Kev Kho Mob Zoo Ntawm Lub Raum Fibrosis: Thioredoxin Domain Muaj 5 (TXNDC5)

Yog xav paub ntxiv:ali.ma@wecistanche.com

Tshooj Ⅱ:Endoplasmic reticulum protein TXNDC5 txhawb nqa lub raum fibrosis los ntawm kev tswj TGF- signaling hauv raum fibroblasts

Yen-Ting Chen, Pei-Yu Jhao & et al.

NYEM QHOV NO RAU PART Ⅰ

Lub raum fibrosis, ib qho kev tshwm sim ntawm pathological tshwm sim ntawm txhua yam ntawmmob raum mob(CKD), feem ntau ua rau muaj mob raum caws pliav thiab ua rau muaj kab mob raum kawg. Tam sim no, tsis muaj kev kho mob zooraum fibrosis. Tsis ntev los no, peb lub chaw kuaj mob tau txheeb xyuas cov protein nyob hauv ER,thioredoxin domain muaj 5(TXNDC5), as a critical mediator of cardiacfibrosis. Transcriptome tsom xam ntawm lub raum biopsy cov qauv los ntawm cov neeg mob nrog CKD qhia cim TXNDC5 (thioredoxin domain muaj 5)upregulation nyob rau hauv lub raum fibrotic, qhia txog lub luag hauj lwm muaj peev xwm ntawm TXNDC5 (thioredoxin domain muaj 5) hauvlub raumfibrosis. Kev ua haujlwm ntau yam fluorescence reporter nas kab, peb pom tias TXNDC5 (thioredoxin domain muaj 5)tau tshwj xeeb upregulated nyob rau hauv collagen-secreting fibroblasts nyob rau hauv fibrotic nas ob lub raum. Tsis tas li ntawd, peb pom tias TXNDC5 (thioredoxin domain muaj 5)yog xav tau rau TGF- 1-induced fibrogenic teb nyob rau hauv tib neeg lub raum fibroblasts (HKFs), whereas TXNDC5 (thioredoxin domain muaj 5)overexpression yog txaus los txhawb HKF ua kom, proliferation, thiab collagen ntau lawm. Mechanistically, peb pom tias TXNDC5 (thioredoxin domain muaj 5), transcriptionally tswj los ntawm ATF6-dependent ER txoj kev nyuaj siab, kho nws cov teebmeem profibrogenic los ntawm kev tswj TGF- signaling kev ua los ntawm posttranslational stabilization thiab upregulation ntawm hom I TGF- receptor nyob rau hauv lub raum fibroblasts. Siv tamoxifen-inducible, fibroblast-specific Txndc5 knockout nas kab, peb tau pom tias tshem tawm Txndc5 nyob rau hauv lub raum fibroblasts mitigated qhov kev loj hlob ntawm tsim.raumfibrosis, suggesting therapeutic potential of TXNDC5 (thioredoxin domain muaj 5)tsom raulub raumfibrosisthiab CKD.

