Molecular Mechanisms Of Renal Progenitor Regulation: Muaj pes tsawg daim nyob rau hauv lub Puzzle?
Feb 24, 2022
Abstract: Lub raumNtawm cov nas, nas thiab tib neeg muaj cov progenitors uas tswj hwm homeostasis txhua hnub thiab koom nrog cov txheej txheem endogenous regenerative tom qab raug mob, vim lawv lub peev xwm loj hlob thiab sib txawv. Hauv glomerular thiab tubular compartments ntawm nephron, cov kev tshawb fawb zoo ib yam pom tau tias muaj cov yam ntxwv zoo, cov neeg sib txawv ntawm cov hlwb progenitor, nyob rau hauv lub parietal epithelium ntawm Bowman capsule thiab tawg nyob rau hauv lub proximal thiab distal tubules, tuaj yeem tsim cov kab mob tshwj xeeb hauv lub cev. thiab tom qab cov ntaub so ntswg raug mob. Txawm li cas los xij, cov lus teb tsis zoo los yog txawv txav ntawm cov progenitors tuaj yeem ua rau cov mob pathologic. Cov yam ntxwv ntawm molecularlub raumProgenitors tau raug tshawb fawb ntau, qhia tias ntau txoj hauv kev zoo li qub thiab hloov pauv tau khaws cia, xws li Notch lossis Wnt / -catenin, ua lub luag haujlwm tseem ceeb hauv kev tswj hwm ntawm tes. Lwm tus, xws li retinoic acid, renin-angiotensin-aldosterone system, TLR2 (Tau-zoo li receptor 2) thiab leptin, kuj tseem ceeb hauv cov txheej txheem no. Hauv qhov kev tshuaj xyuas no, peb sau cov plethora ntawm molecular mechanisms cojlub raumProgenitor teb thaum homeostasis thiab tom qabmob raum.Thaum kawg, peb yuav tshawb xyuas seb qhov kev sib txuas ntawm ib leeg RNA tuaj yeem coj tus cwj pwm ntawmlub raumprogenitors mus rau qib tom ntej, thaum paub txog lawv cov molecular kos npe tau txais qhov tseem ceeb hauv tsev kho mob.
Ntsiab lus:raum progenitors; molecular mechanisms; mob raum; ib leeg-cell RNA sequencing; molecular kos npe
CISTANCHE yuav txhim kho rau lub raum/ raum mob
Taw qhia Mechanisms ntawm endogenous regeneration thiab kho tau raug npaj rau ob peb yam tsiaj txhu [1]. Classical regenerative organs, xws li kab mob plab thiab daim tawv nqaij, tau kawm ntau xyoo dhau los thiab tau coj los ua lub luag haujlwm tseem ceeb ntawm endogenous progenitors [2]. Nyob rau hauv txoj hnyuv, cov kab mob hauv plab hnyuv tswj txhua hnub homeostasis, thaum cov qia / progenitor hlwb yog tus saib xyuas cov txheej txheem kho sai tom qab raug mob [2]. Ib yam li ntawd, cov kab mob epidermal tsim muaj cov kab mob heterogeneous qia cell koom nrog hauv epidermal homeostasis, nrog rau cov ntaub so ntswg kho, tom qab qhov txhab [3]. Tus neeg lausraumyog ib qho khoom nruab nrog uas tsis muaj cellular turnover thiab endowed nrog progenitors muaj peev xwm ntawm proliferating thiab txawv [4,5]. Cov cuab yeej tseem ceeb no tso cai rau cov kws tshawb fawb thiab cov kws kho mob xav txog cov kev kho mob tshiab kom rov qab loslub raum ua haujlwmtom qab raug mob. Ntawm no, peb nthuav tawm cov ntsiab lus ntawm cov txheej txheem molecular uas tshwm sim hauv glomerular thiab tubularlub raumprogenitors nyob rau hauv physiological thiab pathological tej yam kev mob (Daim duab 1) thiab ntawm yuav ua li cas ib tug dysregulation ntawm txoj kev no yuav yog nyob rau hauv lub hauv paus ntawmmob raum. Peb kuj yuav tshuaj xyuas seb yuav ua li caslub raumprogenitors tuaj yeem ua tus cwj pwm ntxiv uas siv tib lub xov tooj ntawm tes RNA sequencing (scRNAseq) thev naus laus zis thiab kev soj ntsuam qhov cuam tshuam ntawm molecular kos npe ntawm cov hlwb no.
Lub raum Progenitors
Lub raum progenitors tau tshawb pom los ntawm Sagrinati li al. hauv tib neeglub raum, raws li kev qhia ntawm cov qia cell markers CD133 thiab CD24, nyob rau hauv qhov tsis muaj los yog tsis tshua muaj kev qhia ntawm txawv cim ers [6,7]. CD133 ntxiv rau CD24 ntxiv cov hlwb nyob hauv cheeb tsam ntawm lub tso zis ntawm Bowman capsule, nrog rau tawg mus rau hauv tubular compartmmt ntawm nephron ntawm cov hlwb sib txawv [6]. Ib txhialub raumprogenitors, suav nrog cov chaw nyob hauv Bowman capsule thiab ib pawg ntawm cov sc attered raws lub tubule, kuj qhia CD106 (tseem hu ua vascular cell adhesion molecule 1, VCAM1), thaum feem ntau ntawm cov progenitors nyob hauv lub tubule tsis [6, 8]. Cov phenotypical dCfferences qhia txog kev muaj peev xwm ua haujlwm sib txawv; Tseeb tiag, CD133 ntxiv rau CD24 ntxiv rau CD106- cov hlwb tawg ua ke raws cov tubules qhia txog kev ua haujlwm ntawm tubular progenitors, thaum CD133 ntxiv rau CD24 ntxiv rau CD106 ntxiv rau parietal epithelial eells (PECs) yog ntau yam [6]. Tsis tas li ntawd, ib pawg ntawm CD1 33 ntxiv rau CD24 ntxiv rau CD1 06 ntxiv rau cov progenitors nyob ze rau ntawm tus ncej ntawm Bowman capsule thiab qhia podocalyxin tuaj yeem tsim cov podocytes nkaus xwb [6]. Nyob rau hauv tas li ntawd, cov kev soj ntsuam no configure ib tug hierarchical kab ntawmlub raumprogenitors nyob rau hauv lubraumuas ua rau nco txog hemopoietic system [9]. PECs uas muaj cov yam ntxwv zoo sib xws thiab cov kab mob hauv lub cev kuj tau txheeb xyuas hauv nas thiab nas.lub raum[4, 10, 11]. Cov noob caj noob ces ntawm PECs nyob rau hauv cov kab transgenic inducible nas tau pom tias t PECs tsiv mus rau glomerular tuft thiab sib txawv rau hauv podocytes hauv ad oles cent nas [11]. Mo re rec ently, Pax2 ha s been tified as a marker for naslub raumprogenitors, thiab cov creation ntawm ib tug inducible nas modol rau kab mob tracing ntawm lub Pax2 ntxiv cell popul ation tso cai rau demanstrate qhov sib txawv ntawmlub raumprogenitors localized ntawm PECs rau hauv podocytes thaum postnatal glomerular loj hlob [4]. Cov kev tshawb fawb ntxiv tau pom tias cov juxtamedullary thiab corticol glomeruli muaj cov lej sib txawv ntawm Pax2 ntxiv rau cov progenitors, nrog cov cortical uas tau txais txiaj ntsig nrog ob zaug ntau dua Pax2 ntxiv rau cov noob qes glomerular podocyte suav hauv kev noj qab haus huv [12]. Nyob rau hauv cov laus naslub raum, cov hlwb tsis paub qab hau qhia txog neural cell adhesion molecule (NCAM) thiab cov progenitor cell marker CD24 tau piav qhia ntawm cov hlwb epithelial hauv ob sab phlu Bowman capsule [10].
