Mesenchymal Stem Cells Thiab Extracellular Vesicles hauv Kev Kho Mob Raum Kab Mob
Mar 06, 2023
Yuling Huang thiab Lina Yang*
Abstract
Cov kab mob raum ua rau muaj kev hem thawj rau tib neeg kev noj qab haus huv vim lawv qhov tshwm sim nce thiab tuag taus. Hauv kev tshawb fawb txog kev kho mob thiab kev kho mob, nws tau lees paub tias cov kab mob mesenchymal qia hlwb (MSCs) zoo thiab muaj kev nyab xeeb thaum siv los kho cov kab mob raum. MSCs ua si lawv lub luag haujlwm feem ntau los ntawm kev zais cov khoom trophic thiab xa cov hlwv extracellular (EVs). Cov ntaub ntawv caj ces thiab cov proteins uas muaj nyob rau hauv MSC-derived EVs (MSC-EVs), uas yog ib qho tseem ceeb ntawm kev sib txuas lus ntawm tes, tau dhau los ua kev tshawb fawb tsom rau kev kho mob raum. Tam sim no, MSC-EVs tau pom tias muaj kev kho mob tshwm sim ntawm mob raum raug mob (AKI), kab mob raum ntev (CKD), mob ntshav qab zib nephropathy (DN), thiab kab mob atherosclerotic renovascular (ARVD); Txawm li cas los xij, lawv lub luag haujlwm hauv lub raum hloov pauv tseem muaj teeb meem. Qhov kev tshuaj xyuas no qhia txog cov txheej txheem uas MSC-EVs kho cov kab mob no hauv cov qauv tsiaj thiab nthuav tawm qee yam teeb meem, cia siab tias yuav pab txhawb kev coj noj coj ua yav tom ntej.
Ntsiab lus: Kab mob raum, Mesenchymal qia hlwb, Extracellular vesicles
Taw qhia
Cov kab mob raum tau dhau los ua qhov teeb meem tseem ceeb hauv ntiaj teb kev noj qab haus huv vim lawv qhov xwm txheej thiab cov neeg tuag tau nce [1]. Cov kab mob hauv lub raum muaj xws li mob raum raug mob (AKI), kab mob raum ntev (CKD), mob ntshav qab zib nephropathy (DN), lupus nephritis, thiab mob ntshav siab nephropathy, tshwm sim los ntawm ntau yam ua rau. Txoj kev kho mob tseem ceeb ntawm cov kab mob raum no suav nrog kev kho tshuaj, kev lim ntshav, thiab hloov lub raum [2, 3]; Txawm li cas los xij, cov kev kho tshiab tau tshwm sim vim muaj kev txwv ntawm kev kho tshuaj, qhov tsis yooj yim ntawm kev lim ntshav, thiab qhov tsis txaus ntawm cov neeg pub rau lub raum hloov pauv [4]. Nyob rau hauv xyoo tas los no, qia hlwb, raws li kev kho tshiab, tau siv los kho ntau yam kab mob, suav nrog kab mob raum [5]. Yog li ntawd, MSCs tau dhau los ua ib txoj hauv kev tshiab ntawm kev kho mob raum. Piv nrog rau MSCs, kho cov kab mob raum nrog MSC-derived extracellular vesicles (MSCEVs) yog tus cwj pwm los ntawm qhov zoo xws li qis dua immunogenicity thiab tumorigenicity [6]; Txawm li cas los xij, txoj hauv kev thiab kev ua haujlwm ntawm MSC-EVs hauv kev kho mob raum tsis tau piav qhia, thiab kev siv tshuaj kho mob ntawm MSC-EVs tseem tab tom tshawb nrhiav. Xav txog qhov no, hauv qhov kev tshuaj xyuas no, peb nthuav qhia cov xwm txheej ntawm kev tshawb fawb txog MSC-EVs hauv kev kho mob.kab mob raum.
Cistanche txiv neej cov txiaj ntsig
MSC-EV
Biological yam ntxwv ntawm MSCs
Cov qia hlwb tuaj yeem muab faib ua ob pawg: embryonic thiab cov neeg laus qia hlwb, raws li lawv theem ntawm kev loj hlob. Cov neeg laus qia hlwb xa mus rau cov hlwb tsis txawv ntawm cov ntaub so ntswg sib txawv thiab muaj nyob hauv ntau cov ntaub so ntswg thiab cov kabmob ntawm lub cev. MSCs, raws li ib hom kev rov ua dua tshiab ntawm tus kheej cov neeg laus qia cell, tuaj yeem sib txawv rau ntau hom hlwb. MSCs tuaj yeem raug cais tawm ntawm ntau cov ntaub so ntswg xws li pob txha pob txha-derived MSCs (BMMSCs) [7], adipose-derived MSCs (ADMSCs) [8], human umbilical cord-derived MSCs (huMSCs) [9], human placenta-derived MSCs. [10], thiab cov uas los ntawm cov ntaub so ntswg, tawv nqaij, ntshav, thiab zis [5, 11]. Hauv kev tshawb fawb uas twb muaj lawm, BMMSCs, ADMSCs, thiab huMSCs feem ntau yog siv. Kev tshawb fawb tau pom tias MSCs nrhiav thaj chaw raug mob los ntawm kev sib cuam tshuam ncaj qha thiab cov nyhuv paracrine [12, 13] thaum tsis tshua muaj nyob ntawm qhov sib txawv [14]. Los ntawm kev kos npe, nws pom tias, tom qab txhaj rau hauv lub cev, MSCs tuaj yeem tshwj xeeb nyob rau hauv cov chaw raug mob ntawm lub raum [15–17]. Cov txheej txheem molecular ntawm MSC homing yog ua raws li tus qauv multistep, suav nrog kev sib