Nyem rau Cistanche herba rau mob raum

Hauv txoj kev tshawb no, peb pom tias TXNDC5 (thioredoxin domain muaj 5), ib qho ER-neeg nyob hauv cov protein disulfide isomerase enriched nyob rau hauv lub raum fibroblasts, pab cuam tshuam rau lub pathogenesis ntawmraum fibrosis. TXC 5 (thioredoxin domain muaj 5)tau upregulated ob lub raum los ntawm cov neeg mob nrog CKD thiab los ntawm nas qauv ntawmraum fibrosisinduced los ntawm UUO, uIRI, los yog FA kev kho mob. Kev tshawb nrhiav tshuab qhia tias TXNDC5 (thioredoxin domain muaj 5)txhawb nqa lub raum fibrogenesis los ntawm kev txhim kho profibrotic TGF- signaling los ntawm kev ua kom cov protein folding thiab ruaj khov ntawm TGFBR1, ua rau kev ua kom thiab proliferation ntawm lub raum fibroblasts uas tsim ECM cov protein ntau. Tsis tas li ntawd, TGF- 1 induces TXNDC5 (thioredoxin domain muaj 5)qhia los ntawm kev nce qib ER kev ntxhov siab thiab ATF6- nyob ntawm kev tswj hwm kev hloov pauv hauv lub raum fibroblasts. Ua ke nrog cov teebmeem profibrogenic ntawm TXNDC5 (thioredoxin domain muaj 5)pom nyob rau hauv lub raum fibroblasts, ntiaj teb no deletion ntawm Txndc5 (thioredoxin domain muaj 5)tiv thaivlub raumfibrosisinduced los ntawm UUO, uIRI, los yog FA. Targeted deletion of Txndc5 (thioredoxin domain muaj 5)nyob rau hauv collagen-secreting raum fibroblasts, tab sis tsis nyob rau hauv TECs, endothelial hlwb, thiab podocytes, yuav txo tau lub tsim thiab txo qhov kev loj hlob ntawm cov kab mob.lub raumfibrosisteb rau kev raug mob. Ua ke, cov txiaj ntsig no qhia txog lub luag haujlwm tshiab ntawm TXNDC5 (thioredoxin domain muaj 5)nyob rau hauv txoj kev loj hlob ntawmlub raumfibrosislos ntawm txoj cai ntawm TGFBR1 thiab TGF- 1 signaling. Cov ntaub ntawv no kuj qhia tias lub hom phiaj TXNDC5 (thioredoxin domain muaj 5)yog ib txoj hauv kev uas muaj peev xwm kho tau zoo los kho lossis tiv thaivlub raumfibrosisthiab CKD. Ib qho schematic hauv daim duab 11D qhia txog kev tswj hwm thiab kev ua haujlwm fibrogenic ntawm TXNDC5 (thioredoxin domain muaj 5)nyob rau hauv lub raum fibroblasts.

TGF- 1 signaling plays lub luag haujlwm tseem ceeb hauv kev txhim kholub raumfibrosis(32-34). Tom qab kev thuam rau lub raum, TGF- 1 raug tso tawm los ntawm TECs raug mob thiab ua rau muaj kev ua haujlwm ntawm TGF- 1 qhia hauv lub raum fibroblasts(4).TGF- 1 khi rau TGFBR2, uas nrhiav neeg, phosphorylates, thiab ua kom TGF-BR1. Phosphorylated TGFBR1 ces activates SMAD3-dependent canonical TGF- 1 signaling, as well as Ras and TAK1, constituents of SMAD-independent, noncanonical TGF- 1 signaling (35). Pharmacological inhibition ntawm TGF- signaling siv neutralizing antibodies (36-38) los yog inhibitors (39,40) tau qhia txog kev tiv thaivlub raumfibrosisnyob rau hauv preclinical qauv. Hauv particular, pentoxifylline, ib qho nonspecific phosphodiesterase inhibitor kev kho mob ua pov thawj kom txo qis glomerular pom tus nqi thiab txhim kho proteinuria (16,41), tau pom tias txo qis.lub raumfibrosislos ntawm kev thaiv cov Smad3/4-mediated fibrogenic teebmeem(14). Txawm hais tias TGF- 1 txoj hauv kev inhibition zoo nkaus li yog lub tswv yim txaus nyiam los kholub raumfibrosis, feem ntau, yog tias tsis yog tag nrho, cov tshuaj kws tshuaj tsom mus rau TGF- 1 lossis TGF- receptors ncaj qha ua tsis tiav hauv kev sim tshuaj (42). Vim tias TGF- signaling plays lub luag haujlwm tseem ceeb hauv lub cev hauv kev loj hlob, kev sib txawv ntawm tes, cov ntaub so ntswg homeostasis, thiab lub cev tiv thaiv kab mob (43), kev cuam tshuam ncaj qha ntawm TGF- signaling tuaj yeem ua rau lub cev tsis muaj zog thiab kev tsis zoo nrog rau daim siab (44) thiab mob toxicity (45, 46). Cov txiaj ntsig tau nthuav tawm no nthuav tawm cov lus tawm tswv yim zoo tshiab ntawm TGF- 1/ATF6/TXNDC5/TGFBR1 signaling axis hauv raum fibroblasts, qhov twg TGF- 1 induces upregulation ntawm TXNDC5 (thioredoxin domain muaj 5)los ntawm ER kev ntxhov siab thiab ATF6- tswj hwm kev hloov pauv hloov pauv. TXNDC 5 (thioredoxin domain muaj 5)theem ntxiv txhim kho qhov folding thiab ruaj khov ntawm TGFBR1, ua rau kom nthuav dav TGF- 1 cov lus qhia thiab cov lus teb fibrogenic tom qab. Target TXNDC 5 (thioredoxin domain muaj 5), yog li ntawd, tuaj yeem cuam tshuam fibrogenic TGF- 1 taw qhia los ntawm kev rhuav tshem qhov kev tawm tswv yim zoo no thiab yog li txo qis lub raum fibrogenesis. Cov xwm txheej fibroblast-txheej txheem ntawm TXNDC5 kuj ua rau nws lub hom phiaj zoo-tsim tshuaj kom tsis txhob muaj kev pheej hmoo ntawm kev cuam tshuam TGF- - nyob ntawm kev ua haujlwm ntawm lub cev hauv cov hlwb nonfibroblast.