Cov noob caj noob ces ntawm Pax2 ntxiv rau cov progenitors ntawm Bowman capsule ntawm nas tso cai ua kom pom tias cov progenitors sib txawv rau hauv podocytes hauv cov qauv ntawm focal segmental glomerulosclerosis (FSGS), thiab lawv cov lus teb rau kev raug mob txiav txim siab qhov tshwm sim ntawm glomerular disorders, ntxiv substantiating lawv lub luag hauj lwm raws li podocytes. niam txiv [4,12]. Tsis ntev los no, siv tus qauv transgenic nas nyob rau hauv uas podocytes tau sau nrog GFP (ntsuab fluorescent protein) thiab PECs tau ib txhij sau npe nrog tdTomato, Kaverina thiab cov npoj yaig kuj tau muab pov thawj muaj zog uas PECs ua lub hauv paus ntawm cov podocytes tshiab hauv cov nas laus thaum raug mob. Cov hlwb no tau tshaj tawm ob daim ntawv fluorescent, tau txais cov cim podocyte thiab pom cov txheej txheem tseem ceeb, theem nrab thiab qib thib ob [13]. Ib qho txawv txav progenitor teb rau kev raug mob kuj tuaj yeem ua rau glomerular disorders [4,10,14,15]. Tseeb, nyob rau hauv tej yam kev mob, nyob rau hauv tib neeg, nas thiab nas, ib tug chaotic tsiv teb tsaws thiab proliferation ntawm Bowman capsule progenitor hlwb tau pom los pab rau crescent tsim thiab glomerular caws pliav [4,10,14]. Kev tshawb fawb ntawm tib neeglub raumbiopsies tau ua raws li lub tswv yim hais tias proliferating progenitors tsim hyperplastic lesions nyob rau hauv crescentic thiab collapsing glomerulopathy [14], thiab cov txiaj ntsig zoo sib xws tau txais hauv nas [10]. Hauv cov nas, cov kab mob tracing ntawm PECs pom tau tias lawv qhov kev loj hlob ua rau muaj kev nce hauv cov xov tooj ntawm tes hauv crescents ntawm murine nephrotoxic serum nephritis thiab collapsing glomerupathies [16] thiab tsim cov kab mob sclerotic thiab extracellular matrix deposition hauv FSGS [15]. Tsis ntev los no, qhov tshwj xeeb kev soj ntsuam cov noob caj noob ces ntawm cov progenitors ntawm PECs tau pom tias lawv muaj kev koom tes hauv kev tsim cov kab mob glomerular hyperplastic glomerular uas tuaj yeem pom tau tias yog qhov tsis ua tiav los tsim kho podocyte tom qab raug mob [4]. Los ntawm tag nrho cov kev tshawb fawb no, nws tam sim no pom tseeb tiaslub raumprogenitors nyob rau hauv cov PECs teb rau podocyte raug mob, ua rau ib tug regenerative kev pab cuam, tab sis ib tug inefficient los yog ntau heev teb yuav ua rau ib tug ua hauj lwm cov ntaub so ntswg los ua ib tug caws pliav zoo li cov ntaub so ntswg uas muaj li ntawm cov hlwb thiab disorganized extracellular matrix. Yog li ntawd, paub txog cov mechanisms uas tsav qhov tseeb proliferative thiab txawv teb ntawmlub raumprogenitors thaum lub sij hawm homeostasis thiab tom qab raug mob yog qhov tseem ceeb heev thiab yuav tso cai rau kev txheeb xyuas ntawm putative modulators boost lub regenerative muaj peev xwm ntawmlub raumprogenitors.
Regulators ntawm Glomerular Progenitor Physiology: Thaum Lub Orchestra Tunes lub Suab
Qhov kev taw qhia txoj hauv kev tswj glomerular progenitor quiescence, proliferation thiab sib txawv rau podocytes noj qab nyob zoolub raum? Kev tshawb fawb ntawm nephrogenesis pom tau hais tias kev ua kom muaj zog ntawm -catenin / Wnt signaling sawv cev rau cov kauj ruam tseem ceeb tsav PEC sib txawv rau hauv podocytes thaum lub sij hawm kev loj hlob [17,18]. Tseeb tiag, kev tshem tawm ntawm Ctnnb1 (-catenin 1) hauv PECs nyob rau hauv ib qho xwm txheej knockout nas nyob rau lub caij S-zoo li lub cev theem induced glomerular anomalies thiab hloov PECs hauv Bowman capsules nrog zoo-differentiated podocytes. Tracing nephrogenesis nyob rau hauv embryonic conditional -catenin knockout nas qhia tau hais tias cov "parietal podocytes" muab tau los ntawm precursor hlwb nyob rau hauv lub parietal txheej ntawm lub S-zoo li tus lub cev los ntawm cov kab ncaj nraim mus. Cov fifindings no qhia tau hais tias -catenin / Wnt signaling yuav tsum tau rau qhov sib txawv thiab maturation ntawm PECs rau hauv podocytes [17]. WT1, tus thawj tswj hwm ntawm cov txheej txheem no [19], kuj yog ib qho muaj zog inhibitor ntawm -catenin / Wnt signaling pathway [18]. Cov kev tshawb fawb tau ua nyob rau hauv quiescent PECs pom tau hais tias qhov kev qhia ntawm WT1 yog suppressed los ntawm theem siab ntawm Pax2 thiab los ntawm kev qhia ntawm siab microRNA-193a (miR-193a) [20]. Thaum PECs txo qis cov kev qhia ntawm miR-193a, qhov no tso cai rau kev tswj hwm ntawm WT1, uas cuam tshuam -catenin/Wnt signaling thiab induces PEC sib txawv rau hauv podocytes. Tsis ntev los no hauv vitro cov txiaj ntsig tau pom tias apolipoprotein L1 (APOL1) kuj tswj PEC molecular phenotype los ntawm kev hloov pauv ntawm miR193a qhia thiab tias APOL1 thiab miR193a qhia txog kev sib raug zoo ntawm kev tawm tswv yim [21]. Tseeb tiag, hauv kab lis kev cai, PEC sib txawv rau hauv podocytes tau nrog los ntawm kev txo qis hauv miR-193 ib qho kev qhia. Ib yam li ntawd, kev tawm tsam ntawm miR-193ib qho kev nthuav qhia APOL1 [21]. Cov hauj lwm yav tom ntej yuav tsum hais txog seb qhov APOL1–miR-193a axis ua haujlwm zoo ib yam hauv vivo li nws ua hauv vitro hauv cov qauv hloov pauv cov nas thiab hauv tib neeglub raum. Interestingly, APOL1 yog ib tug susceptibility noob, nrog genetic variants uas ua rau kom muaj feem yuav tsim podocytopathies [22].
Kev tswj hwm ntawm kev txiav txim siab txoj hmoo ntawm tes thiab kev loj hlob ntawm tes hauv ntau qhov sib txawv yog ua los ntawm kev sib koom ua ke ntawm Wnt thiab Notch signaling pathways [23]. Lasagni et al. qhia tias, hauvlub raumprogenitors localized nyob rau hauv Bowman capsule, Notch activation txhawb kev nkag mus rau hauv S-theem ntawm lub voj voog ntawm tes thiab tom qab mitosis kom txog thaum lawv nyob rau hauv ib qho kev tsis sib haum xeeb [24]. Txawm li cas los xij, impaired downregulation ntawm txoj kev Notch thaum lub sij hawmlub raumprogenitor sib txawv induced tiam ntawm podocytes nrog txawv DNA ntsiab lus thiab lawv cov nram qab no tuag los ntawm mitotic kev puas tsuaj [24,25]. Cov txiaj ntsig tsis ntev los no qhia tau hais tias podocyte-derived CXCL12 (CXC motif chemokine ligand 12) inhibits Notch signaling, yog li tswj qhov quiescence ntawm podocyte progenitors [12]. Notch downregulation associates nrog upregulation ntawm cell voj voog inhibitors p21, p27 thiab p57 thiab downregulation ntawm cyclin D1 [24], conferring rau lub podocyte tus yam ntxwv ntawm ib tug postmitotic, nonproliferative cell. CXCL12-kev kho mob podocyte-renal progenitor tawm tswv yim mechanism kuj txwv kev tsim kho podocyte tom qab raug mob glomerular [12]. Tseeb, siv cov kab tracing ntawm Pax2 ntxivlub raumprogenitors nyob rau hauv nas nrog Adriamycin-induced nephropathy, cov kws tshawb fawb pom tau hais tias ib tug CXCL12 blockade txhawb de novo podocyte tsim thiab attenuates glomerulosclerosis [12].