txuas pib los ntawm kev xaiv, kev ua kom los ntawm cytokines, ntes los ntawm integrins, diapedesis lossis transmigration, thiab tsiv mus rau chemokines [18]. Nws yuav tsum raug sau tseg tias chemokines thiab lawv cov receptors raug lees paub tias yog cov neeg kho mob tseem ceeb ntawm MSC homing; Txawm li cas los xij, qib qis ntawm homing molecules txwv qhov ua tau zoo ntawm MSC txoj kev kho [19]. de Witte et al. thiab Schrepfer et al. tau piav qhia tias qhov teeb meem tseem ceeb tom qab MSC kev tswj hwm yog tias lawv tsis tsom rau lub hom phiaj cov ntaub so ntswg, txwv lawv cov txiaj ntsig kho mob [20, 21]. Tom qab ntawd, kev tswj hwm lub hom phiaj, kev taw qhia sib nqus, kev hloov pauv caj ces, thiab kev tsim hluav taws xob ntawm tes, thiab lwm yam, tau kawm los pab txhawb MSC homing [18]. MSCs yog tswj hwm rau cov ntaub so ntswg feem ntau los ntawm kev xa tawm thiab xa tawm hauv zos, yav dhau los suav nrog hauv cov hlab ntsha thiab cov hlab ntsha thiab cov tom kawg suav nrog cov tshuaj pleev, intra-muscular, cov ntaub so ntswg ncaj qha, thiab catheter-raws li kev cog lus ncaj qha. Txawm li cas los xij, tsis muaj kev pom zoo rau txoj kev zoo rau MSC infusion [12]. Tsis tas li, MSCs tuaj yeem ua rau cov hlwb peripheral los ntawm secreting trophic yam xws li kev loj hlob, chemokines, thiab cytokines los yog xa cov qauv subcellular thiab txawm tias mitochondria los ntawm kev tsim tunneling nanotubes, secreting extracellular vesicles (EVs) thiab fusing nrog hlwb [22]. Nyob rau hauv tas li ntawd, cov synthesis thiab tso tawm ntawm EVs uas muaj proteins, messenger ribose nucleic acid (mRNA), thiab micro-ribose nucleic acid (miRNA) los ntawm paracrine tau dhau los ua qhov tseem ceeb ntawm kev tshawb fawb tam sim no. Hauv luv luv, MSCs/MSC-EVs tuaj yeem ua haujlwm sib txawv, raws li qhia hauv daim duab 1.
Biological yam ntxwv ntawm EVs
EVs, ib hom nanoscale vesicles encapsulated los ntawm cytomembranes, yuav muab faib ua exosomes (Exos), microvesicles (MVs), thiab apoptotic cev (Fig. 1), uas nws diameters yog 30–150 nm, 200–1000 nm, thiab 800– 5000nm, raws [23]. EVs, uas yog ib qho tseem ceeb ntawm kev sib txuas lus intercellular, muaj dav nyob rau hauv lub cev kua, nrog rau cov ntshav, zis, thiab amniotic kua. EVs nkag mus rau endosomes los tsim lub cev multivesicular (MVBs) los ntawm txoj kev budding, ces MVBs tau ua ke nrog cytomembranes tso tawm EVs [24]. EVs muaj DNA, RNA, proteins, thiab lipid, thiab cov tshuaj muaj nyob rau hauv EVs tshwj xeeb yog txiav txim los ntawm metrocytes [25]. Qhov no yog lub hauv paus rau kev siv EVs ua tus cim kev kuaj mob. Raws li cov cim ntsuas tsis muaj kev cuam tshuam, EVs tau nyiam ntau yam.
Fig. 1 Kev ua haujlwm ntawm MSCs/MSC-EVs. MSCs tuaj yeem nyob tshwj xeeb hauv thaj chaw raug mob ntawm lub raum. Tom qab ntawd, MSCs ua rau cov hlwb peripheral los ntawm kev zais cov khoom trophic xws li kev loj hlob, chemokines, thiab cytokines, lossis xa cov qauv subcellular thiab txawm tias mitochondria los ntawm kev tsim cov tunneling nanotubes, secreting EVs, thiab fusing nrog cov hlwb. EVs nkag mus rau endosomes los tsim MVBs los ntawm txoj kev budding, ces MVBs tau ua ke nrog cytomembrane tso tawm EVs. EVs tuaj yeem muab faib ua exosomes, MVs, thiab apoptotic lub cev. EVs, tshwj xeeb tshaj yog Exos, muaj DNA, RNA, proteins, thiab lipid. MSCs, mesenchymal qia hlwb; EVs, extracellular vesicles; MVBs, ntau lub cev; MVs, microvesicles
Piv txwv li, miRNAs ntawm urinary Exos ntseeg tau hais txog kev nce qib ntawm AKI [26]. EVs yog siv los ua tus yam ntxwv ntawm kev tsis lees paub hauv kev hloov lub plawv allogeneic [27]. MSC-EVs tuaj yeem ncua kev loj hlob ntawm cov kab mob raum los ntawm cov txheej txheem ntawm kev tiv thaiv apoptosis, tiv thaiv kab mob, tiv thaiv fibrosis, antioxidation, thiab lwm yam. Lwm cov kev tshawb fawb kuj pom tias EVs tau los ntawm lwm qhov chaw tuaj yeem txhim kho lub raum ua haujlwm, suav nrog rau lub raum tubular hlwb [ 28, 29], glomerular MSCs [30], MSCs cais tawm ntawm testis [31], thiab txawm tso zis [32]. Cov EVs no tau siv txoj hauv kev tshiab los kho cov kab mob raum.
