Transcriptome Thiab Lipidome Profile Ntawm Tib Neeg Mesenchymal Stem Cells Nrog Txo Senescence Thiab Ntxiv Trilineage Sib Txawv Muaj Peev Xwm Raws Li Kev Kho Mob

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Tib neeg Mesenchymal qia hlwb (hMSCs) yog cov muaj peev xwm ntau lub hlwb uas tau siv dav hauv kev kho ntawm tes. Txawm li cas los xij, feem ntau tshwm sim senescence thiab txo qis ntawm kev sib txawv muaj peev xwm txwv cov kev siv dav dav ntawm MSC. Ob peb lub tswv yim xws li kev kho me me molecule tau kawm dav thiab siv los txhim kho cov yam ntxwv qia los ntawm kev hla kev senescence tab sis cov txheej txheem tseeb rau lawv kom txo qis senescence tsis tau kawm tag nrho. Hauv txoj kev tshawb no, hMSCs tau kho nrog rapamycin, oltipraz, metformin, thiab vitamin C rau lub sijhawm qhia thiab cov hlwb no tau raug soj ntsuam kev laus thiab kev sib txawv ntawm trilineage. Tsis tas li ntawd, transcriptomics thiab lipidomics datasets ntawm hMSCs tom qab kev kho tshuaj tau raug tshuaj xyuas los txhais cov txheej txheem lom neeg lub luag haujlwm rau lawv cov teebmeem los tiv thaiv kev laus. Txawm hais tias plaub cov tshuaj tau nthuav tawm cov haujlwm tseem ceeb hauv kev txhawb nqa MSC osteogenic sib txawv, metformin yog cov tshuaj zoo tshaj plaws los txhawb kev sib txawv ntawm trilineage. GO cov ntsiab lus qhia tau hais tias kev tiv thaiv kev laus ntawm cov tshuaj feem ntau cuam tshuam nrog cellular senescence, mitotic, thiab meiosis txheej txheem. Biosynthesis ntawm phosphatidylcholines (PC) thiab phosphatidylethanolamine (PE) tau inhibited whereas zus tau tej cov phosphatidylcholines (PIs) thiab saturated fatty acids (SFA) / mono-unsaturated fatty acids (MUFA) hloov dua siab tshiab tau qhib. Medium-free fatty acids (FFA) tau nce hauv hMSCs nrog ntau hom kev tiv thaiv kev laus. Yog li ntawd, peb tau tsim ib txoj hauv kev los ntsuam xyuas kev cuam tshuam tshuaj raws li cov txiaj ntsig ntawm transcriptomics thiab lipidomics. Cov txheej txheem tuaj yeem siv los kawm txog cov tshuaj lom neeg sib txawv ntawm kev cuam tshuam tshuaj hauv MSC uas yuav txuas ntxiv rau kev siv tshuaj kho mob ntawm hMSCs.