Exploiting ntiaj teb no Txndc5 (thioredoxin domain muaj 5)deletion nas kab, peb pom tias poob ntawm TXNDC5 (thioredoxin domain muaj 5)tuaj yeem tiv thaiv lub raum fibrogenesis teb rau kev raug mob raum. Txawm li cas los xij, nws yog qhov tseem ceeb tshaj plaws los txiav txim siab yog tias lub hom phiaj TXNDC5 (thioredoxin domain muaj 5)tuaj yeem cuam tshuam lossis txawm daws qhov uas twb muaj lawmraumfibrosis. Txhawm rau teb cov lus nug no, tamoxifen-inducible, fibroblast-specific Txndc5 (thioredoxin domain muaj 5)conditional knockout nas kab (Txnd5ko) tau siv, thiab nws pom tias qhov induction ntawm Txndc5 (thioredoxin domain muaj 5)Kev tshem tawm hauv lub raum fibroblasts 10 hnub tom qab UUO, lub sijhawm taw qhia thaumlub raumfibrosistau tsim los (Daim duab 11B), txo qhov kev loj hlob thiab nthuav dav ntawmlub raumfibrosistshaj nyob rau hauv tswj nas. Cov ntaub ntawv no qhia tau hais tias muaj peev xwm ntawm lub hom phiaj TXNDC5 (thioredoxin domain muaj 5)raws li ib tug tshiab kho txoj kev mus halt txoj kev loj hlob ntawmlub raumfibrosishauv cov neeg mob CKD. Nco ntsoov, cov ntshav ntshav urea nitrogen (BUN) thiab creatinine tsis tau ntsuas hauv cov qauv nas siv hauv txoj kev tshawb fawb tam sim no vim qhov tseeb tias BUN / creatinine qib tsis cuam tshuam rau UUO thiab ulRI qauv thiab qee qhov sib txawv ntawm cov folic acid. nephropathy qauv (47-49). Cov kev tshawb fawb ntxiv yuav tsum tau txiav txim siab qhov cuam tshuam ntawm Txndc5 (thioredoxin domain muaj 5)kev tshem tawm ntawm lub raum ua haujlwm siv CKD nas qauv raug ntxias los ntawm txoj hauv kev los kho lossis tiv thaivlub raumfibrosisthiab CKD. Ib qho schematic hauv daim duab 11D qhia txog kev tswj hwm thiab kev ua haujlwm fibrogenic ntawm TXNDC5 (thioredoxin domain muaj 5)nyob rau hauv lub raum fibroblasts.