Suav tshuaj ntsuab cistanche
Tsis tas li ntawd, EVs tuaj yeem ua qhov dav dav ntawm lub luag haujlwm raws li bioengineering tsim thiab tswj. EVs tuaj yeem nqa ntau hom tshuaj los ntawm kev hloov kho ua ntej thiab tom qab tso tawm [33] thiab ua si lawv lub luag haujlwm kho mob los ntawm kev thauj khoom ntawm qhov ntawd thiab tom qab lub hom phiaj [34], xws li micro-molecules, proteins, thiab nucleic acids [35]. EVs tau dhau los ua qhov kev tshawb fawb tsom mus rau kev siv tshuaj rau ntau yam kab mob, xws li nqa cov tshuaj antineoplastic [36] thiab tshuaj tiv thaiv kab mob [37]. Qhov tshwj xeeb ntawm uptake ntawm EVs yog nyob ntawm qhov chaw ntawm EVs thiab cov hlwb txais, nrog rau cov khoom siv, proteoglycans, lectins, glycolipid, thiab lwm yam, uas tuaj yeem pab hauv kev tsom mus rau [38]. Txawm li cas los xij, qhov kev tuav pov hwm qis thiab kev ruaj ntseg tsis zoo ntawm EVs tom qab hloov pauv kev txwv tsis pub siv ntxiv hauv tsev kho mob xyaum. Txhawm rau txhim kho cov txiaj ntsig kho mob ntawm MSC-EVs rau cov kab mob raum, EVs tau ntim rau hauv collagen matrix [39], matrix metalloproteinase{13}}sensitive selfassembling peptide hydrogel [40], thiab arginine-glycineaspartate (RGD) hydrogel [41] kom ncua lawv txoj kev tuav pov hwm thiab yog li induce sustained tso. Ua kom pom tseeb, RGD hydrogels cuam tshuam nrog EVs kev sib kho los ntawm integrin subunits v, 3, thiab 8 [41]. Dhau li ntawm kev ua kom qeeb ntawm kev tshem tawm cov txheej txheem ntawm EVs, encapsulation tuaj yeem pab EVs lub raum kom txo tau lub raum raug mob los ntawm kev puas tsuaj los ntawm kev txo qis, txhawb kev loj hlob ntawm tes, inhibition ntawm lub raum cell apoptosis, amplification ntawm autophagic activation, thiab txhim kho angiogenesis nrog rau ameliorating fibrosis [39- 41] ib. Nws kuj tseem pom tias qhov kev tshaj tawm ntawm Lub Kaum Hli -4 tuaj yeem txhim kho cov txiaj ntsig kho mob ntawm MSC-EVs [42], thiab hypoxia txhawb nqa MSCs kom zais ntau EVs [43]. Erythropoietin-processed MSC-EVs tuaj yeem nce cov ntsiab lus miRNA hauv EVs thiab yog li ntawd tuaj yeem pab txhim kho kev tiv thaiv ntawm lub raum [44].
MSC-EVs thiab kab mob raum
MSC-EVs and AKI
AKI feem ntau tshwm sim hauv cov neeg mob hnyav, txawm tias kev tuag ntawm cov neeg mob AKI tsis nyob hauv cov tsev kho mob hnyav yog siab li 10-20 feem pua [45]. Tseem muaj qhov tsis muaj kev kho tshwj xeeb thiab ua tau zoo rau AKI, thaum kev hloov pauv ntawm cov qia cell vam meej. Ntau qhov kev sim tau lees paub cov txiaj ntsig ntawm MSCs hauv kev kho AKI, thiab ntau txoj hauv kev los txhim kho cov txiaj ntsig ntawm MSCs tau tshwm sim nyob rau xyoo tas los no. Piv txwv li, IL-17A pom muaj peev xwm nce qhov feem pua ntawm Treg ntawm COX-2/PGE2 txoj hauv kev thiab simulate kev tiv thaiv kab mob ntawm MSCs [46]; los ntawm txheej MSCs nrog cov tshuaj tiv thaiv kab mob tiv thaiv lub raum raug mob molecule -1, kev tuav ntawm MSCs hauv lub raum ischemic yog ntev [47]; nyob rau hauv tus nas qauv ntawm cisplatin-induced AKI, MSCs yog txhaj ncaj qha mus rau lub aorta siv cov txheej txheem minimally invasive, uas txhim kho tus nqi ntawm kev siv MSCs [48]. Raws li kev tshawb fawb nce ntxiv, cov pov thawj qhia tau tias MSCEVs ua lub luag haujlwm tseem ceeb hauv kev kho AKI. MSC-EVs tuaj yeem txo cov AKI los ntawm inhibiting oxidation, apoptosis, thiab o thiab tswj cov angiogenesis, cell cycle, regeneration, autophagy, thiab proliferation [49–54] (Fig. 2). Txawm li cas los xij, rau AKIs nrog cov kab mob sib txawv, cov teeb liab tshuaj hloov los ntawm MSC-EVs mus rau lub hom phiaj hlwb qhia lawv cov yam ntxwv tshwj xeeb. Cov kab mob tseem ceeb ntawm AKI suav nrog rau lub raum toxicity ntawm cov tshuaj, ischaemic-reperfusion raug mob (IRI) tshwm sim los ntawm kev hloov pauv, thiab sepsis. Raws li txoj cai, kev sim AKI qauv feem ntau yog tshwm sim los ntawm cisplatin, gentamicin, paraquat, ischemia-reperfusion (I / R) los ntawm occlusion ntawm unilateral lossis ob sab raum cov hlab ntsha, thiab sepsis tshwm sim los ntawm caecal ligation thiab puncture (CLP). Cov txheej txheem ntawm MSC-EVs hauv cov qauv AKI sib txawv hauv qhov kev tshuaj xyuas no tau sau tseg hauv Table 1.
Cistanche tubulosa beneficios - raum
(Cistanche deserticola yog ib hom tshuaj suav tshuaj uas feem ntau siv hauv kev kho mob, uas muaj cov teebmeem ntawm kev ua kom sov thiab ua kom lub raum tonifying, moistening hnyuv thiab defecation, thiab tonifying ntshav essence. Cov tshuaj no muaj zog ua kom sov thiab tonifying raum yang. Nws tuaj yeem siv los kho tus mob khaub thuas hauv lub duav thiab lub hauv caug los ntawm lub raum tsis muaj zog, tso zis tsis zoo, tso zis ntau zaus, impotence, ejaculation ntxov ntxov, spermatorrhea, thiab lwm yam kab mob.)