Thov nias ntawm no kom paub ntxiv

Taw qhia

Kev laus, cov txheej txheem nyob ntawm lub sijhawm, yuav ua rau lub cev tsis ua haujlwm. Kev laus yog qhov tseem ceeb tshaj plaws rau ntau yam kab mob, suav nrog mob qog noj ntshav, kab mob neurodegenerative, thiab ntshav qab zib. Stem cell qaug zog thiab cellular senescence yog ib qho ntawm cov cim qhia txog lub cev phenotype thaum laus [1]. Tib neeg mesenchymal qia hlwb (hMSCs) yog cov hlwb muaj peev xwm nthuav tawm hauv cov pob txha, cov ntaub so ntswg adipose, placenta, umbilical qaum, nqaij, thiab ntau lwm cov ntaub so ntswg [2-6]. Raws li cov kab mob tshwj xeeb nruab nrab, hMSCs tuaj yeem hloov pauv mus rau adipocyte, osteoblast, thiab chondrocytes nrog rau lwm cov kab mob hauv vitro. Yog li, hMSCs ua lub luag haujlwm tseem ceeb hauv cov tshuaj kho dua tshiab thiab kev kho ntawm tes. Txawm li cas los xij, kev siv tshuaj kho mob ntawm MSC raug txwv los ntawm kev laus thaum lub sij hawm ntev kab lis kev cai hauv vitro. hMSCs kev laus feem ntau yog txuam nrog kev hloov ntawm telomere ntev, cell ceev, proliferation muaj peev xwm, tilineage txawv peev xwm, epigenetics, mitochondrial muaj nuj nqi, thiab secretome [7]. Yog li ntawd, kev kov yeej MSC kev laus tau lees paub ntau qhov kev tshawb fawb tob los tshawb txog cov tswv yim los tiv thaiv hMSC senescence. Metformin (TAME) yog thawj cov tshuaj uas tau pom zoo hauv kev sim tshuaj los ncua kev laus [8] thiab tseem yog FDA pom zoo thawj kab tshuaj rau kev kho mob hom e 2 mob ntshav qab zib mellitus [9].cistanchTxoj kev nyuaj siab Nrf2 yog xav tias lub hauv paus txheej txheem rau metformin los kho lub neej elongation [10]. Oltipraz, tus neeg sawv cev antischistosomal, kuj tau siv los tiv thaiv kev mob qog noj ntshav ntawm txoj kev NRF2 hauv tus qauv nas [11, 12]. Nws kuj tau tshaj tawm tias oltipraz tau nthuav tawm cov txiaj ntsig los tiv thaiv kev laus los ntawm kev tawm tsam antioxidant NRF2 txoj hauv kev [13]. Ntxiv mus, rapamycin (Sirolimus) tau siv los coronary stents, tiv thaiv kev hloov pauv hauv nruab nrog cev thiab kho lymphangioleiomyomatosis [14]. Nws tau tshaj tawm tias rapamycin tuaj yeem cuam tshuam kev ua haujlwm ntawm T hlwb thiab B hlwb los ntawm mTOR inhibition [15], uas tau raug lees paub ntxiv los ntawm qhov ua rau muaj qhov tsis txaus ntawm cov qia hlwb [16]. Vitamin C yog ib qho zoo-paub reductant thiab tau tshaj tawm los txo kev laus hauv Werner syndrome qia cell qauv [17]. Txawm li cas los xij, txawm tias lawv tau sib koom txoj hauv kev zoo sib xws los siv lawv lub luag haujlwm hauv kev tiv thaiv kev laus thiab cov txheej txheem tshwj xeeb rau kev tiv thaiv cellular aging hauv tib neeg tseem tsis tau meej. Tsis tas li ntawd, cov ntawv sau thiab lipidome rau cov MSC kho los ntawm plaub cov tshuaj tsis tau tshawb xyuas tag nrho uas tau hais kom peb ua cov kev sim hauv qab no los teb cov lus nug tseem ceeb no.

Cistanche tuaj yeem tiv thaiv kev laus

Hauv txoj kev tshawb no, metformin, oltipraz, rapamycin, thiab vitamin C tau siv los kho pob txha pob txha hMSCs (BM-hMSCs). Ua ntej, qhov sib txawv ntawm cov phenotypes ntawm hMSCs tom qab kev kho mob yog tus cwj pwm los qhia txog lawv cov peev xwm tiv thaiv kev laus. Transscriptomics thiab lipidomics tsom xam tau ua nyob rau hauv cov tshuaj kho hlwb. Tom qab ntawd, GO tsom xam raws li cov ntaub ntawv transcriptomics tau ua los txhawm rau txhawm rau cov xwm txheej qhia txog lub luag haujlwm rau senescence thiab kev tiv thaiv kev laus. Metabolic profiling thiab kev tsom xam txoj hauv kev tau ua uas qhia txog qhov hloov pauv ntawm lipids ntau lawm thaum kho tshuaj. Ua ke, peb tau tsim ib qho kev ntsuam xyuas tag nrho ntawm kev cuam tshuam tshuaj ntawm hMSCs senescence. Lub kaw lus tuaj yeem siv los kawm txog cov tshuaj lom neeg sib txawv raws li kev cuam tshuam tshuaj hauv MSC uas yuav txuas ntxiv rau kev kho mob ntawm hMSCs.