CISTANCHE yuav txhim kho lub raum / raum ua haujlwm
Raws li kev txhim kho ntawmlub raumProgenitor sib txawv rau hauv podocytes tuaj yeem sawv cev rau kev kho kom zoo nkauj los txhawb kev tshem tawm cov kab mob glomerular, ntau cov kev tshawb fawb tau ua los txheeb xyuas cov sib txawv sib txawv. Retinoic acids (RA) yog derivatives ntawm vitamin A nrog tsim muaj txiaj ntsig hauv kev kho mob qog noj ntshav [26]. RA kuj tau tshwm sim los tiv thaivmob raumnyob rau hauv ntau yam kev sim qauv ntawmkab mob raum,suav nrog cov kab mob hloov me me, membranous nephropathy, FSGS, human immunodefificiency virus (HIV)-associated nephropathy (HIVAN) thiab lupus nephritis [27]. Ntau cov kev tshawb fawb tau qhia txog lub luag haujlwm ntawm RA hauv kev sib txawv ntawm cov podocyte hauv vitro [28,29], thiab peb siv RA hauv xov tooj ntawm tes kab lis kev cai los txhawblub raumProgenitor sib txawv ntawm cov kab mob podocyte [7] Interestingly, raug rau albumin, uas khi RA nrog siab affinity, thaum nyob rau hauv vitro kab lis kev cai yuav inhibit.lub raumprogenitor sib txawv rau podocytes los ntawm sequestering RA. Hauv vivo, peb tau tshaj tawm tias RA raug tso tawm hauv Bowman qhov chaw tom qab raug mob glomerular thiab nres qhov endogenous RA synthesis hauv tus qauv ntawm focal segmental glomerulosclerosis ua rau albuminuria, glomerular raug mob thiab kev tuag [30]. Kev tswj hwm exogenous ntawm RA, neutralizing cov sequestering kev ua ntawm albumin, tso cai rau lub regenerative teb ntawmlub raumprogenitors, tsim kom muaj kev nce hauv podocyte tus lej thiab kev txhim kho ntawmlub raum ua haujlwm[30]. Cov txiaj ntsig tsis ntev los no los ntawm Lasagni et al. [4] corroborated lub hypothesis hais tias pharmacological txoj hauv kev uas nce podocyte teb rau RA signaling yuav txo tau qhov kev loj hlob ntawm kev sim.mob raum. Tseeb, kev kho mob hauv vitro ntawmlub raumprogenitors nrog RA nyob rau hauv lub xub ntiag ntawm 6-bromo-indirubin-30 -oxime (BIO), ib tug glycogen synthase kinases 3 (GSK3) inhibitor, induced muaj zog sib txawv ntawm tib neeg.lub raumprogenitors mus rau podocytes los ntawm kev ua kom cov RA-responsive ntsiab (RARE) transcriptional kev ua ub no, piv txwv li, nce lub raum progenitor rhiab heev rau qhov sib txawv los ntawm endogenous RA. Kev txhim kho ntawm lub raum progenitor sib txawv rau hauv podocytes los ntawm kev siv BIO hauv cov qauv murine ntawm FSGS ua rau muaj kev cuam tshuam tseem ceeb ntawm tus kab mob, ua rau kom muaj kab mob hauv cov nas kho. Hauv kev nce qib nas qauv ntawm kev rog-txog ntshav qab zib hom 2, BIO ua ib qho ntxiv rau ob lub renin-angiotensin system (RAS) / sodium-glucose transporter (SGLT)-2 inhibition nrog metformin, ramipril thiab empagliflflozin attenuated glomerular fifiltration rate (GFR) poob los ntawm kev txo qis glomerulosclerosis, ua rau cov lej podocyte los ntawm kev txhawb nqa tshwj xeeb, nrog rau kev txhawb nqa de novo sib txawv ntawm podocyte progenitors thiab txhim kho cov fifiltration slit ntom [31].
Endlich et al. pom lub luag haujlwm ntawm Dach1 (Dachshund homolog 1) hauv kev txiav txim siab txoj hmoo ntawm tes ntawm PEC rau hauv podocytes thiab rau kev ua haujlwm zoo ntawm podocyte. Podocytes qhia txog qib siab ntawm Dach1 hauv vivo thiab hauv vitro, thaum PEC qhia txog qib qis ntawm Dach1. Cov kws sau ntawv pom tias qhov induction ntawm Dach1 qhia nyob rau hauv PEC tseem ceeb upregulates cov podocyte tshwj xeeb proteins synaptopodin thiab WT1. Interestingly, Dach1 yog ib feem ntawm Eya-Six-Hox-Pax kev tswj hwm network, thiab cov kev cai ntawm synaptopodin qhia tau nrog los ntawm concomitant downregulation ntawm Pax2 qhia [32].
Guhr et al. soj ntsuam los ntawm uas mechanismslub raumprogenitors tuav lub peev xwm los nthuav qhia podocyte proteins nyob rau hauv pathophysiologic tej yam kev mob thiab pom tau hais tias lawv muaj ib tug activated ubiquitin-proteasome system (UPS) uas ua rau kom sai degradation ntawm tshiab synthesized podocyte-tshwj xeeb cov proteins [33]. Ntawm qhov tod tes, UPS tuav cov podocyte tus kheej los ntawm kev tswj cov qib ntawm cov proteins tshwj xeeb hauv podocyte, xws li actin-binding proteins -actinin 4 (ACTN4) thiab synaptopodin (SYNPO), qhov transcription factor Wilms qog 1 (WT1), cov neeg hauv tsev neeg stomatin podocin, lub slit diaphragm protein nephrin, adapter protein NCK1 thiab activated protein kinase Cλ (PKCλ) [33]. UPS kev ua ub no yog qhov tseem ceeb ntawm kev txiav txim siab ntawm glomerular cell phenotypes thiab kev sib txawv.Nws yog zoo-paub tias, nyob rau hauv lubraum,Cov neeg kho tshuab ib puag ncig yog raug hloov kho hauv cov qauv tsim ntawm cov kab mob glomerular thiab tuaj yeem cuam tshuam rau lub xeev sib txawv ntawm ntau hom cell, suav nrog podocytes [34]. Tsis ntev los no peb tau txheeb xyuas qhov cuam tshuam ntawm substrate stiffness ntawmlub raumprogenitor cwj pwm, qhia tau hais tias, tsawg kawg hauv vitro, phenotype ntawm tib neeglub raumprogenitors yog heev nyob ntawm tus hluas lub modulus ntawm lub substrate, uas yog ib qho kev ntsuas ntawm qhov nruj ntawm cov khoom uas txhais tau tias yog qhov piv ntawm kev nyuaj siab rau strain, nrog stiffer substrates txhawb lub raum progenitor proliferation thiab tsiv teb tsaws. Lub substrate stiffness modulates kuj muaj peev xwm ntawmlub raumprogenitors kom sib txawv rau cov podocytes, nrog rau ib tug hluas lub modulus ntawm 12 kPa yog qhov zoo ntawm cov kev soj ntsuam. Siv tshuaj lom neeg thiab tshuaj tua kab mob, peb tau pom tias Rho kinase (ROCK) kev ua haujlwm yuav tsum tau los kho cov teebmeem ntawm qhov tawv nqaij.lub raumProgenitor kev loj hlob, tsiv teb tsaws thiab sib txawv [35] Qhov txo qis glomerular txhav yog ib qho ntawm ntau hom kev raug mob glomerular, suav nrog FSGS [34,36], qhia txog lub luag haujlwm tseem ceeb rau ROCK kuj hauvmob raum.
Renin angiotensin aldosterone system inhibitors (RAAS-I) yog cov tshuaj muaj txiaj ntsig zoo hauv kev ua kom tsis muaj zogmob raumlos ntawm ntau yam kev ua. Cov txheej txheem ua lub luag haujlwm rau kev kho cov teebmeem ntawm cov tshuaj no, nrog rau lawvlub raumcellular hom phiaj, tau kawm loj nyob rau hauv ntau yam tsiaj qauv ntawm tib neegmob raum. Cov ntaub ntawv tsis ntev los no tau pom tias lawv kuj tuaj yeem siv lawv cov txiaj ntsig zoo los ntawm kev txhawb nqalub raumProgenitor sib txawv rau hauv podocytes. Tseeb, nyob rau hauv tus qauv nas ntawm kev raug mob glomerular, kev kho mob nrog ACE-I induced ib tug txo ntawm progenitor proliferation, lub diminution ntawm crescent tsim thiab zam kev loj hlob mus rau glomerulosclerosis [10]. Yog li, kev ua kom zoo ntawm progenitor cell activation los ntawm cov tshuaj tau rov ua dua ib qho glomerular architecture [10]. Interestingly, kev qhia ntawm angiotensin (Ang) II receptor, AT1, raug txwv rau tsawg CD24 ntxiv rau PEC hauv tib neeg.lub raumtab sis tau hloov kho hauv cov kab mob hyperplastic [37], qhia txog kev koom tes ntawm Ang II / AT1 receptor txoj hauv kev txhawb nqa qhov txawv txav.lub raumProgenitor migration thiab proliferation nyob rau hauv cov kab mob proliferative [37] Raws li, nyob rau hauv tus neeg mob cuam tshuam los ntawm CGN (crescentic glomerulonephritis), ACE-I kev kho mob cuam tshuam nrog kev rov qab ntawm cov kab mob hyperplastic thiab normalizes AT1 receptor qhia ntawmlub raumprogenitors. Cov txiaj ntsig no muab lwm qhov kev piav qhia rau cov txiaj ntsig zoo tau pom tom qab kev kho mob angiotensin II receptor blocker (ARB). Ib yam li ntawd, ARB kev kho mob tau txhim kho qhov tshwm sim hauv tus qauv nas ntawm mesangial proliferative glomerulonephritis, ua rau muaj kev nce ntxiv ntawm PECs qhia cov cim ntawm cov qia hlwb [38].