I/R-induced raum raug mob
I / R yog ib hom kab mob ntawm AKI. Hauv kev sim tsiaj, I / R cov qauv feem ntau yog tsim los ntawm occluding lub unilateral lossis ob sab raum cov hlab ntsha thiab cov leeg thiab tom qab ntawd muab cov pa oxygen. Cov kev tshawb fawb yav dhau los tau qhia tias huMSC-EVs tuaj yeem txo lub raum IRI hauv cov nas ywj pheej los ntawm kev txhawb nqa angiogenesis vim yog hypoxia-inducible factor-1 [49]. MSC-EVs tseem tuaj yeem cuam tshuam cov macrophages hauv I / R qauv ntawm ntau txoj hauv kev los daws AKI. Hauv kev sim ua los ntawm Zou et al., MVs muab los ntawm tib neeg Wharton's jelly MSCs (hWJMSCs) inhibit qhov kev qhia ntawm lub raum chemokine CX3CL1 los ntawm miR-15a/15b/16 thiab txo cov CD68 ntxiv rau macrophages [55 ]. Shen et al. pom tias CC chemokine receptor-2 tau hais tawm ntawm BMMSC-Exos inhibits kev nrhiav neeg ua haujlwm thiab ua kom CCL2 rau macrophages los ntawm kev ua tus decoy los khi ligand CCL2 [56].
Apoptosis muaj feem cuam tshuam nrog IRI. Gu et al. txheeb xyuas, los ntawm kev sim hauv vivo thiab hauv vitro, tias EVs muab los ntawm hWJMSCs (hWJMSC-EVs) txo cov apoptosis ntawm lub raum tubular epithelial hlwb (TECs) los ntawm inhibiting mitochondria fission siv miR-30 [57]. Tsis tas li ntawd, Li et al. tau hais tias MSC-Exo qeeb qhov kev loj hlob ntawm IRI los ntawm inhibiting kev nthuav qhia ntawm inflammatory yam (IL-6, TNF-, NF-kappa B, thiab IFN- ) thiab apoptosis-txog yam (caspase -9), cleaved caspase-3, Bax, and Bcl-2) [50].
Fig. 2 Kev ua haujlwm ntawm MSC-EVs hauv cov qauv AKI sib txawv. MSC-EVs tuaj yeem txo qis AKI los ntawm inhibiting oxidation, apoptosis, thiab o thiab tswj cov angiogenesis, cell cycle, regeneration, autophagy, thiab proliferation. MSCs, mesenchymal qia hlwb; EVs, extracellular vesicles; AKI, mob raum raug mob; I / R, ischaemia-reperfusion; CLP, caecal ligation thiab puncture
Antioxidation yog ib qho kev ntsuas zoo los txo I / R. Zhang et al. qhia tias hWJMSC-EVs ua si lawv cov tshuaj tiv thaiv oxidative los ntawm kev ua kom muaj qhov cuam tshuam nuclear-erythroid 2- cuam tshuam txog Nrf2/ARE [57]. Tom qab ntawd, kev sim los ntawm Cao et al. pom tau hais tias BMMSC-EVs qhib lub Keap1-Nrf2 kev taw qhia txoj hauv kev hauv TECs los ntawm kev hloov miRNA-200a-3p, yog li modulating mitochondria los ua lub luag haujlwm antioxidative [51].
Cisplatin-induced AKI qauv
Cov qauv ntawm AKI induced los ntawm cov tshuaj feem ntau yog tsim los ntawm induction ntawm cisplatin. Siv cov cisplatin-induced AKI qauv, Bruno li al. pom tias BMMSC-MVs tiv thaiv lub raum los ntawm inducing kev qhia ntawm anti-apoptotic genes (Bcl-XL, Bcl2, thiab BIRC8) nyob rau hauv TECs thiab inhibiting kev qhia ntawm pro-apoptotic noob (Casp1, Casp8, thiab LTA) [58]. Zhou et al. xaus lus tias huMSC-Exos tuaj yeem txhawb kev loj hlob ntawm nephrocytes hauv vivo thiab hauv vitro los ntawm inducing lub phosphorylation thiab ua kom muaj zog ntawm extracellular regulated kinase (ERK) 1/2 txoj kev [52]. de Almeida et al. taw qhia txog kev ua haujlwm ntawm ADMSC-MVs hauv kev tswj cov hlwb raug mob thiab cov miRNA-mRNA network tshwj xeeb. Piv txwv li, miR-141 lub hom phiaj Ulk2 los tswj autophagy thiab miR{18}} lub hom phiaj Cul1 los hloov pauv lub voj voog ntawm tes [53]. Wang et al. tshawb pom tias huMSC-Exo ua ntej tuaj yeem tiv thaiv cisplatin-induced raum toxicity hauv vivo thiab hauv vitro los ntawm kev ua kom autophagy [59]. Jia et al. ua ob txoj kev tshawb fawb thiab txheeb xyuas 14-3-3ζ raws li lub tshuab tshiab ntawm autophagy qhib los ntawm huMSC-Exos:14-3-3ζ ua rau ATG16L, uas ua rau autophagy thiab yog li tiv thaiv cisplatin-induced AKI [60, 61]. Ullah et al. Tsis ntev los no tau hais tias BMMSC-EVs thiab pulsed tsom ultrasound ob leeg alleviate cisplatin-induced cell raug mob los ntawm inhibiting hsp70-mediated NLRP3 inflammasomes [62].
AKI qauv vim yog myolysis induced los ntawm glycerin
Nyob rau hauv xyoo tas los no, AKI qauv vim yog myolysis induced los ntawm glycerin kuj tau txais kev saib xyuas ntau. Nyob rau hauv xws li ib tug qauv, Bruno et al. pom tias BMMSC-EVs (feem ntau Exos) yog enriched nyob rau hauv tshwj xeeb mRNA (CCNB1, CDK8, thiab CDC6), uas cuam tshuam rau qhov pib thiab kev loj hlob ntawm cell cycles. Cov miRNAs muaj txiaj ntsig txhawb kev loj hlob los ntawm kev loj hlob (HGF thiab IGF-1) thiab yog li txo qis AKI [63]. Los ntawm bioengineering, Tapparo et al. nce miRNAs tshwj xeeb (has-miR-10a-5p, has-miR-29a- 3p, has-miR-127-3p, thiab has-miR -486-5p) hauv BMMSCEVs los simulate pro-regenerative effect ntawm no thiab alleviate lub raum raug mob los ntawm glycerin [54].