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BM-hMSC raug rau senescence tom qab lub sij hawm ntev ntawm kab lis kev cai nyob rau hauv vitro

BM-hMSCs yog cov qia hlwb uas muaj ntau yam nrog cov yam ntxwv ntawm tus kheej rov txuas dua tshiab thiab sib txawv rau ntau hom cell. Txawm li cas los xij, nrog cov lus nce hauv vitro, cov hlwb tau maj mam ua rau muaj qhov tsis zoo thiab yuav plam feem ntau ntawm lawv cov peev xwm sib txawv. Cov xwm txheej ntawm BM-hMSCs tau txheeb xyuas ntawm cov kab lus sib txawv (P2, P8, P13) thiab cov kab mob ntawm tes tau mob zuj zus, ua pov thawj los ntawm kev ua kom qeeb ntawm cell proliferation, nce kev tuag, thiab qhov ntev ntawm morphology (Daim duab 1A). Tsis tas li ntawd, lub peev xwm trilineage sib txawv ntawm P8 BM-hMSCs kuj tau sim. Raws li pom nyob rau hauv daim duab 1B, piv nrog rau qhov ntawm peb cov kev tshawb fawb yav dhau los [18], qhov sib txawv muaj peev xwm ntawm P8 BM-tau txo qis, tab sis tseem tuaj yeem sib txawv rau osteoblasts, adipocytes, thiab chondrocytes nyob rau hauv induction nruab nrab.cistanche AustraliaRaws li nyob rau hauv vitro MSC senescence qauv raws li qhia [18], peb ntxiv kho BM-hMSCs nrog plaub tus neeg sib tw tshuaj aiming mus cuam tshuam rau lub senescence nyob rau hauv vitro. Raws li pom nyob rau hauv daim duab iC, cov hlwb raug plated nyob rau hauv ib tug 24- zoo phaj nrog ib tug ceev ntawm 60 feem pua, thiab cov tshuaj tau ntxiv rau lub hlwb tom qab 48 teev. Lub supernatant ntawm hlwb tau sau txhua peb hnub xya zaug. Hnub 21 tom qab siv tshuaj

(Cov duab ntxiv 1A). Oltipraz, rapamycin, thiab vitamin C tuaj yeem txhim kho qhov sib txawv ntawm qhov muaj peev xwm ncaj qha rau qhov kev tawm tsam ntawm kev laus (Cov duab ntxiv 1B). Interestingly, tsuas yog oltipraz pom qhov zoo ntawm adipocytes sib txawv nruab nrab (Ntxiv daim duab 1C,1D).cov txiaj ntsig cistanche,Hauv cov ntsiab lus, oltipraz yog cov tshuaj zoo tshaj plaws rau kev txhim kho trilineage sib txawv muaj peev xwm, rapamycin thiab vitamin C tuaj yeem txhim kho osteogenic thiab chondrogenic sib txawv muaj peev xwm, thaum metformin tsuas pom muaj txiaj ntsig zoo ntawm kev sib txawv osteogenic.

Transcriptomics profile ntawm cov tshuaj kho BM-hMSCs Muab hais tias tag nrho plaub cov tshuaj tuaj yeem tiv thaiv qhov tsis zoo ntawm BM-hMSCs nrog ntau yam kev ua tau zoo, tom ntej no peb nrhiav los tshawb txog cov txheej txheem hauv qab rau lawv cov txiaj ntsig sib txawv los ntawm kev tshawb xyuas cov ntaub ntawv transscriptomic ntawm BM-hMSCs thaum kho tshuaj. . Peb suav cov fold-hloov ntawm cov noob qhia ntawm txhua tus khub tshuaj-tswj raws li. Rau txhua tus khub tswj hwm tshuaj, qhov sib txawv ntawm cov noob (DEGs) nrog kev hloov pauv saum toj no 2 tau xaiv, uas muaj ob qho tib si upregulating thiab downregulating genes (Table Ntxiv 1). Peb tau txais 1758 cov noob hauv tag nrho tom qab tshuaj xyuas tag nrho cov DEGs los ntawm cov tshuaj kho BM-hMSCs (Daim duab 3A). Txhawm rau tshawb xyuas cov haujlwm ntawm DEGs, peb txheeb xyuas cov txiaj ntsig ntawm noob caj noob ces ontology (GO) cov ntsiab lus ("p<0.01) based="" on="" each="" drug's="" degs="" [19](supplementary="" table="" 2).="" these="" enriched="" go="" terms="" represent="" the="" functions="" influenced="" by="" the="" drugs.="" furthermore,="" we="" plot="" the="" venn="" diagram="" to="" study="" the="" similarity="" and="" specificity="" of="" the="" enriched="" go="" terms.="" as="" shown="" in="" figure="" 3b,="" although="" each="" drug="" has="" its="" unique="" regulated="" go="" terms,="" the="" drugs="" also="" share="" a="" common="" go="" which="" suggests="" that="" there="" are="" common="" functions="" influenced="" by="" all="" four="" drugs.="" these="" common="" go="" terms="" may="" associate="" with="" the="" effects="" of="" the="" drug="" on="" senescence="" alleviation="" and="" trilineage="" differentiation="">

