov ntaub so ntswg regeneration thiab homeostasis, xws li VEGF, SCF, IGF-1, HGF, bFGF, Ang-1, thiab EGF, thiab anti-inflammatory cytokines, xws li as NO, indoleamine 2,3-dioxygenase (IDO), PGE-2, IL-10, thiab IL-6.

Ntawm qhov tsis sib xws, inflammatory cytokines CCL2and TGF- 1 raug txo [51].

Qhov cuam tshuam rau qhov sib txawv nruab nrab kuj tuaj yeem ua rau muaj kev hloov pauv hauv cov tsis-coding RNAin EVs thiab EXOs ntawm PDLSCs.

Tshwj xeeb, 69–557 ncig RNA (circRNAs) thiab 2907–11,581lncRNAs tau pom nyob rau hauv EVs cais los ntawm PDLSCs thiab PDLSCs raug rau osteogenicdifferentiation nruab nrab ntawm lub sijhawm sib txawv.

Piv nrog cov PDLSCsEVs uas tsis txawv txav, 3 circRNAs thiab 2 lncRNAs tau raug tswj hwm thiab 39 circRNAs thiab 5 lncRNAs tau raug txo qis tsis tu ncua tom qab 5 thiab 7 hnub ntawm kev sib txawv nruab nrab [52].

Ntxiv mus, 72 miRNAs tau upregulated thaum 35 tau downregulated nyob rau hauv PDLSCs EXOsafter osteogenic induction [53].Cov ntsiab lus ntawm lub ntsiab yam tseem ceeb pom nyob rau hauv lub secretome ntawm txawv hniav MSCscan muaj nyob rau hauv Table 1.

Yog, angiopoietin; BDNF, hlwb-derived neurotrophic yam; BMP, pob txha morphogenetic protein; BMSCs, pob txha MSCs; circRNA, ncig RNA; CM, txias nruab nrab; KUB 7, culin 7; CXCL, CXC motif chemokineligand; DACCs, tsim apical complex hlwb; DFSCs, kho hniav follicle qia hlwb; DPSCs, kho hniav stemcells; ECM, extracellular matrix; EGF, epidermal loj hlob yam; ECM, extracellular matrix; EVs, extracellularvesicles; EXOs, exosomes; FGF, fibroblast kev loj hlob zoo; G-CSF, granulocyte colony-stimulating factor; GDNF, glial-cell-derived neurotrophic yam; GM-CSF, granulocyte-macrophage colony-stimulating factor; GMSCs, gingival MSCs; HGF, hepatocyte loj hlob yam; ICAM, Intercellular Adhesion Molecule; IDO, indoleamine2, 3-dioxygenase; IFN, interferon; IGF, kev loj hlob zoo li insulin; IL, interleuchin; lncRNA, ntev noncoding RNA; MCP, Monocyte Chemoattractant Protein; miRNA, microRNA; MMP, matrix metalloproteinase; NGF, nervegrowth yam; NT, neurotrophin; PDGF, platelet-derived kev loj hlob yam; PDLSCs, periodontal ligament qia hlwb; piRNA, PIWI-interacting RNAs; PSMA1, Proteasome subunit, alpha yam; SCAPs, qia hlwb los ntawm apical papilla; SDF, stromal cell-derived factor; SHEDs, qia hlwb los ntawm tib neeg exfoliated deciduous hniav; TGF, transforminggrowth factor; THSG, 2,3,5,40-tetrahydroxystilbene-2-O- -D-glucoside; TIMP, cov ntaub so ntswg inhibitor ntawm metalloproteinase; TNF, Tumor Necrosis Factor; UC-MSCs, umbilical qaum mesenchymal qia hlwb; VEGF, vascular endothelialgrowth factor ↑, nce / txhim kho; ↓, txo.