CLP
Tus qauv AKI npaj los ntawm CLP simulates sepsis ntsig txog AKI ntawm cov neeg mob hnyav. Nyob rau hauv nas nrog sepsis, Zhang et al. qhia tau tias huMSC-Exos inhibit NF-κB kev ua haujlwm los ntawm kev txhawb nqa miR-146b theem thaum txo qis interleukin-1 receptor-associated kinase qhia [64]. Ib yam li ntawd, Gao et al. tau hais tias ADMSC-Exo tuaj yeem tswj hwm NF-κB ntawm SIRT1 txoj kev taw qhia, yog li inhibiting o ntawm sepsis ntsig txog AKI [65].
MSC-EVs thiab CKD
Muaj cov pov thawj tshiab ua pov thawj tias, ntau zaus, AKI tuaj yeem hloov mus rau CKD [66]. Tom qab tsim AKI, qhov kev pheej hmoo ntxiv ntawm kev cog lus rau cov kab mob hauv lub raum kawg thiab CKD tau kwv yees tias yuav nce ntxiv los ntawm 0.4 thiab 10 tus neeg mob txhua xyoo hauv txhua 100 AKI cov neeg mob, raws li [67]. CKD yog tus cwj pwm los ntawm kev hloov pauv tsis hloov pauv ntawm lub raum parenchyma. Ntau yam kab mob tuaj yeem hloov mus rau hauv CKD, suav nrog AKI, ntshav qab zib, atherosclerosis, thiab nephrotic syndromes. Ntau daim ntawv pov thawj tau txais txog kev kho mob ntawm CKD nrog MSCs hauv kev sim ua ntej thiab tom qab kuaj mob. Nws tau pom nyob rau hauv kev tshawb fawb tsis ntev los no hais tias melatonin preconditioning txhim kho kev kho mob muaj peev xwm ntawm MSCs hauv autologous thiab allogeneic transplantation [68, 69]. Hauv kev sim tshuaj ntsuam xyuas nrog rau 18-hli kev soj ntsuam ntawm xya tus neeg mob CKD tsim nyog, ib koob tshuaj autologous MSCs tau raug pov thawj tias muaj kev nyab xeeb thiab zam tau rau cov neeg mob CKD [70]. Cov kws tshawb fawb tom qab ntawd pom tias qhov nruab nrab ntawm huMSCs txo cov fibrosis tshwm sim los ntawm unilateral ureteral obstruction (UUO) los ntawm pro-proliferation thiab antiapoptosis [71]. Txog niaj hnub no, ntau cov kev tshawb fawb hauv tsev kho mob tau ua pov thawj tias MSC-EVs tau zoo hauv kev kho CKD.
Nyob rau hauv tus qauv nas ntawm lub raum mob toxicity vim cyclosporine, qhov nruab nrab qis ntawm EVs, MSC-EVs, thiab EVs tuaj yeem txhim kho cov kab mob hauv lub raum [72]. Hauv cov qauv aristolochic acid nephropathy, MSC-EVs txo cov kev qhia ntawm pro-fibrogenic noob xws li -SMA, TGF 1, thiab Col1a1 [73]. Hauv UUO qauv, Wang et al. pom tias BMMSC-Exos alleviate lub raum interstitial fibrosis los ntawm inhibiting TGF{10}} nrog miRNA-let7c [74]. Tsis ntev los no, qee cov kws tshawb fawb pom (hauv tus qauv nas) uas huMSCExos txo qis rau lub raum interstitial fibrosis los ntawm kev tawm tsam ROS-mediated P38MAPK/ERK txoj hauv kev [75]. Chen et al. npaj siab tias glial-derived neurotrophic yam hloov kho ADMSC-Exos txhawb cov perivascular capillaries hauv tubulointerstitial fibrosis los ntawm kev ua kom SIRT1 / eNOS txoj kev [76]. Tsis tas li ntawd, kev tshawb fawb yav dhau los kuj tau qhia tias ADMSC-Exos txhawb kev qhia txog kev hloov pauv ntawm Sox9 ntawm TECs, thiab cov xeeb ntxwv ntawm Sox9 ntxiv rau cov hlwb pab txhawb kev tsim kho ntawm lub raum tubules ntau dua li kev hloov pauv ntawm fibrotic, yog li ua rau qeeb ntawm AKI-CKD kev hloov pauv [17, 77] ib.
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MSC-EVs and DN
DN yog lub ntsiab pathogenesis rau ESRD. Ntau qhov kev tshawb nrhiav tau ua pov thawj tias kev hloov pauv ntawm MSC tuaj yeem ua rau qeeb ntawm DN. Ib qho kev soj ntsuam randomized tau tshaj tawm tias nws muaj kev nyab xeeb thiab muaj peev xwm siv cov hlwb mesenchymal precursor hauv cov neeg mob ntshav qab zib hom 2 [78]; Txawm li cas los xij, muaj teeb meem kev tiv thaiv kab mob hauv kev hloov pauv ntawm allogeneic thiab kev puas tsuaj los ntawm hyperglycemia rau autologous MSCs. Txhawm rau daws cov teeb meem no, Nagaishi et al. innovatively siv Wharton's jelly extract supernatant los txhim kho morphologies, proliferation muaj peev xwm, thiab cellular mobilization muaj peev xwm ntawm cov ntshav qab zib-derived BMMSCs, uas enables zoo autologous transplantation [79]. Tsis ntev los no, qee cov kws tshawb fawb kuj tau sim ua ke kev coj noj coj ua MSCs nrog peritoneal macrophages [80] thiab hloov kho MSCs nrog angiotensin-hloov enzyme 2 [81] los txhim kho kev kho mob ntawm MSCs rau DN.