Kaum ob lub ntsiab lus GO tau sib koom los ntawm plaub yam tshuaj (Daim duab 3B, 3D), uas feem ntau ua rau muaj txiaj ntsig zoo ntawm kev tswj hwm ntawm tes tsis zoo (Daim duab 3E), kev tswj hwm zoo ntawm actomyosin lub koom haum, kev tswj hwm ntawm cov txheej txheem ntawm tes thiab lub koom haum cellular tivthaiv, lub koom haum cytoskeleton. , macromolecule catabolic txheej txheem, kev tswj hwm ntawm cell proliferation, protein catabolic txheej txheem thiab me me GTPase mediated teeb liab transduction (Daim duab 3C, 3E). Cov haujlwm no muaj feem cuam tshuam nrog txoj hmoo ntawm tes, tshwj xeeb tshaj yog muaj feem cuam tshuam txog phenotypes.

Tom qab tshuaj xyuas cov ntsiab lus ntawm GO ntawm metformin thiab oltipraz, peb pom tias lawv sib koom ua haujlwm zoo ib yam li NRF2 agonists. Raws li pom hauv daim duab 3F, kev ua haujlwm ntawm lub voj voog ntawm tes, cov txheej txheem macromolecule catabolic, thiab lub koom haum lub hnab ntawv nuclear tau hloov kho. Ntxiv mus, kev ua haujlwm rau kev txav mus los, kev txav chaw ntawm tes / adhesion, thiab cov lus teb rau cov vitamin E / organic cyclic compound / lipid raug txo qis (Daim duab 3G). Cov txiaj ntsig no tag nrho qhia tias metformin thiab oltipraz tuaj yeem cuam tshuam rau kev sib txawv ntawm tes, txoj hmoo ntawm tes, thiab cov metabolism hauv cell. Raws li oltipraz yog cov tshuaj zoo tshaj plaws los txhim kho trilineage kev sib txawv muaj peev xwm, peb tau nrhiav ntxiv los txheeb xyuas cov kev tshwj xeeb hloov pauv los ntawm oltipraz. Interestingly, lub enriched 85 GO cov ntsiab lus yog feem ntau hais txog cellular senescence, cell voj voog, mitotic thiab meiosis txheej txheem, cellular teb rau cov tshuaj, vitamin, cAMP, DNA puas stimulus, as-ham thiab osmotic kev nyuaj siab (Ntxiv daim duab 2A,2B). Lipidomics profile ntawm cov tshuaj kho BM-hMSCs Los tshawb xyuas lub ntiaj teb hloov pauv ntawm lipids hais txog BM-hMSCs osteogenic sib txawv ntawm kev kho tshuaj, LC-MS-based lipidomics profiling tsom xam tau ua.A tag nrho ntawm 139 hom lipid tau txheeb xyuas hauv cellular lipidome, suav nrog lysophosphatidylethanolamines (LPE), 21 PEs, 4 PE-Os, 4 phosphatidylinositol (PI), 5 phosphatidylserines (PS), 8 Ceramides (Cer), 4 Cerys, 11 sphingomyelins (SM), 6 diacylglycerides (1) diacylglycerides TG) thiab 20 dawb fatty acids (FFA) (Daim duab 4A-4M). Raws li cov teeb meem ntawm pawg, cov hlwb kho nrog oltipraz pom qhov hloov pauv loj tshaj plaws ntawm lipids, uas tau pom zoo nrog nws cov txiaj ntsig zoo tshaj plaws ntawm cell senescence alleviation thiab trilineage sib txawv txhim kho. Hauv kev nthuav dav, monophosphatidylglycerols LPCs tau nce hauv pawg kho mob oltipraz piv nrog kev tswj hwm, qhov uas lawv cov PCs thiab PEs tau raug txo qis (Daim duab 4B,4D,4E). Cov theem ntawm PIs thiab SFAs kuj tau nce siab thaum theem ntawm Ceres thiab MUFAs raug txo (Daim duab 4F, 4L, 4H, 4M). Cov txiaj ntsig no