Kev raug mob rau podocytes yog suav tias yog ib qho tseem ceeb pab rau cov ntshav qab zibmob raumkev vam meej mus rau theem kawgmob raum[39–41]. Suganami et al. qhia txog kev tiv thaiv thiab thim rov qabmob raumlos ntawm kev tswj hwm leptin hauv tsiaj qauv ntawm ntshav qab zib nephropathy [39]. Tsis ntev los no, Pichaiwong et al. pom tau hais tias hloov leptin tuaj yeem thim rov qab cov txheej txheem thiab kev ua haujlwm tsis zoo ntawm cov ntshav qab zib nephropathy siab heev hauv leptin-defificient BTBR ob/ob nas [41]. Tshwj xeeb, kev kho mob leptin, tab sis tsis yog RAAS-I, ua rau muaj qhov nce ntxiv hauv podocyte ntom ntom thiab tus lej thiab nce ntawm WT1- zoo proliferating PEC. Cov txheej txheem hauv qab ntawm cov txheej txheem no tau piav qhia ntxiv nyob rau hauv daim ntawv rov qab, qhov uas lawv tau pom tias kev kho ob leeg ntawm leptin-defificient ob/ob nas nrog cov xaiv antagonist ntawm endothelin-1 hom A receptor (ETAR) ua ke. Nrog RAAS inhibition coj mus rau qhov kev txhim kho phenotype [40], tus cwj pwm los ntawm kev ua kom PECs thiab nce tus naj npawb ntawm podocytes. Cov txiaj ntsig no muab pov thawj tsis ncaj qha tias PECs tuaj yeem yog lub peev xwm khaws cia kom rov qab tau cov podocytes ploj thiab tias qhov muaj peev xwm sib txawv ntawm PECs tuaj yeem yog lub hauv paus tseem ceeb rau kev rov qab los ntawm cov ntshav qab zib nephropathy uas tej zaum yuav yog tshuaj kho mob.
Regulators ntawm Glomerular Progenitors nyob rau hauv Pathology: Thaum Lub Orchestra tawm ntawm TuneThaumlub raumprogenitors tuaj yeem tsav podocyte rov tsim dua tom qab raug mob [4], lawv tuaj yeem tuaj yeem tshwm sim cov kab mob loj zuj zus lossis cov kab mob crescents uas yog cov cim ntawm ob qho tib si kab mob thiab cov kab mob glomerular uas tsis yog-flammatory [42]. Tseeb tiag, pov thawj hauv kev sim ua qauv [15] thiab hauv tib neeg biopsies qhia tias crescents yog tsim los ntawmlub raumprogenitors [14] uas txawv txav hloov lawv cov tshuaj tiv thaiv los ntawm kev kho kom raug mob. Nws tsis yog to taub tag nrho cov yam tseem ceeb yog lub luag haujlwm rau tilting qhov nyiaj tshuav. CGN yog tus kab mob zoo tshaj plaws nyob rau hauv uaslub raumprogenitors yog cov culprits loj. Cellular crescent yog qhov hloov pauv morphological pom hauv CGN. Nws yog txhais raws li lub multilayered accumulations ntawmlub raumprogenitors thiab lwm hom cell nyob rau hauv Bowman chaw. Yog li ntawd, nws occludes cov zis tso zis thiab cov flflow ntawm thawj cov zis, thiab tom qab ntawd, implicated nephron yog impaired. Lub rupture ntawm glomerular capillaries nyob rau hauv crescentic kab mob ua rau raug mobrenal progenitors mus rau lub siab concentration ntawm plasma uas ua rau kom loj hlob ntawm tib neeglub raumProgenitors hauv kab lis kev cai [43] Ob peb lub plasma cov ntsiab lus tuaj yeem suav rau qhov tsim crescent, tab sis, tam sim no, muaj cov ntaub ntawv zoo ib yam nkaus xwb rau kev ua kom fifibrinogen, ib tug tswv cuab ntawm lub tshuab ua kom coagulation cascade thaum raug mob vascular. Ib qho tsis muaj fifibrinogen los yog fifibrinolysis tiv thaiv crescent tsim nyob rau hauv ob peb nas qauv [43,44].
Collapsing nephropathy thiab pseudo crescents kuj tshwm sim los ntawmlub raumcov txiv neej [14]. Ntawm qhov sib txawv nrog crescents, nws tau npaj siab tias pseudocresescents los ntawmlub raumprogenitors raws li ib tug dysregulated teb rau qhov loj thiab ceev podocyte detachment tshwm sim nyob rau hauv tej yam kev mob ntawm ncaj qha podocyte raug mob (xws li raug rau tej yam tshuaj, tiv thaiv kab mob los yog kab mob uas ncaj qha mus rau lub podocyte) tshwm sim nyob rau hauv lub tsis muaj inflammatory Cheebtsam thiab ua rau. capillary poob [22,45]. Cov kab mob no kuj nquag pom hauv cov kab mob glomerulopathies, xws li HIV- thiab parvovirus-nephropathy [22]. Hauv cov kab mob glomerulopathies no, interferon (IFN-)- thiab IFN- tsis tsuas yog ua rau mob hauv zos hauv lub glomerulus tab sis, kuj, ua rau PECs thiab podocytes, nrog IFN- inhibiting kev tsiv teb tsaws ntawm PECs thiab ob qho tib si suppressing.lub raumProgenitor sib txawv rau hauv podocytes hauv vitro [46] Hauv vivo, hauv tus qauv ntawm Adriamycin nephropathy, kev txhaj tshuaj ntawm IFN- lossis IFN- aggravated proteinuria thiab glomerulosclerosis [46]. Tsis ntev los no, kev sib tsoo FSGS tau piav qhia hauv cov neeg mob ntawm cov poj niam African tsis ntev los no uas muaj kev pheej hmoo siab APOL1 genotype thiab kis tus kab mob ua pa hnyav rau tus mob coronavirus 2 (SARS-CoV-2) [47,48]. Nws tau raug pom zoo tias SARS-CoV-2 tuaj yeem kis ncaj qha rau podocyte [49] thiab/lossis ua rau muaj kab mob ua paug uas cuam tshuam nrog kev ua kom muaj kev cuam tshuam ntawm interferon-chemokine txoj hauv kev, uas, dhau los, cuam tshuam nrog APOL1 variant gene [ 50]. Raws li tau hais los saum no,lub raumprogenitor sib txawv rau hauv podocytes koom nrog APOL1 qhia thiab yog li tuaj yeem koom nrog tus kab mob coronavirus 2019 (COVID-19)-koom nrog nephropathy.