Lub tshuab ntawm MSC-EVs, uas yog ib txoj kev tshiab rau kev kho DN, yog nyob rau hauv kev tshawb nrhiav tas li. Gallo et al. pom tias MSC / tib neeg lub siab qia cell (HLSC)-EVs tuaj yeem tiv thaiv cov hlwb mesangial los ntawm kev puas tsuaj los ntawm hyperglycemia los ntawm kev hloov ntawm miR-222 [82]. Tsis tas li ntawd, hyperglycemia tuaj yeem cuam tshuam ncaj qha rau kev raug mob ntawm podocytes. Cov kev hloov pauv pathological ntawm podocytes muaj feem cuam tshuam nrog kev loj hlob ntawm DN. MSC-EVs tuaj yeem tiv thaiv podocytes thiab lwm lub raum hlwb los ntawm ntau txoj kev, suav nrog kev tiv thaiv apoptosis, anti-fibrosis, thiab cov teebmeem pro-autophagic, yog li kho DN (Daim duab 3). Duan et al. qhia tias Exo cais tawm ntawm qhov nruab nrab ntawm tib neeg cov zis-derived qia hlwb inhibits qhov kev qhia ntawm VEGFA thiab apoptosis ntawm podocytes los ntawm miRNA-16-5p, li no relieving DN [83]. Nws yog pov thawj los ntawm Duan et al. tias ADSCEV miRNA-26a-5p inhibits hyperglycemia-induced apoptosis ntawm podocytes hauv cov nas los ntawm kev txo qis TLR4 thiab NF-κB/VEGFA txoj kev taw qhia [84]. Anti-fibrosis kuj yog ib qho tseem ceeb mechanism uas tau hais hauv kev kho DN nrog MSC-EVs. Zhong et al. tau tshaj tawm tias MSC-MVs muaj peev xwm tiv thaiv lub voj voog ntawm tes inhibitors P15 thiab P19 hauv vivo thiab hauv vitro ntawm miRNA-451a, rov pib lub voj voog ntawm tes thiab yog li thim rov qab EMT thiab interstitial fibrosis [85]. Grange et al. tau txiav txim siab tias EVs ntawm HLSCs thiab MSCs tuaj yeem cuam tshuam thiab thim rov qab qhov kev loj hlob ntawm glomerular thiab tubule-interstitial fibrosis hauv DN nas qauv los ntawm kev txo qis fibrosis ntsig txog noob Serpia1a, FAS ligand, CCL3, TIMP1, MMP3, hom I collagen, thiab Snail [ 86]. Jin et al. txheeb xyuas tias ADMS C-Exo ua rau EMT tsis muaj zog ntawm podocytes los ntawm kev txwv cov noob caj noob ces ntawm ZEB2 los ntawm miRNA-215-5p [87]. Autophagy kuj tseem tsis ntev los no tau suav tias yog lub tshuab ua kom ncua DN. Ebrahim et al. tau lees paub tias MSC-Exos txhim kho autophagy thiab tom qab ntawd qeeb qhov kev loj hlob ntawm DN ntawm mTOR txoj kev taw qhia [88]. Jin et al. qhia ntxiv tias ADMSC-Exo tuaj yeem cuam tshuam Smad1 / mTOR teeb liab txoj hauv kev los ntawm miRNA-486, uas txhawb nqa autophagy thiab inhibits apoptosis hauv podocytes, yog li ua kom cov tsos mob ntawm DN [89]. Cov ntsiab lus ntawm cov kev sim uas tau hais los saum no yog sau tseg hauv Table 2.
MSC-EVs thiab cov kab mob atherosclerotic renovascular
Daim duab 3 Kev ua haujlwm ntawm MSC-EVs hauv DN. MSC-EVs tuaj yeem tiv thaiv podocytes thiab lwm cov hlwb los ntawm ntau txoj kev, suav nrog kev tiv thaiv apoptosis, anti-fibrosis, thiab cov teebmeem pro-autophagic, yog li kho DN. MSCs, mesenchymal qia hlwb; EVs, extracellular vesicles; DN, ntshav qab zib nephropathy
Atherosclerosis yog thawj qhov ua rau lub raum hlab ntsha stenosis. Atherosclerotic renovascular kab mob (ARVD) tuaj yeem ua rau lub raum tsis ua haujlwm ntev thiab ua rau mob fibrosis, uas tshwm sim rau hauv ESRD. Percutaneous transluminal raum angioplasty yog ib qho kev phais ntau rau kev kho ARVD; Txawm li cas los xij, nws yog qhov nyuaj los kho cov haujlwm ntawm lub raum atrophic. Cov kev sim tsiaj tau lees paub tias kev sib xyaw ntawm MSCs nrog ARVD los kho atherosclerotic lub raum hlab ntsha stenosis pab rov qab ua haujlwm ntawm lub raum [90]. Tom qab ntawd, ntau qhov kev sim tshuaj ntsuam xyuas tau ua rau muaj kev nyab xeeb ntawm infusing autologous ADMSCs hauv kev kho mob ARVD [91–93]. Ua raws li qhov no, ADMSC-EVs kuj tau dhau los ua qhov tseem ceeb ntawm kev tshawb fawb tsis ntev los no. Nyob rau hauv tus qauv ntawm unilateral renovascular kab mob complicating metabolic syndrome (MetS), Eirin li al. ua pov thawj tias autologous ADMSC-EVs txhim kho lub raum microvascular system hauv npua nrog cov kab mob metabolic raum vascular [94]. Tsis tas li ntawd, Simeoni et al. ntxiv cov miRNA hauv MSC-EVs yog lub hom phiaj tseem ceeb rau ARVD [95]. Tsis tas li ntawd, MSC-EVs kuj tau pom los txhim kho qhov zoo ntawm Treg los ntawm TGF- nyob rau hauv thiab yog li txhim kho cov haujlwm ntawm lub raum nrog rau lub raum hlab ntsha stenosis hauv MetS ntxiv rau RAS qauv [96]. Autologous ADMSC-EVs tseem tuaj yeem ua rau muaj kev hloov pauv ntawm phenotypes ntawm macrophages los ntawm M1 mus rau M2 ntawm IL-10, txhawm rau txo qis lub raum hlab ntsha stenosis [97].