3. Kev Kho Hniav Stem Cell Secretome Neuroprotective thiab neuroregenerative Muaj peev xwm hauv Preclinical Qauv

Txhawm rau soj ntsuam cov kab mob neurodegenerative thiab neuroprotective muaj peev xwm ntawm dentalMSC secretome, cov teebmeem ntawm CM thiab EVs tau raug soj ntsuam hauv cov qauv ua ntej ntawm cov kab mob neurodegenerative thiab neurological thiab cov qauv ntawm kev puas tsuaj neuronal, xws li kev raug mob asspinal cord (SCI).

Tsis tas li ntawd, secretome-mediated teebmeem ntawm neuronal outgrowth, nws lub peev xwm los txhawb kev sib txawv neuronal, thiab nws cov teebmeem ntawm glial hlwb kuj tau soj ntsuam.

Peb tau ua ib qho kev tshawb nrhiav PubMed nrhiav kev tshawb fawb uas qhia txog cov neurodegenerative thiab neuroprotective peev xwm ntawm cov hniav MSCs secretome hauv vitro thiab hauv vivo qauv.

3.1. Hniav Pulp Stem Cell Secretome

DPSCs secretome yog ib qho ntawm cov kev tshawb fawb tshaj plaws. Cov kev tshawb fawb sib txawv tau ntsuas nws cov txiaj ntsig zoo hauv kev tsim cov neurite outgrowth. Nws tau tshaj tawm tias DPSC-CM txhawb nqa neurite outgrowthin dorsal root ganglion (DRG) neurons.

Tshwj xeeb, tag nrho qhov ntev thiab sib koom ua ke ntawm neurites tau nce tom qab kho nrog CM. Ntxiv mus, DPSC-CM txhawb nqa Schwann cellviability thiab myelin tsim [54].DPSCs-CM txhim kho cell ciaj sia taus thiab induced neurite outgrowth ntawm PC12 hlwb, asshown los ntawm neuronal nuclear protein (NeuN), microtubule-txuas protein 2 (MAP-2 ), thiab III-tubulin.

Tshwj xeeb, DPSCs-CM tau ua haujlwm zoo dua hauv kev ua rau PC12 neuriteoutgrowth piv rau DPSCs / PC12 co-cultures, qhia tias cell co-cultures muaj ncua sij hawm lag luam hauv kev tsim cov txiaj ntsig zoo ntawm trophic yam.

DPSCs-CM kuj tseem ua kom cov cell migration. Interestingly, tus naj npawb ntawm cov muaj sia nyob PC12 hlwb raug txo thaum CM tau ntxiv nrog anti-GDNF. Hloov chaw, qhov sib ntxiv ntawm anti-NGF, anti-GDNF, andanti-BDNF antibodies attenuate PC12 neurite outgrowth.

Cov ntaub ntawv no tau pom tias NGF, BDNF, thiab GDNF tau koom nrog PC12 ciaj sia taus thiab sib txawv [55].Lub DPSC secretome qhia tau hais tias muaj txiaj ntsig zoo rau SH-SY5Y hlwb. Ntxiv mus, nws cov nyhuv ntawm neural maturation tau raug soj ntsuam. Nrog rau lub hom phiaj no, SH-SY5Y hlwb raug tsim los rau cov hlwb neuronal tom qab lawv raug rau DPSC secretome.

SHSY5Y hlwb raug rau DPSC secretome pom tau tias muaj kev loj hlob ntawm neurite, tau txais cov yam ntxwv ntawm cov hlwb neuronal, thiab nthuav tawm cov kev tiv thaiv kab mob ntxiv rau cov cim neuronal. Ntxiv mus, CM-kho SH-SY5Y hlwb tsim cov yam ntxwv txawv xws li Cd2+-sensitive tam sim no, uas qhia tias CM-DPSC-maturated SH-SY5Yacquired voltage-gated Ca{10}} channels [56].

Raws li txoj kev tshawb fawb dhau los, CM tau txais los ntawm DPSC daim ntawv ua rau muaj kev tsim thiab kev loj hlob ntawm cov neurites hauv neuronally sib txawv SH-SY5Y neuroblastoma hlwb. Cov kev cuam tshuam no tau txhim kho thaum DPSC cov ntawv tau raug kho nrog FGF2.