Lipidomics- thiab transcriptomics-raws li txoj kev tsom xam hauv cov tshuaj kho mob hMSCs

Txhawm rau tshawb xyuas cov txheej txheem hauv qab no rau kev txhim kho trilineage sib txawv los ntawm oltipraz, txoj kev tsom xam tau ua raws li cov ntaub ntawv lipidomic thiab transcriptomic. Raws li pom nyob rau hauv daim duab 5A, CDP-Diacylglycerol Synthase 1 (CDS1) yog tib enzyme up-regulated nyob rau hauv oltipraz kho hlwb, uas tej zaum yuav yog vim li cas ua rau elevation ntawm PIs thiab txo cov PCs. Txawm li cas los xij, qhov txo qis ntawm lecithin cholesterol acyl transferase (LCAT) thiab tsis hloov pauv lysophosphatidylcholine acyltransferase3 (LPCAT3) tsis sib haum nrog cov LPCs ntau ntxiv, qhia tias LPCs ntau dhau yuav tsis raug tsim los ntawm PCs / Pes (Daim duab 5A). Qhov zoo siab, kev hloov pauv pom tseeb tuaj yeem pom ntawm SFAs thiab MUFAs (Daim duab 5B). Qhov nce hauv cov roj ntsha saturated fatty acids (SFA) thiab txo qis hauv MUFAs tuaj yeem tshwm sim los ntawm kev tswj hwm qis qis stearoyl-CoA desaturase (SCD). Qhov kev teeb tsa no zoo li nthuav tawm cov txheej txheem rau kev txo qis ntawm lipogenesis tom qab kho nrog oltipraz. Txawm hais tias kev kho mob oltipraz tuaj yeem txo qhov kev tsim ntawm Ceres, kev hloov kho los ntawm Tsheb tsis tau hloov pauv ntau (Daim duab 5C).

Ntiaj teb no profiles ntawm lipid hom nyob rau hauv hMSCs supernatant raws li kev kho tshuaj

Tsis tas li ntawd, cov kev hloov pauv lipidomics hauv nruab nrab yog qhov ua tau zoo txhawm rau tshawb xyuas qhov cuam tshuam ntawm cov tshuaj ntawm hMSCs. Raws li pom nyob rau hauv Cov Lus Qhia Ntxiv 3, kev tshuaj xyuas pawg pom tau tias cov lipids tau muab faib ua ob pawg, piv txwv li. Feem ntau ntawm FFAs thiab lwm yam lipids (non-FFAs).txo cov roj cholesterolRaws li pom nyob rau hauv daim duab 6, nyob rau hauv plaub pawg, FFAs nthuav tawm pom kev hloov pauv ntawm cov sijhawm kho mob sib txawv. Hauv qhov sib piv, cov tsis-FFAs pom qhov hloov pauv me ntsis hauv plaub pawg (Daim duab 6A-6D). FFAs tau nce siab thaum ntxov hauv txhua pab pawg (Daim duab 6E-6H).cistanche deserticola phivNtxiv mus, FFAs hauv cov hlwb raug ntxias los ntawm metformin (Daim duab 6E), oltipraz, thiab kev kho cov vitamin C tau nce sai ntawm lub sijhawm thib ob mus rau lub sijhawm thib 3. Txawm li cas los xij, hauv cov hlwb uas kho nrog rapamycin, FFAs tau nce los ntawm cov npe mus rau lub sijhawm thib 2 (Daim duab 6F-6H). Qhov zoo siab, FFAs hauv cov hlwb uas kho metformin pom qhov poob qis dua li ntawm peb pawg (Daim duab 6E). Tom qab ntawd, qhov nce me ntsis ntawm FFAs tuaj yeem pom hauv pawg kho mob oltipraz thiab vitamin C thaum lub sijhawm 4th mus rau 5th lub sijhawm, FFAs pom qhov poob qis me ntsis hauv pawg kho metformin (Daim duab 6E, 6F, 6H).