Nyob rau tib lub sijhawm, qee cov kws tshawb fawb tau hais tias MSC-Exos tuaj yeem tsuas yog qee qhov txo qis cov laus lub raum vim yog lub raum hlab ntsha stenosis [98]. Mets muaj peev xwm hloov pauv qhov ntim ntawm miRNA ntawm EVs, txhawb kev laus-txog miRNA hauv EVs, thiab tseem txwv kev siv EVs hauv exogenous regenerative therapy los ntawm kev hloov pauv txawv txav [99–101]. Zhao et al. pom tias autologous ADMSCs tuaj yeem khaws microcirculation zoo dua los ntawm kev sib piv cov kev tshawb fawb, thaum ADMSC-EVs ua tau zoo dua hauv kev khaws cov nephrocytes tsis zoo thiab txo cov necrosis [102]. Hauv cov ntsiab lus, daim ntawv thov tus nqi ntawm MSC-EVs hauv kev kho mob ARVD tseem nyob hauv kev tsis sib haum xeeb, thiab kev tshawb fawb ntxiv tau lees paub los qhia lawv cov txiaj ntsig.
MSC-EVs thiab hloov lub raum
Lub raum hloov pauv yog txoj kev kho mob zoo tshaj plaws rau cov neeg mob lub raum tsis ua haujlwm kawg. Qhov tsis txaus ntawm tus neeg pub khoom nruab nrog cev thiab ib nrab-lub neej ntawm kev hloov pauv txwv txoj kev kho [4]. Tsis tas li ntawd, ischemia-induced AKI tau dav pom nyob rau hauv lub raum hloov pauv vim lub sijhawm muaj rau kev txhim kho ntawm ischemia muab ncua sijhawm ntawm kev nkag mus rau lub raum los ntawm tus neeg pub rau lub raum ischemia reperfusion hauv receptors [103].
Qhov no kuj yog ib qho laj thawj tseem ceeb ntawm kev ua haujlwm qeeb ntawm kev hloov pauv. Txhawm rau daws cov teeb meem no, kev cia txias zoo li qub, lub tshuab hypothermic perfusion (HMP), thiab ntau tus neeg siv tshuaj tshiab tsom rau ischemia thiab reperfusion yog nyob rau hauv kev kawm [104]. Kev ua haujlwm ntawm del Rio et al. txheeb xyuas tias HMP thiab normothermic regional perfusion yog qhov zoo dua rau kev cia txias txias [105]. Tsis tas li ntawd, cov kws tshawb fawb tau mob siab rau nrhiav lwm txoj hauv kev zoo los ua kom tiav cov txheej txheem tam sim no.
Kev sim nrog 105 Suav raum hloov pauv cov ntsiab lus uas tau txais autologous MSCs hauv kev rov ua dua ntawm lub raum hloov pauv qhia tias nws muaj peev xwm thiab muaj kev nyab xeeb siv MSCs hauv lub raum hloov pauv [106]; Txawm li cas los xij, qhov kev sim zoo sib xws tau ua los ntawm lwm pab pawg tshawb fawb tsis ntev los no tau pom tias cov teeb meem tom qab kev hloov pauv hauv lub raum, cov kab mob sib kis, lub raum tsis ua haujlwm, kev tsis lees paub ntau zaus, thiab lub sijhawm muaj sia nyob txhua qhov tsis qhia qhov sib txawv ntawm kev tswj hwm hauv 1- xyoo tshiab [107] Yog li ntawd, kev tiv thaiv ntawm MSC-EVs nyob rau hauv lub raum transplanted tseem yog ib qho teeb meem ntawm kev tsis sib haum xeeb. Gregorini et al. ua pov thawj tias ntxiv MSCs / EVs rau cov tshuaj Belzer hauv HMP lub sijhawm tuaj yeem tiv thaiv lub raum los ntawm ischemic raug mob los ntawm kev khaws cia cov txheej txheem enzymatic tseem ceeb rau cell viability [108]. Kev sim los ntawm Koch et al. tau qhia tias MSC-EVs tswj hwm kev tiv thaiv kab mob rau lub raum allogeneic hloov mus rau qee qhov [109]. Qhov txawv ntawm qhov no, los ntawm kev tsim cov qauv nas ntawm heterotopic hloov raum, Jose Ramirez-Bajo li al. pom tias autologous MSCs ncua lub sijhawm ciaj sia ntawm kev hloov pauv thiab cov ntsiab lus hauv cov qauv nas ntawm lub raum tsis lees paub, thaum EVs tsis [110]. Lub ntsiab lus no tsis tshua muaj kev kawm, thiab kev tshawb fawb ntxiv yuav tsum tau ua ua ntej yuav xaus lus.
Cistanche ntxiv nyob ze kuv↓↓↓
Cistanche lub cev tsim
Teeb meem thiab kev cia siab
Hauv kev tshawb fawb yav dhau los, MSCs tau pom tias ua lub luag haujlwm zoo hauv kev kho ntau yam kab mob raum. Piv txwv li, MSC-CM txo qhov kev sim tshuaj tiv thaiv glomerular hauv qab daus membrane glomerulonephritis los ntawm kev tsim txiaj ntawm M2 macrophage-mediated anti-inflammatory action [111]. Nyob rau hauv systemic lupus erythematosus (SLE), allogeneic MSC transplantation mitigates raum raug mob [112]. Kev sim tshuaj kho mob kuj tseem qhia tau tias nws muaj kev nyab xeeb thiab muaj peev xwm los kho cov neeg mob SLE nrog allogeneic MSCs los ntawm cov neeg pub noj qab haus huv [113]. Hauv cov qauv ntawm nephrotic syndrome tshwm sim los ntawm Adriamycin, MSCs feem ntau ua si lawv lub luag haujlwm hauv kev kho lub raum los ntawm kev tswj qhov mob [114]. Ntxiv mus, cov neeg noj qab haus huv pub dawb thiab cov neeg mob idiopathic nephrotic syndrome (INS) tsis pom qhov txawv txav hauv cov haujlwm thiab cov qauv ntawm MSCs, uas qhia tau tias MSCs tuaj yeem siv los kho INS nrog cov hlwb autologous [115]. MSC kev kho mob tau txais txiaj ntsig zoo ntawm IgAN los ntawm cov txheej txheem ntawm paracrine uas hloov pauv qhov sib npaug ntawm Th1 / Th2 cytokine [116]. Hauv cov qauv nas ntawm cov tshuaj tiv thaiv Thy1. MSCs txo lub raum kub siab thiab txhim kho lub raum ua haujlwm hauv 2- raum, 1-clip qauv [118]. Tsis muaj cov xwm txheej tsis zoo thiab cov xwm txheej tsis zoo tau raug soj ntsuam hauv kev kho mob thaum kho lub cev tiv thaiv antineutrophil cytoplasmic antibody-associated vasculitis [119] thiab autosomal dominant polycystic raum kab mob [120] nrog autologous mesenchymal stromal hlwb. Cov kev tshawb fawb uas twb muaj lawm kuj qhia tias MSCs tuaj yeem txo cov focal segmental glomerulosclerosis ntawm IL-22 [121].