TGF- 1 signaling plays lub luag haujlwm tseem ceeb hauv kev txhim kholub raum fibrosis(32-34). Tom qab kev thuam rau lub raum, TGF- 1 raug tso tawm los ntawm TECs raug mob thiab ua rau muaj kev ua haujlwm ntawm TGF- 1 qhia hauv lub raum fibroblasts(4).TGF- 1 khi rau TGFBR2, uas nrhiav neeg, phosphorylates, thiab ua kom TGF-BR1. Phosphorylated TGFBR1 ces activates SMAD3-dependent canonical TGF- 1 signaling, as well as Ras and TAK1, constituents of SMAD-independent, noncanonical TGF- 1 signaling (35). Pharmacological inhibition ntawm TGF- signaling siv neutralizing antibodies (36-38) los yog inhibitors (39,40) tau qhia txog kev tiv thaivlub raumfibrosisnyob rau hauv preclinical qauv. Hauv particular, pentoxifylline, ib qho nonspecific phosphodiesterase inhibitor kev kho mob ua pov thawj kom txo qis glomerular pom tus nqi thiab txhim kho proteinuria (16,41), tau pom tias txo qis.lub raumfibrosislos ntawm kev thaiv cov Smad3/4-mediated fibrogenic teebmeem(14). Txawm hais tias TGF- 1 txoj hauv kev inhibition zoo nkaus li yog lub tswv yim txaus nyiam los kholub raumfibrosis, feem ntau, yog tias tsis yog tag nrho, cov tshuaj kws tshuaj tsom mus rau TGF- 1 lossis TGF- receptors ncaj qha ua tsis tiav hauv kev sim tshuaj (42). Vim tias TGF- signaling plays lub luag haujlwm tseem ceeb hauv lub cev hauv kev loj hlob, kev sib txawv ntawm tes, cov ntaub so ntswg homeostasis, thiab lub cev tiv thaiv kab mob (43), kev cuam tshuam ncaj qha ntawm TGF- signaling tuaj yeem ua rau lub cev tsis muaj zog thiab kev tsis zoo nrog rau daim siab (44) thiab mob toxicity (45, 46). Cov txiaj ntsig tau nthuav tawm no nthuav tawm cov lus tawm tswv yim zoo tshiab ntawm TGF- 1/ATF6/TXNDC5/TGFBR1 signaling axis hauv raum fibroblasts, qhov twg TGF- 1 induces upregulation ntawm TXNDC5 (thioredoxin domain muaj 5)los ntawm ER kev ntxhov siab thiab ATF6- tswj hwm kev hloov pauv hloov pauv. TXNDC 5 (thioredoxin domain muaj 5)theem ntxiv txhim kho qhov folding thiab ruaj khov ntawm TGFBR1, ua rau kom nthuav dav TGF- 1 cov lus qhia thiab cov lus teb fibrogenic tom qab. Target TXNDC 5 (thioredoxin domain muaj 5), yog li ntawd, tuaj yeem cuam tshuam fibrogenic TGF- 1 taw qhia los ntawm kev rhuav tshem qhov kev tawm tswv yim zoo no thiab yog li txo qis lub raum fibrogenesis. Fibroblast-restricted nature of TXNDC5 (thioredoxin domain muaj 5)kuj tseem ua rau nws lub hom phiaj tshuaj muaj txiaj ntsig kom tsis txhob muaj kev pheej hmoo ntawm kev cuam tshuam TGF- - nyob ntawm kev ua haujlwm ntawm lub cev hauv cov hlwb nonfibroblast.