Cov teebmeem txhawb nqa neurite tau raug tshem tawm thaum cov neurotrophicfactors raug txwv, qhia tias lawv xav tau rau cov txiaj ntsig zoo ntawm DPSCsheets ntawm kev ua haujlwm neuronal cell [57].

Tsis ntev los no, Chouaib et al. pov thawj tias DPSC-CM txhim kho ntawm neurite outgrowthin sensory neurons yog concentration-dependent. Cov kws sau ntawv kuj pom tias 48 h ntawm DPSCconditioning yog qhov kev xaiv zoo tshaj plaws kom tau txais CM nrog kev ua haujlwm tau zoo thaum ncua lub sijhawm txias tsis tau txhim kho cov teebmeem ntawm DPSC-CM.

Interestingly, lub frozenstorage tsis cuam tshuam cov txiaj ntsig kev sim. CM muaj qee yam uas paub txog lawv lub luag haujlwm hauv neurogenesis thiab neuroprotection tab sis kuj angiogenesis thiab osteogenesis. Tsis tas li ntawd, kev kho mob ntawm DPSCs nrog rau B-27 ntxiv tau txhim kho cov teebmeem ntawm neurodegenerative ntawm lawv cov secretome, ua rau muaj kev hloov pauv hauv nws cov ntsiab lus hauv kev loj hlob.

Tshwj xeeb, CM tau ua haujlwm zoo dua thaum B-27 tau ntxiv rau DPSCs ua ntej kho [58].CM los ntawm DPSCs txhim kho neuritogenesis thiab ua rau cov tshuaj tua kab mob kuj tseem muaj cov kab mob onneural stem cells (NSCs).

Lub priming ntawm DPSCs nrog leukocyte- thiab platelet-nplua nuj fibrin (LPRF) nce BDNF secretion tab sis tsis muaj kev cuam tshuam ntxiv rau ntawm paracrine-mediatedrepair mechanisms [59].

DPSC-derived CM kuj tau pom tias muaj peev xwm tiv thaiv thiab rov tsim cov kab mob sib cais thawj trigeminal ganglion neuronal hlwb (TGNC). Tseeb tiag, CM txhim kho TGNC survivalassociated nrog nws cov neurite outgrowth thiab branching.

Nyob rau hauv parallel, DPSC-CM ho txhawb nqa NeuN, III-tubulin, thiab synapsin-I neuronal marker qhia zoo li TRPV1. Interestingly, DPSC-CM muaj NGF, BDNF, NT-3, thiab GDNF [60].

G-CSF-mobilized DPSCs qhia ntau dua neurotrophic yam piv rau basalDPSCs thiab lawv cov secretome pom ib qho kev txhim kho neurite txuas ntxiv. Tseeb tiag, kev sib koom ua ke DPSC CM muaj kev cuam tshuam ntau dua ntawm neurite outgrowth hauv TGW hlwb [61]. Yav dhau los, nws tau pom tias CM los ntawm kev txhawb nqa DPSC txhim kho qhov kev loj hlob thiab kev tsiv teb tsaws ntawm neuronal Schwann RT4-D6P2T hlwb [62].

Interestingly, CM los ntawm SHEDs thiab DPSCs tau pom tias muaj peev xwm txhawb kev muaj peev xwm ntawm cerebral granular neurons inhibiting axon kev loj hlob inhibitor signals byparacrine mechanisms [63].Lub DPSCs secretome kuj qhia tau hais tias muaj txiaj ntsig zoo dua piv rau lwm cov MSCs.

Kumar et al.pom qhia tias cov secretome muab los ntawm DPSCs, SCAPs, thiab DFSCs induced neuraldifferentiation nyob rau hauv IMR{0}} hlwb, ib tug preneuroblastic cell kab, ntau npaum li BMSCs.

Tshwj xeeb, ntev neurite tau siab dua thaum IMR-32 hlwb raug kho nrog DPSC secretome. DPSC secretome muaj GCSF, IFN- , thiab TGF-, uas yuav txhawb kev sib txawv ntawm neural [64].