Hauv kev xaus, ob qho tib si tsiaj qauv thiab kev sim tshuaj ntsuam tau muab pov thawj ntau ntawm MSCs hauv kev kho mob raum; Txawm li cas los xij, tsis muaj kev tshawb fawb me me rau kev kho cov kab mob uas tau hais tseg saum toj no nrog MSC-EVs, uas tseem yuav tau tshawb nrhiav. Qhov no ua tau vim tias kev sib cais, kev ua kom huv, thiab kev tsim khoom loj ntawm EVs tseem yog qhov nyuaj; Ntxiv mus, cov txheej txheem los ntawm MSC-EVs kho cov kab mob raum tsis tau piav qhia. Tsis tas li ntawd, nyob rau hauv kev txiav txim siab ntawm qhov zoo tshaj plaws, qhov tsim nyog npaum li cas, thiab txoj hauv kev tsim nyog ntawm kev tswj hwm ntawm EVs, kev tshawb fawb ntxiv yuav tsum tau ua los ntsuas qhov ua tau zoo ntawm kev siv MSC-EVs rau kev kho mob raum kab mob.
Xaus
Hauv qhov kev tshuaj xyuas no, peb tau sau tseg cov kev nce qib tsis ntev los no hauv kev nyuaj thiab tseem ceeb ntawm MSC-EVs hauv cov kab mob raum, suav nrog AKI, CKD, DN, ARVD, thiab hloov lub raum. Ntau cov ntawv txhawb nqa uas feem ntau cov kab mob hauv lub raum tuaj yeem tau txais txiaj ntsig los ntawm MSC-EVs; Txawm li cas los xij, qhov cuam tshuam ntawm kev hloov lub raum tseem muaj teeb meem. Txawm hais tias MSC-EVs cais tawm los ntawm ntau qhov chaw qhia tau hais tias muaj kev cog lus zoo raws li cov kws kho mob rau cov kab mob hauv lub raum hauv kev tshawb fawb tsiaj thiab kev sim ua ntej, kev tshawb fawb ntxiv yog tsim nyog vim tsuas yog qee qhov kev kho mob tau piav qhia nyob rau lub sijhawm no.
Cov ntawv luv
MSCs: Mesenchymal qia hlwb;
EVs: Extracellular vesicles;
MSC-EVs: MSCderived EVs;
CKD: Mob raum mob;
DN: Mob ntshav qab zib nephropathy;
ARVD: Kab mob atherosclerotic renovascular;
AKI: mob raum mob;
BMMSCs: Pob txha pob txha-derived MSCs;
ADMSCs: Adipose-derived
MSCs; huMSCs: Tib neeg txoj hlab ntaws-derived MSCs;
mRNA: Neeg xa xov liaison ribose nucleic acid;
miRNA: Micro-ribose nucleic acid;
MVs: Microvesicles;
Exos: Exosomes;
MVBs: Multivesicular cev;
RGD: Arginine-glycine-aspartate;
IRI: Ischemic reperfusion raug mob;
I/R: Ischaemia-reperfusion;
CLP: Caecal ligation thiab puncture;
hWJMSCs: Human Wharton's jelly MSCs;
hWJMSCEVs: EVs derived from hWJMSCs;
TECs: Tubular epithelial hlwb;
ERK: Extracellular tswj kinase;
UUO: Unilateral ureteral obstruction;
HLSC: Tib neeg lub siab qia cell;
ARVD: Kab mob atherosclerotic renovascular;
MetS: Metabolic Syndrome; HMP:
Hypothermic tshuab perfusion;
SLE: Systemic lupus erythematosus;
INS: Idiopathic nephrotic Syndrome
Kev lees paub
Peb ua tsaug rau National Natural Science Foundation of China (Grant No. 81970663) thiab Natural Science Foundation of Liaoning Province (Grant No. 2019-BS-277).
Cov neeg sau ntawv pab txhawb
Lina Yang tau pab txhawb rau kev kawm tsim. Yuling Huang thiab Lina Yang tau sau cov ntaub ntawv, tshuaj xyuas cov ntaub ntawv, thiab sau tsab xov xwm. Txhua tus kws sau ntawv tau nyeem thiab pom zoo cov ntawv sau kawg.
Nyiaj txiag
Qhov kev tshawb fawb no tau txais kev txhawb nqa los ntawm National Natural Science Foundation ntawm Tuam Tshoj (Grant No. 81970663) thiab Natural Science Foundation of Liaoning Province (Grant No. 2019-BS-277).
Muaj cov ntaub ntawv thiab cov ntaub ntawv
Cov ntaub ntawv siv thiab tshuaj xyuas hauv kev tshawb fawb tam sim no muaj los ntawm tus neeg sau ntawv raws li qhov kev thov tsim nyog.
Cov lus tshaj tawm
Kev pom zoo ntawm kev ncaj ncees thiab kev tso cai los koom
Tsis siv tau.
Tso cai rau kev tshaj tawm
Tsis siv tau.
Kev nyiam sib tw
Cov kws sau ntawv tshaj tawm tias lawv tsis muaj kev sib tw nyiam.
Tau Txais: 4 Lub Ib Hlis 2021 Txais: 15 Lub Peb Hlis 2021
Cov ntaub ntawv
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