Ntau qhov kev tshawb fawb tsis ntev los no tau qhia txog lub luag haujlwm tseem ceeb rau kev qhia ntawm de novo ntawm CD9 thiab, tom qab, ntawm CD44 ua tus kab mob hloov pauv ntawm PECs los ntawm qhov tsis txaus ntseeg mus rau qhov ua kom muaj phenotype hauv CGN thiab hauv FSGS [16,51,52], lees paub lub luag haujlwm pathogenic. ntawm PECs hauv cov kab mob no thiab muab cov hom phiaj tshiab molecular rau kev kho kab mob glomerular. Hauv kev txhawb nqa ntawm lub tswv yim no, Kaverina li al. pom tau tias PECs poob CD44 qhia thaum sib txawv rau hauv podocytes hauv raug mob glomeruli ntawm cov nas qub, qhia tias CD44 nce hauv PECs sawv cev tsis yog ib qho kev hloov dua tshiab tab sis kev hloov pauv pathological [53]. Hauv FSGS, CD44 tau pom tias muaj lub luag haujlwm tseem ceeb hauv cell tsiv teb tsaws mus rau qhov raug mob fifiltration barrier, qhov uas raug mob podocytes upregulate lub migration inhibitory factor (MIF) thiab stromal cellderived factor 1 (SDF1) uas txhawb CD44 qhia thiab CD{{12} }kev sib haum xeeb tsiv teb tsaws [54]. Tsis tas li ntawd, PECs tau tsim ob qho tib si PEC-derived thiab podocyte-specific extracellular matrix protein isoforms nyob rau hauv CD44-dependant yam [55]. Thaum kawg, txoj kev tshawb nrhiav keeb kwm ntawm PECs qhia tias CD44 tsis koom nrograumrov tsim dua tshiab los ntawm kev sib txawv rau hauv podocytes thiab tsuas yog koom nrog txoj hauv kev pro-fibrotic [56].
Tubular Progenitors
Lub raumProgenitors los ntawm parietal epithelial txheej ntawm Bowman capsule muaj peev xwm rov tsim dua cov tubular epithelial hlwb ntawm lub glomerulotubular hlws ris [57]. Txawm li cas los xij, tubular-community progenitors tau tawg nyob rau hauv cov tubules ze ze thiab cov distal kuj muaj nyob hauv tib neeg [6,58–60] thiab hauv cov nas [5,61–63] thiab nce ntxiv rau tubular raug mob hauv cov neeg mob cuam tshuam nrog mob hnyav lossis ntev tubular puas tsuaj [6 ]. Kumar et al. tau ua cov kab ke taug qab ntawm Sox tsis tshua muaj 9- nthuav tawm cov hlwb hauv cov tubule ze ze thiab txheeb xyuas lawv tias yog cov tubular tubular progenitor cov pej xeem koom nrog hauv postacutemob raum(AKI) rov qab [64]. Sox9 yog ib qho kev hloov pauv uas, hauvraumtxoj kev loj hlob, tswj epithelial branching thiab qhia nyob rau hauv nephron precursors [64,65]. Interestingly, thaum Sox9 raug tshem tawm ntawm ntu S1 thiab S2, kev rov qab qeeb qeeb ntawm lub cev.lub raum ua haujlwm, txhim kho tubular raug mob, nrog rau ncelub raumfibrosis, tshwm sim [64]. Tom qab ib feem ntawm nephrectomy, Sox9 ntxiv cov hlwb proliferate thiab tsim cov epithelial hlwb ntawm lub proximal tubule, Henle lub voj, distal tubule, sau duct thiab parietal txheej ntawm glomerulus [66]. Tsis ntev los no, Lazzeri et al. muab pov thawj tias tubular progenitors raug mitosis thiab hloov kwv yees li ib nrab ntawm cov tubular uas ploj lawm thaum AKI [5]. Ua cov kab ke taug qab ntawm Pax2 ntxiv rau cov hlwb hauv tus qauv nas ntawm tubular raug mob, lawv tau txheeb xyuas tubular progenitors raws li cov tubular cell subpopulation uas tiv taus kev tuag thiab pom muaj kev ua haujlwm siab clonogenic, ua rau cov tiam ntev tubule ntu [5].
Regulators ntawm Tubular Progenitor Physiology: Ib Lub Koom Haum Polyphonic
Tib neeglub raumProgenitors nthuav qhia B lymphoma Mo-MLV (Moloney murine leukemia virus) tso rau thaj tsam 1 (Bmi-1) [57]. Bmi-1 yog ib tug tswv cuab ntawm tsev neeg ntawm polycomb ntawm transcriptional repressors. Nws muaj kev koom tes hauv kev tswj hwm lub voj voog ntawm tes thiab kev ua haujlwm ntawm cov qia hlwb endogenous rau ntau yam hauv nruab nrog cev, xws li prostate, cov hnyuv me thiab lub ntsws [67-70]. Hauvlub raum, BMI-1 qib nce sai tom qab raug mob hauv tus qauv nas ntawm AKI [71]. Cov fifindings taw tes rau kev koom tes ntawm Bmi -1 qhia nyob rau hauv tubular progenitors nyob rau hauvlub raumrov tsim dua tshiab. Xwb, Lv et al. qhia tau hais tias mob tubular necrosis ua rau Bmi -1 nce thiab tom qab tubular progenitor mobilization hauv cov nas qus, thaum tubular progenitors tsis tau mob hauv Bmi -1 cov nas nas [72]. Bmi-1 cov nas tua nas pom muaj zoglub raumphenotype, suav nrog interstitial fifibrosis, tubular atrophy thiab hnyavlub raumKev ua haujlwm tsis zoo, nrog txo qis ntawm cov cell proliferation, nce cell apoptosis thiab senescence thiab inflammatory cell infifiltration [72,73]. Hauv kev tshawb fawb tsis ntev los no, Zhou et al. ntxiv elucidated lub luag hauj lwm ntawm Bmi -1 nyob rau hauvlub raumprogenitors, qhia tias Bmi -1 khaws cia tus kheej-renewal thiab stemness ntawmlub raumprogenitors los ntawm kev tswj cov redox tshuav nyiaj li cas thiab tiv thaiv cell voj voog ntes, los ntawm inhibition ntawm reactive oxygen hom (ROS), p16 thiab p53 [74].
Lwm qhov tseem ceeb molecule koom nrog hauv kev tswj hwm ntawm tubular progenitor yog Tus Hu-zoo li receptor 2 (TLR2), lossis CD282, ib qho evolutionary conserved membrane protein uas ua lub luag haujlwm tseem ceeb hauv kev paub txog kab mob thiab ua kom lub cev tiv thaiv kab mob. TLR2 ua raws li qhov ntsuas ntawm cov ntaub so ntswg raug mob los ntawm kev tshawb pom ntawm kev puas tsuaj-txuas nrog cov qauv molecular molecules (DAMPs) tso tawm los ntawm cov ntaub so ntswg puas. Kev ua kom TLR2 ua rau muaj kev ua kom muaj kev hloov pauv hauv nqes dej uas tswj kev qhia ntawm cov noob muaj sia nyob lossis cov cytokines proinflammation thiab chemokines [75–77]. Sallustio et al. qhia tias tubular progenitors qhia TLR2, uas nws stimulation los ntawm agonists uas mimic inflammatory mediators los yog DAMPs induces loj secretion ntawm monocyte chemoattractant proteins -1 (MCP-1), interleukin 6 (IL-6), interleukin 8 (IL-8) thiab ntxiv rau C3 ntawm NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) activation [59]. Ntxiv mus, TLR2 stimulation modulated tus proliferation tus nqi thiab sib txawv muaj peev xwm ntawm tubular progenitors, qhia txog lub luag hauj lwm tseem ceeb hauvlub raumkev kho mob [59]. Cov kev tshawb fawb soj ntsuam los ntawm tib pab pawg tau txheeb xyuas qhov sib txawv ntawm miRNAs tshwj xeeb qhia hauv tubular progenitors [78]. Ntawm cov ntawd, miR-1915 thiab miR-1225-5p tswj kev qhia ntawm CD133 thiab PAX2, nrog rau TLR2. Sallustio et al. Tom qab ntawd txiav tawm cov txheej txheem rov qab los tom qab AKI thiab pom lub luag haujlwm tseem ceeb rau TLR2 hauvlub raumkev tsim kho [79]. Lawv tau tsim tias, tom qab raug mob, TLR2 kev puas tsuaj rau kev nkag siab ua rau lub zais ntawm inhibin-A thiab decorin los ntawm tubular progenitors, uas, nyob rau hauv lem, txhawb tubular regeneration los ntawm cell proliferation [79]. Ob lub cytokines no muaj nyob rau hauv TGF- (hloov kev loj hlob yam tseem ceeb-) qhia txoj hauv kev thiab koom nrog hauv kev tswj hwm lub voj voog ntawm tes, qhov nce ntawm cell proliferation thiab inhibition of apoptosis [80–84].