Exploiting ntiaj teb no Txndc5 (thioredoxin domain muaj 5)deletion nas kab, peb pom tias poob ntawm TXNDC5 (thioredoxin domain muaj 5)tuaj yeem tiv thaiv lub raum fibrogenesis teb rau kev raug mob raum. Txawm li cas los xij, nws yog qhov tseem ceeb tshaj plaws los txiav txim siab yog tias lub hom phiaj TXNDC5 (thioredoxin domain muaj 5)tuaj yeem cuam tshuam lossis txawm daws lub raum uas twb muaj lawmfibrosis. Txhawm rau teb cov lus nug no, tamoxifen-inducible, fibroblast-specific Txndc5 (thioredoxin domain muaj 5)conditional knockout nas kab (Txnd5ko) tau siv, thiab nws pom tau hais tias qhov induction ntawm Txndc5 deletion nyob rau hauv lub raum fibroblasts 10 hnub tom qab UUO, lub sij hawm taw tes thaumlub raumfibrosistau tsim los (Daim duab 11B), txo qhov kev loj hlob thiab nthuav dav ntawmlub raumfibrosistshaj nyob rau hauv tswj nas. Cov ntaub ntawv no qhia tau hais tias muaj peev xwm ntawm lub hom phiaj TXNDC5 (thioredoxin domain muaj 5)raws li ib tug tshiab kho txoj kev mus halt txoj kev loj hlob ntawmlub raumfibrosishauv cov neeg mob CKD. Nco ntsoov, cov ntshav ntshav urea nitrogen (BUN) thiab creatinine tsis tau ntsuas hauv cov qauv nas siv hauv txoj kev tshawb fawb tam sim no vim qhov tseeb tias BUN / creatinine qib tsis cuam tshuam rau UUO thiab ulRI qauv thiab qee qhov sib txawv ntawm cov folic acid. nephropathy qauv (47-49). Cov kev tshawb fawb ntxiv yuav tsum tau txiav txim siab qhov cuam tshuam ntawm Txndc5 (thioredoxin domain muaj 5)Kev tshem tawm ntawm lub raum ua haujlwm siv CKD cov qauv nas raug ntxias los ntawm 5/6 nephrectomy thiab / lossis kev kho mob cyclosporin / cisplatin, cov qauv uas pom tseeb hloov pauv hauv BUN thiab creatinine qib (48).

Qhov loj ntawm fibrotic cheeb tsam txo tau pom nyob rau hauv Tendeseko nas kuj qis dua qhov pom hauv Txndc 57mice. Qhov no tuaj yeem yog vim qhov tsis tiav ntawm Txndc5 (thioredoxin domain muaj 5)nyob rau hauv lub raum fibroblasts hais txog kev ua tau zoo ntawm Cre-mediated recombination. Txawm hais tias nyob hauv lub raum fibroblasts raug suav hais tias yog qhov chaw loj ntawm caws pliav myofibroblasts hauv cov kab mob hauv lub raum fibrogenic (50), epithelial-to-mesenchymal hloov pauv (EMT, refs. 51, 52) thiab endothelial-to-mesenchymal hloov (EndoMT, ref.53) ) tau pom tias yuav pab txhawb txoj kev loj hlob ntawmlub raumfibrosis. vim TXNDC5 (thioredoxin domain muaj 5)kuj tau qhia nyob rau hauv ib feem ntawm TECs thiab endothelial hlwb, peb tsis tuaj yeem tshem tawm qhov ua tau tias TXNDC5 tuaj yeem ua rau lub raum fibrogenesis los ntawm kev txhawb nqa EMTor EndoMTin cov hlwb no. Cov kev tshawb fawb ntxiv yuav tsum tau kuaj xyuas qhov kev xav no ncaj qha. Cov tamoxifen-inducible, fibroblast-tshwj xeeb tej yam kev mob knockout nas kab siv nyob rau hauv txoj kev tshawb no, txawm li cas los xij, tso cai tshem tawm Txndc5in collagen-tsim cov active myofibroblasts tsis hais lawv keeb kwm (xws li, los ntawm TECs lossis endothelial hlwb). Qhov kev xav tias fibroblast-specific deletion ntawm Txndc5 (thioredoxin domain muaj 5)zoo eased txoj kev loj hlob thiab kev loj hlob ntawm postinjurylub raumfibrosisHauv cov nas, yog li ntawd, tseem tsis hloov pauv txawm tias TXNDC5 (thioredoxin domain muaj 5)ua lub luag haujlwm hauv EMT-lossis EndoMT-mediated raum fibrogenesis.