DPSCs, BMSCs, thiab AMSCs txhawb kev nce hauv kev ciaj sia ntawm co-cultured retinalganglion hlwb. Tshwj xeeb, qhov nce hauv kev ciaj sia tau txhim kho hauv DPSC-kho retinalcultures.

Interestingly, coculture nrog DPSC induced ib tug tseem ceeb nce nyob rau hauv ob qho tib si tus naj npawb ntawm neurite-bearing retinal ganglion hlwb thiab neurite ntev piv nrog cocultures nrog BMSCs thiab AMSCs. Txawm li cas los xij, cov teebmeem no tau thaiv kev siv cov neurotrophic factor receptors Fc-receptor blockers.

Qhov sib txawv ntawm MSCs tau pom cov qauv sib txawv ntawm qhov qhia txog cov teeb meem neurotrophic, thiab, tshwj xeeb tshaj yog, DPSCs tso tawm ntau theem ntawm kev loj hlob ntau yam xws li NGF, BDNF, thiab VEGF piv nrog BMSCs thiab AMSCs.

Ib qho ntxiv, VGF tuaj yeem kho cov teebmeem neuroprotective ntawm DPSCs [65].CM-DPSCs tau pom muaj kev tiv thaiv kev tiv thaiv ntawm oxygen-glucose deprivation (OGD)-inducedcytotoxicity hauv astrocytes nyob rau hauv ib koob tshuaj.

Tshwj xeeb, ob qho tib si ua ntej thiab tom qab kho nrog CM-DPSCs, tab sis kuj CM-BMSCs, attenuated OGD-induced glial fibrillary acidicprotein (GFAP), nestin, thiab musashi-1 qhia hauv astrocytes. Kev kho mob nrog CM kuj thaiv OGD-induced reactive oxygen hom (ROS) ntau lawm thiab IL-1 upregulation.Interestingly, CM-DPSCs confer superior cytoprotection tiv thaiv cell tuag piv nrog BMSCs [66].

Venugopal et al. piv cov neuroprotective peev xwm ntawm EXOs, CM, los yog neuron--MSC-co-culture system tiv thaiv kainic-acid-induced excitotoxicity hauv vitro. Ntxiv mus, txhawm rau txheeb xyuas hom MSC hloov tau zoo tshaj plaws, EXOs thiab CM tau txais los ntawm DPSCs thiab BMSCs raug kuaj.

Tag nrho peb txoj hauv kev tau pom tias muaj peev xwm tiv thaiv neuroprotective ua tsaug rau qhov kev loj hlob ntawm kev nthuav qhia thiab kev cuam tshuam ntawm apoptosis los ntawm kev ua kom PI3K-Bcl-2 txoj hauv kev.

Nws yog ib qho tseem ceeb uas yuav tsum nco ntsoov tias EXOs tau pom zoo los tiv thaiv necroticproperties piv rau neuron-MSC co-culture lossis CM. Hais txog CM, tsuas yog cov fractions muaj protein ntau nyob rau hauv thaj tsam ntawm 3-10 kDa pom kev tiv thaiv kab mob thiab cawm cov neurons los ntawm excitotoxicity [67].

Cov secretome ntawm DPSCs kuj pom muaj txiaj ntsig zoo hauv cov qauv ntawm cov kab mob neurodegenerative. Kev kho mob nrog DPSC secretome txo amyloid (A) cytotoxicity nyob rau hauv anin vitro qauv ntawm Alzheimer's kab mob (AD), nce cell viability thiab txo apoptosis.

DPSC secretome tau pom tias muaj qib siab ntawm VEGF, Fractalkine, RANTES, monocyte chemoattractant protein-1 (MCP-1), thiab GMCSF piv rau BMSCsand AMSCs.

Interestingly, neprilysin, ib tug protease muaj peev xwm degrade A, kuj pom nyob rau hauv lub DPSC secretome. DPSC secretome proteolytically degrades A 1-42 hauv vitro, ua rau tsis tiav degradation tom qab 12 h [68].

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