Kev qhia ntawm molecules los ntawm Wnt txoj kev tau raug tshaj tawm hauv cov neeg lauslub raumprogenitors nyob rau hauv nas [85] thiab tib neeg [86]. Siv tus qauv nas ntawm kab tracing, Rinkevich li al. qhia tau tias, ob qho tib si thaum homeostasis thiab tom qab raug mob, tus neeg laus mammalianlub raumtau txais ntu tshwj xeeb clonal nthuav tawm los ntawm cov hlwb muab los ntawm WNT cov lus teb ua ntej [63]. Lawv tau hais tias lub peev xwm los teb rau WNT cov teeb liab xaiv rau cov hlwb uas yuav ua rau muaj zog clonal expansion. Kev tshawb fawb hauv SIX2 ntxiv rau cov zis tso zislub raumprogenitors qhia tias WNT txoj kev ua kom los ntawm GSK3 inhibition induces qhov sib txawv ntawmlub raumprogenitors rau hauv lub raumepithelial proximal tubular hlwb [87] Tsis tas li ntawd, Wnt3 exerted pro-regenerative teebmeem thiab tau upregulated hauv CD133 ntxivlub raumprogenitors nyob rau hauv vitro qauv ntawm cisplatin raug mob [88]. Hauv txoj kev tshawb no, cov kws sau ntawv tau nthuav tawm lub luag haujlwm ua haujlwm ntawm CD133 nws tus kheej hauv kev kho lub raum tubular los ntawm kev saib xyuas cov lus teb proliferative thiab kev tswj ntawm senescence los ntawm kev ua ib qho kev tso cai rau -catenin signaling, tiv thaiv nws degradation hauv cytoplasm [88]. Hauv zebrafifishlub raum,puas tubules raug hloov los ntawm nephrons tshiab los ntawmlub raumprogenitors qhia txog Wnt receptor frizzled9b thiab qhov kev hloov pauv ntawm lef1. Tom qab raug mob, kev qhia ntawm Wnt ligands Wnt9a thiab Wnt9b tau raug moblub raumntawm qhov chaw uas cov hlwb progenitor tsim cov nephrons tshiab [89]. Cov txiaj ntsig no qhia tias lub luag haujlwm tseem ceeb ntawm Wnt / frizzled signaling txoj hauv kevraumregeneration yog heev conserved ntawm hom.
CISTANCHE yuav txhim kho rau lub raum/ raum mob
Raws li tau hais dhau los, Notch signaling yog ib txoj hauv kev txuag kev hloov pauv uas muaj lub luag haujlwm tseem ceeb hauvmob raumthiab kho [24,90–93], tshwj xeeb yog thaum AKI [94,95]. Kang et al. qhia tias Sox9 pluslub raumProgenitors tau qhia txog qib siab ntawm Notch, thiab tshaj tawm ntawm Notch1 intracellular domain (NICD1) hauv Sox9 ntxiv rau cov pej xeem tau txhim kho cov kab mob.lub raumhistology nyob rau hauv ib tug folic acid-induced qauv ntawm AKI [62]. Ma et al. qhia tias kev ua kom Sox9 ntxiv rau lub raum progenitors, nws lub luag haujlwm tseem ceeb hauvraumkho, tau kho los ntawm txoj kev Notch, lees paub tsab ntawv tshaj tawm dhau los tias Notch 1-3, Jagged1/2, Dll4 thiab Sox9 qhia qib nce ntxiv tom qab ischemia-reperfusion raug mob (IRI) [66]. Tseeb, nyob rau hauv lwm yam kabmob xws li txiav txiav, Sox9 activation modulates txoj kev Notch los ntawm kev tswj hwm Hes1 kom tswj tau lub pas dej progenitor cell [96]
Ntau cov tshuaj tau pom tias txhim khoraumregeneration, thiab, ntawm cov, histone deacetylase (HDAC) inhibitors (HDACis) yuav yog ib qho kev cog lus kho mob rau kev kho mob ntawm AKI [97–102]. HDACs tsim ib pab pawg ntawm cov enzymes koom nrog ntau cov txheej txheem ntawm tes los ntawm kev tshem tawm cov acetyl pawg los ntawm histone lossis nonhistone proteins [103]. Marumo et al. qhia txog kev txo qis hauv HDAC5 kev ua, nce histone acetylation thiab reactivation ntawm pob txha morphogenetic protein 7 (BMP-7) nyob rau hauv proximal tubular hlwb thaum lub sij hawm rov qab theem tom qab.lub raumTSI [104]. Cov kev soj ntsuam no qhia tias HDACis tuaj yeem siv lawv cov txiaj ntsig zoo raulub raumrov qab los ntawm kev nthuav qhia ntau ntxiv ntawm BMP-7, ib qho protein uas tswj lub raum progenitor pas dej ua ke nyob rau hauv undifferentiated xwm txheej thaum lub sij hawmraumkev loj hlob [105]. Qhov zoo siab, kev kho mob nrog HDACis nthuav davlub raumProgenitor cell pejxeem hauv zebrafifish [106]. Hauv nephrotoxic serum nephritis qauv ntawmglomerulonephritis hauv nas, kev kho mob trichostatin A (TSA) tau qhibraumsab pejxeem (SD) cell [107]. SD hlwb tsim ib lub subset ntawm cov hlwb nrog multilineage muaj peev xwm thiab paub txog renoprotective zog uas attenuate ntev.mob raum(CKD) los ntawm kev nce ntawm BMP-7 qhia [107]. Siv cov kab tracing txoj hauv kev tau piav qhia saum toj no, Lazzeri li al. tau pom tias kev kho mob nrog ob qho kev siv dav dav HDACis, TSA thiab 4-phenylbutyrate (4-PBA), tau coj mus rau Pax2 ntxiv rau progenitor proliferation, thiaj li zam kev txhim kho cov nqaij mos fifibrosis thiab CKD [5]. Kev txhim kho ntawm HDACis xaiv, nrog kev txhim kho kev ua tau zoo thiab tsis muaj tshuaj lom, yuav txhim khoraumrov qab los ntawm tubular progenitor proliferation. Nco ntsoov, HDACis tau pom cov txiaj ntsig kho tau zoo hauv ntau cov qauv kev sim ntawmkab mob raumDhau li ntawm AKI, suav nrog glomerulosclerosis, tubulointerstitial fifibrosis, glomerular thiab tubulointerstitial inflammation, lupus nephritis, polycystic.mob raumthiablub raumcell carcinoma (RCC), raws li tshuaj xyuas hauv [108]. Ob peb HDACis tam sim no nyob rau theem 1 lossis 2 kev sim rau kev kho mob ntawm RCC thiab lub raum tsis zoo (clinicaltrial.org).
Regulators ntawm Tubular Progenitors nyob rau hauv Pathology: Ib tug Cacophonus Choir
Biological thiab molecular nta ntawmraummob qog noj ntshav qhia tiaslub raumprogenitors yuav nyob rau hauv lub hauv paus ntawm kev loj hlob ntawm txawvraumhom qog. Hauv kev tshawb fawb tsis ntev los no, Peired et al. qhia tias tib neeglub raumprogenitors overexpressing NICD1 muaj peev xwm loj hlob thiab tsim aberrant mitosis hauv 2D kab lis kev cai thiab tuaj yeem tsim cov qog zoo li hauv 3D kab lis kev cai [8]. Ib yam li ntawd, Pax2 pluslub raumprogenitors overexpressing NICD1 tom qab transgene induction nyob rau hauv cov laus nas los yog tom qab IRI yog nyob rau hauv keeb kwm ntawm papillary adenomas thiab RCCs [8]. Hauv kev lees paub ntawm qhov kev tshawb nrhiav no, kev kho mob thaiv cov endogenous AKI-induced NOTCH1 ua kom muaj kev loj hlob ntawm cov qog tsawg dua [8]. Tsis ntev los no, ob txoj kev tshawb fawb qhia tias angiomyolipomas los ntawm ntau lub zograumepithelial hlwb nyob rau hauv lub tubule thiab nyob rau hauv lub clonal expansion nyob rau hauv teb rau tuberous sclerosis complex (TSC) noob deletion [109,110]. Ob qhov kev tshawb fawb pom tau tias cov hlwb no tuaj yeem yoglub raumprogenitors nrog multilineage sib txawv muaj peev xwm [109,110]. Interestingly, Cho et al. qhia tias qhov kev ua kom lub cev tsis tau tshaj tawm yav dhau los Rheb-Notch-Rheb txoj cai voj, nyob rau hauv uas lub voj voog khi ntawm Notch1 mus rau Notch-responsive ntsiab (NREs) ntawm Rheb txhawb nqa yog ib qho kev tshwm sim tseem ceeb, yog lub ntsiab mechanism tom qab tiam ntawm lub ntau kab mob tshwm sim hauv angiomyolipoma [109]. Ua ke, cov txiaj ntsig no qhia tau tias muaj kev cuam tshuam ntawm Txoj Kev Notch hauvlub raumprogenitors tuaj yeem ua raulub raumpathologies.