Txawm hais tias TGF- signaling feem ntau suav hais tias yog tus neeg nruab nrab nruab nrab ntawmlub raumfibrosis, TGF- signaling per se tuaj yeem yog qhov tseem ceeb los tswj cov homeostasis thiab kev noj qab haus huv ntawm lub raum cov ntaub so ntswg. Cov xwm txheej tshem tawm ntawm Tbgbr2 hauv lub raum tubular hlwb, piv txwv li, ua rau nce NF-kB signaling thiab raum mob (54). Kev tshem tawm ntawm Tbgbr2 hauv kev sau cov ducts exacerbateslub raumfibrosisnyob rau hauv teb rau UUO, tejzaum nws los ntawm kev txhim kho paracrine TGF- signaling ntawm epithelial thiab interstitial hlwb (55).Neelisetty li al, xaiv deletion ntawm Tbgbr2 nyob rau hauv matrix-tsim interstitial hlwb siv Colla2-Cre/ERT2* Tgfbr2 thiab Tenascin C-Cre/ERT*Tgfbr2M nas tsis pom kev tiv thaivlub raum fibrosisinduced los ntawm UUO los yog aristolochic acid (56), tawm tswv yim hais tias tshem tawm TGF- signaling nyob rau hauv lub raum fibroblasts tej zaum yuav tsis txaus los txo cov postinjury.lub raumfibrosis. Ntawm no, peb tau pom tias fibroblast-specific Txndc5 (thioredoxin domain muaj 5)kev tshem tawm (siv Colla2-Cre/ERT2*Txndc5) (thioredoxin domain muaj 5)ua rau txo TGFBR1, TGF- signalingactivityandfibrosishauv lub raum. Kev soj ntsuam uas tshem tawm ntawm Txndc5 (thioredoxin domain muaj 5), tab sis tsis Tgfbr2, nyob rau hauv lub raum fibroblasts / interstitial hlwb txolub raumfibrosisqhia tias tshem tawm Txndc5 (thioredoxin domain muaj 5)tej zaum yuav muaj cov teebmeem ntxiv los tiv thaiv fibrotic uas tsis muaj kev ywj pheej ntawm TGF- signaling. Tseeb, peb tau pom yav dhau los tias hauv plawv fibroblasts, TXNDC5 (thioredoxin domain muaj 5), raws li PDI, kuj txhawb fibrogenesis los ntawm kev yooj yim folding thiab zus tau tej cov ECM proteins (17). Nws tseem ua tau tias Txndc5 (thioredoxin domain muaj 5)Kev tshem tawm tuaj yeem ua rau ntxiv inhibition ntawm fibrogenic teeb liab-ing txoj hauv kev ywj pheej ntawm TGF- receptors xws li PDGF, CCN2, Hedgehog, thiab HIF-1 signaling (57), yog li muaj peev xwm ua rau nws cov tshuaj tua kab mob hauv lub raum. Cov kev sim ntxiv no yuav tsum tau kuaj xyuas cov kev xav no ncaj qha.

Hauv kev xaus, txoj kev tshawb fawb tam sim no tau qhia txog lub luag haujlwm tseem ceeb thiab yav dhau los tsis paub txog lub raum fibroblast-enriched ER protein TXNDC5 (thioredoxin domain muaj 5)nyob rau hauv lub pathogenesis ntawmlub raumfibrosis. Cov pov thawj sim qhia tias TXNDC5 (thioredoxin domain muaj 5)txhawb nqalub raumfibrosislos ntawm augmenting TGF- signaling kev ua los ntawm kev txhim kho lub folding thiab stability ntawm TGFBR1 nyob rau hauv lub raum fibroblasts, ua rau ntau tshaj myofibroblast transdifferentiation, proliferation, thiab ECM ntau lawm. Targeted deletion of Txndc5 (thioredoxin domain muaj 5)nyob rau hauv lub raum fibroblasts tiv thaiv kev loj hlob thiab kev loj hlob ntawm postinjurylub raumfibrosis. Cov txiaj ntsig no qhia tias lub hom phiaj TXNDC5 (thioredoxin domain muaj 5)tuaj yeem yog txoj hauv kev tshiab thiab muaj zog los kho lossis tiv thaivraum fibrosisthiab CKD.

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