Wan et al. pom tias SOX9 kev qhia tau raug tswj hwm hauv RCC cov neeg mob thiab cuam tshuam nrog qib siab pathological [111]. RCC cov neeg mob uas muaj qib SOX9 siab kuj tseem muaj sia nyob luv dua [111]. Cov ntaub ntawv no tau lees paub qhov kev tshawb fawb ua ntej uas cuam tshuam nrog SOX9 qhia nrog RCC Fuhrman grading thiab pom tias cov neeg mob SOX9 () tau txais kev kho mob zoo dua rau tyrosine kinase inhibitors dua li cov neeg uas muaj SOX9 (ntxiv rau ) [112]. Yog li, peb tuaj yeem xav tias qhov nce ntawm SOX9 qhia hauv SOX9 ntxivlub raumProgenitors tuaj yeem pab txhawb rau RCC txoj kev loj hlob. Ib txoj hauv kev zoo sib xws tau piav qhia hauv basal-zoo li mob qog noj ntshav mis, qhov twg SOX9 qhia hauv luminal qia/progenitor cells tuaj yeem tswj cov kab mob qog nqaij hlav cancer los ntawm kev ua kom NF-κB signaling [113].
Outlook nyob rau yav tom ntej ntawm lub raum Progenitors
Ib leeg-Cell RNA Sequencing: Cia Peb Ua Raws Li Lub SijhawmTxoj kev loj hlob sai ntawm scRNAseq yog qhib qhov kev xav tshiab rau kev txiav cov txheej txheem molecular koom nrog hauvlub raumProgenitor txoj cai nyob rau hauv physiological thiab pathological mob. ScRNAseq muaj nyob rau hauv tau txais cov noob qhia profifiling ntawm ib leeg-cell daws teeb meem, muab pov thawj ntawm cov xov tooj ntawm tes sib txawv thiab molecular dynamics ntawm txawm lub tsawg subpopulations. Cov thev naus laus zis tshiab no tau siv los ua tiav hauv ntau lub cev - piv txwv li, los kawm Prominin 1 ntxiv rau daim siab progenitors [114], Dach1-downregulated lymphoid progenitors [115] thiab KTR5 ntxiv rau lub ntsws progenitors hauv COVID-19 cov neeg mob [116]. Tsis pub dhau ob peb xyoos dhau los, ntau pawg tshawb fawb tau siv lub tswv yim no los txheeb xyuas cov xov tooj ntawm teslub raumhauv nas thiab tib neeg [117–120]. Hauv kev tshawb fawb tsis ntev los no, Rudman-Melnick et al. tau txheeb xyuas qhov kev kos npe ntawm txhua tus xov tooj ntawm tes hauv kev sim qauv ntawm AKI, qhia txog qhov pom ntawm yav dhau los tsis tau piav qhia txog kev raug mob ntsig txog cov molecules [119]. Xws li ib txoj hauv kev tuaj yeem nthuav tawm cov txheej txheem tshiab tau qhib rau hauvlub raumprogenitors tom qab AKI, ua rau kev txheeb xyuas cov hom phiaj molecular. Hauv lawv daim ntawv hais lus, Young et al. muaj peev xwm ua kom pom tseeb ntawm tes thiab papillary RCC hlwb rau ib qho subtype ntawm proximal convoluted tubular hlwb txhais los ntawm SLC17A3 thiab VCAM1 qhia [117]. Raws li tau hais ua ntej, VCAM1 lossis CD106 qhia tus yam ntxwv, ua ke nrog CD133, tsis tshua muaj neeg nyob ntawmlub raumprogenitors tawg feem ntau nyob rau hauv proximal tubule [6]. Kev soj ntsuam ntawm scRNAseq cov ntaub ntawv tau qhia tias tib neeg lub raum progenitor transcriptome qhia zoo sib xws rau PT1, lub cell putative ntawm keeb kwm ntawm tib neeg papillary RCC [8]. Cov kev soj ntsuam no ua pov thawj peb qhov kev xav tias papillary RCC keeb kwm los ntawm kev hloov pauv ntawm Notch-mediated thiab proliferation ntawm cov tubule ze ze ntawm lub raum progenitors [8].
Daim Ntawv Thov Kev Kho Mob: Lub Tsev Kho Mob Hu Xov Tooj
Renal progenitor-based therapies sawv cev rau kev cog lus tshiab frontier hauv kev kho mobkab mob raum, raws li ntau qhov kev tshawb fawb qhia tias lawv txhim kholub raum ua haujlwmtom qab raug mob [121]. Txawm li cas los xij, txhaj tshuajlub raumprogenitors ncaj qha mus rau tsiaj qauv ntawmmob raumtxhawm rau ua kom cov ntaub so ntswg rov ua dua tshiab nthuav tawm cov kev txwv tseem ceeb uas tau nthuav tawm rau lwm qhov [121]. Cov caveats no tuaj yeem hla dhau ua tsaug rau cov khoom siv tshiab tshiab ntawmlub raumprogenitors, uas yog lawv lub peev xwm los zais trophic yam, cytokine lossis chemokines uas ua tau zoo kho kom haum xeebraumkho nyob rau hauv paracrine los yog autocrine yam (Daim duab 2). Kenji et al. qhia tias kev txhaj tshuaj intraperitoneal ntawm kab lis kev cai supernatant tau los ntawm cov neeg laus nasraumprogenitors tseem ceeb suppressed tubular cell apoptosis ntawm residuallub raumhlwb, txo qis qhov mob thiab txhawb kev loj hlob ntawm cov hlwb tsis paub tab hauv kev sim IRI qauv los ntawm kev tso tawm ntawm HGF (hepatocyte growth factor), EGF (epidermal growth factor), TGF- thiab Epo (erythropoietin) [122]. Qhov tseeb, kev siv kho mob ntawm ntau yam kev loj hlob tau raug tshaj tawm rau amelioratemob raum, xws li HGF, BMP7, EGF, TGF- thiab VEGF (vascular endothelial growth factor) [123–127]. Sallustio et al. qhia tias tib neeglub raumProgenitors tsis tsuas yog qhia txog kev kho cov kab mob hauv lub cev tab sis kuj tseem muaj cov tshuaj tiv thaiv kab mob los ntawm kev tso tawm ntawm CXCL6 (CXC motif chemokine ligand 6), SAA2 (serum amyloid A2), SAA4 (serum amyloid A4) thiab BPIFA2 (BPI (bactericidal permeability). -increasing) fold-muaj tsev neeg A tus tswv cuab 2) los ntawm paracrine mechanism [128]. Aggarwal et al. qhia tias lublub raumprogenitor secretion ntawm Epo txwvlub raumfifibrosis tom qab raug mob tubular [129]. Ntxiv nrog rau cov ntsiab lus soluble, lub raum progenitors secrete extracellular vesicles (EVs), nanometer-loj lipid bilayer-delimited particles nqa bioactive lipids, proteins thiab RNAs uas tso cai rau kev sib txuas lus ntawm tes-tocell los ntawm kev ua paracrine. Hom EVs tsawg tshaj plaws thiab zoo tshaj plaws tau piav qhia yog cov exosomes, uas tau tshawb xyuas tsis ntev los no rau lawv cov kev tiv thaiv tiv thaiv IRI-induced AKI [130,131]. Li et al. pom tau tias lub raum progenitor-derived exosomes tuaj yeem kho lub raum cov qauv thiab kev ua haujlwm ntawm lawv cov immunomodulatory, antiapoptotic thiab proliferation stimulation peev xwm hauv AKI qauv. MicroRNAs (miRNAs) yog cov feem ntau ntawm cov exosomes, thiab ntawm cov, miR-146a tau raug txheeb xyuas tias yog tus neeg tseem ceeb hauv kev sib kho cytoprotective los ntawm kev txo qis IRAK1 (interleukin 1 receptor txuam nrog kinase 1) / NF-kB signaling [130]. Nyob rau hauv tus qauv ntawm ntshav qab zib nephropathy, urinary progenitor-secreted exosomes tau pom los txo cov podocyte apoptosis los ntawm suppressing caspase-3 thiab txhawb nqa vascular regeneration, uas tej zaum yuav cuam tshuam nrog cytokines VEGF, TGF- 1, angiogenin thiab BMP. -7 muaj nyob rau hauv urinary progenitor-derived exosomes [132]. Qhov inhibition ntawm podocyte apoptosis kuj tseem cuam tshuam nrog kev nthuav dav ntawm miR-16-5p hauv cov zis progenitor-secreted exosomes los ntawm suppressing VEGF-A [133].
Molecules thiab exosomes secreted los ntawmlub raumprogenitors txhawb kev rov qab los ntawmmob raumlos ntawm lawv lub peev xwm los ua kom muaj kev cuam tshuam ntawm cov tshuaj renoprotective thiab regenerative ua tsaug rau lawv cov kev txo qis hauv munoge nicity thiab qis dua kev pheej hmoo ntawm maldifferentiation thiab qog nqaij hlav piv rau kev kho ntawm tes. Cov yam ntxwv zoo kawg li no ua rau lawv txaus siab rau kev siv tshuaj kho mob. Lwm qhov kev sib tw hauv kev kho mob mus kom ze raumob raumyog qhov kev tshawb pom ntawm cov cuab yeej tshiab rau kev kuaj mob thiab saib xyuasmob raumuas yuav yooj yim nkag tau nrog cov txheej txheem noninvasive. Nyob rau hauv cov ntsiab lus no, cov zis sawv cev rau ib tug tseem ceeb biofluid vim nws yooj yim mus use, ceev thiab yooj yim sampling thiab broad ntau yam ntawm cov proteins, metabolites, hlwb thiab cellular cov ntsiab lus tso tawm los ntawm urogenital ib ntsuj av tau [134]. Lub xub ntiag ntawm cov hlwb hauv cov zis uas tso tawm cov khoom qia cell yog thawj zaug piav qhia los ntawm Zhang li al. xyoo 2008 [135]. Hauv xyoo tom ntej no, ntau pab pawg tau tsim cov tswv yim los cais tawm thiab ua tus yam ntxwv ntawm cov zis tso tawm los ntawm cov neeg pub noj qab haus huv thiab cov neeg mob uas muaj zis.raumkev tsis sib haum xeeb [136]. Tseem tsis tau muaj kev pom zoo raws li kev pom zoo uas cov cim yuav raug siv los txheeb xyuas cov neeg uas tau tso zis tso zis. Feem ntau cov kev tshawb fawb qhia tau hais tias lawv qhia mesenchymal qia cell markers (CD44, CD73 thiab VIM) thiab qia cell markers (xws li POU5F1, SSEA4 thiab TRA-1-81, as well as CD117) tab sis tsis muaj cov cim ntawm hematopoietic- lossis urothelium-derived. kab mob ntawm tes thiab qib qis ntawm tubular- lossis podocyte-cov cim tshwj xeeb [136]. Hais txog lawv keeb kwm, Bharadwaj et al. qhia tau tias tso zislub raumProgenitors nqa Y chromosome hauv txiv neej-rau-poj niamhloov raumtus txais, qhia tias lawv tuaj ntawm lublub raum[137]. Cov hlwb no muaj peev xwm sib txawv rau hauv podocytes [138] thiab nthuav qhia podocyte- thiab PEC cov cim tshwj xeeb protein [137,139], qhia tias lawv tuaj ntawm PECs. Kev sib piv transcriptome tsom xam ntawm cov zis-derivedlub raumprogenitors thiabraumbiopsy-derivedlub raumepithelial proximal hlwb tau lees paub lub raum progenitor tus kheej ntawm cov zis-derived progenitors [87], qhia tias lawv tuaj yeem tshwm sim los ntawm cov tubular progenitors tawg. Cov hlwb no tuaj yeem rov ua dua tshiab rau hauv induced pluripotent qia hlwb (iPSC) thiab siv rau cov tshuaj kho dua tshiab, qauv kab mob lossis kev sim tshuaj tshuaj [140,141].
Tsis ntev los no, nws tau raug hais tias qhov kev nthuav qhia ntawm tuslub raumprogenitor marker CD133 nyob rau hauv cov zis EVs sawv cev rau ib tug zoo cim rau kev ntsuam xyuas ntawm lub functionality ntawm lub raum tubular compartment thiab muaj cov hlwb nrog proliferative thiab kho kev ua si nyob rau hauv tubules tom qab raug mob. Qhov tseeb, ob txoj kev tshawb fawb tau tshaj tawm tias CD133 ntxiv rau cov zis EV, nce siab hauv cov neeg noj qab haus huv, tsis tsuas yog txo qis hauv cov neeg mob uas muaj mob hlab ntsha tawg [142] tab sis, kuj, mob glomerular mob [143]. Tsis tas li ntawd, muaj lub raum progenitors lawv tus kheej hauv cov zis tuaj yeem cuam tshuam txog cov xwm txheej pathophysiological ntawmlub raumntaub so ntswg. Hauv particular, Manonelles et al. muab pov thawj tias kev rho tawm ntawm CD133 ntxiv rau CD24 ntxiv rau lub raum progenitors los ntawm cov zis ntawm cov neeg tau txais txiaj ntsig ruaj khov ntawm rau lub hlis tuaj yeem kwv yees cov txiaj ntsig tsis zoo ntawm kev hloov pauv ntawm ob xyoos [144]. Lub raum progenitor proliferation thiab tsiv teb tsaws los ntawm Bowman capsule mus rau glomerular tuft thoob plaws hauv lub tso zis nyob rau hauv thiaj li yuav hloov detached podocytes tuaj yeem piav qhia txog kev tso tawm ntawm lub raum progenitors thiab, yog tias muaj kev txhawb nqa dhau sijhawm, tej zaum yuav tsis khaws cov haujlwm allograft, ua rau GFR poob, albuminuria thiab mob glomerular histological lesion txoj kev loj hlob [144].
tso zisraumcov hlwb kuj tuaj yeem yog cov cuab yeej muaj zog ntawm tus kheej rau kev tshawb fawb txog kev ua haujlwm ntawm cov neeg sib tw sib txawv hauv kev muaj txiaj ntsigmob raum. Raws li piav los ntawm Lazzeri li al., tso zislub raumprogenitors tau txais los ntawm cov neeg mob nqa cov kab mob pathogenic hloov pauv hauv cov noob encoding rau podocyte proteins nthuav dav hauv kab lis kev cai tab sis tsim kev tsis sib haum xeeb hauv kev qhia lossis hauv zos ntawm podocyte proteins tom qab kev sib txawv ntawm podocyte [138]. Hauv kev pom zoo nrog cov ntaub ntawv pov thawj no, tib cov txheej txheem tau siv los ua kom pom cov kab mob ntawm NPHS1 gene variant ntawm qhov tsis paub qhov tseem ceeb hauv tus neeg mob nrog refractory lupus nephritis [145]. Lwm txoj kev tshawb fawb qhia txog qhov muaj peev xwm siv cov zis tso zis los ntawm lub raum epithelial hlwb los ua RNA thiab kev tshawb fawb txog kev ua haujlwm ntawmraum-cov noob tshwj xeeb, ua kom pom tseeb cov kab mob ntawm qhov sib txawv ntawm qhov sib txawv hauv PKHD1 (polycysticraumthiab kab mob siab 1) thiab lees paub qhov kev kuaj mob caj ces ntawm ARPKD (Autosomal Recessive PolycysticKab mob raum) nyob rau hauv tus neeg mob nrog CKD txuam nrog atypical polycysticlub raum [146].
Cov lus xaus
Ib lub cev loj ntawm cov ntaub ntawv piav qhia txog ntau yam txheej txheem ntawm kev tswj hwm ntawmlub raumprogenitors nyob rau hauv lub glomerular thiab nyob rau hauv lub tubular compartments, tso cai rau peb kom muaj lub ntiaj teb no lub zeem muag ntawm lub complexity ntawm cov txheej txheem molecular noj qhov chaw nyob rau hauv lub physiological thiab nyob rau hauv pathological tej yam kev mob. Paub txog lub molecular kos npe ntawmlub raumprogenitors qhib qhov rooj rau kev txheeb xyuas lub hom phiaj tshiab rau cov tshuaj kom txhawb nqaraumregeneration los yog biomarkers los saib xyuasraumnoj qab haus huv.