Hauv rapamycin-kho cov hlwb, qib ntawm FFAs tau tswj hwm los ntawm 3rd mus rau 5th lub sijhawm. Tshwj xeeb, raws li qhia hauv Daim Duab Ntxiv 3 thiab Cov Lus Ntxiv 4, cov qauv hloov pauv ntawm FFAs tuaj yeem muab faib ua 8 pawg ntxiv. Nyob rau hauv no, pawg 6 feem ntau suav nrog SFAs pom zoo ib yam li cov uas tau pom hauv oltipraz thiab vitamin C pab pawg, thaum pawg kuv yog tib yam li pawg rapamycin. Feem ntau, qhov nruab nrab-FFAs hauv txhua pab pawg tshwj tsis yog cov metformin tau nce thoob ntiaj teb nrog rau kev txhawb nqa, qhia txog kev koom tes ntawm FFAs hauv kev coj noj coj ua hauv ib puag ncig thiab cell senescence. Cov hlwb raug ntxias los ntawm metformin thiab vitamin C pab txhawb kev cuam tshuam zoo sib xws rau SFAs hauv ib puag ncig sab hauv piv nrog rapamycin induction (Daim duab 6A,6D,6E,6H).

Lub tswv yim dav dav los kawm txog kev tiv thaiv kev laus ntawm cov tshuaj hauv hMSCs

Raws li pom hauv daim duab 7, txhawm rau txheeb xyuas qhov cuam tshuam los tiv thaiv kev laus ntawm plaub yam tshuaj hauv hMSCs, ib txoj kev tshawb fawb tau ua los ntawm kev cob qhia muaj xws li phenotype characterization, transcriptomics, cell lipidomics, thiab nruab nrab lipidomics tsom xam. Oltipraz alleviated senescence thiab txhim kho trilineage sib txawv efficiency los ntawm kev txhawb cov zus tau tej cov PIs, inhibiting lub biosynthesis ntawm PCs / PEs, thiab thaiv qhov kev hloov ntawm SFA rau MUFA. GO cov ntsiab lus kuj qhia txog cov phenotype txuam nrog cellular senescence, mitotic thiab meiosis txheej txheem, cellular teb rau DNA puas stimulus, ammonium ion, thiab oxygen theem. Qhov zoo siab, NRF2 txoj hauv kev tau tswj hwm los ntawm ob qho tib si oltipraz thiab metformin los txhawb kev sib txawv ntawm tes mus rau qib sib txawv. Lub caij no, qhov nruab nrab lipidomics layout qhia txog lub luag haujlwm tseem ceeb ntawm nruab nrab FFAs hauv MSC sib txawv rau ntau hom cell. Yog li ntawd, lub tswv yim multidimensional muab ntau qhov kev xav los txhais cov txiaj ntsig sib txawv ntawm kev cuam tshuam yeeb tshuaj ntawm hMSCs senescence. Txoj kev no tuaj yeem siv los kawm txog cov tshuaj lom neeg sib txawv raws li kev cuam tshuam tshuaj hauv MSC uas yuav txuas ntxiv rau kev kho mob ntawm hMSCs.

Kev sib tham

Tus kab mob tshiab coronavirus 2019(COVID-19) tau loj hlob los ua kev kub ntxhov thoob ntiaj teb kev noj qab haus huv. Tam sim no, tsis muaj cov tshuaj tshwj xeeb los tiv thaiv cov neeg mob los ntawm cov teebmeem immunomodulatory. Nws tau tshaj tawm tias daim ntawv thov ntawm MSC hauv COVID-19 mob hnyav txhim kho cov txiaj ntsig ntawm cov neeg mob los ntawm kev tswj hwm cov lus teb ntawm lub cev thiab txhawb nqa lub ntsws kho thiab rov tsim dua tshiab [20]. Txawm li cas los xij, feem ntau tshwm sim senescence ntawm hMSCs nyob rau lub sij hawm ntev kab lis kev cai nyob rau hauv vitro hampered kev kho mob daim ntawv thov ntawm hMSCs. Hauv txoj kev tshawb no, peb tsim ib qho kev tshuaj ntsuam xyuas tshuaj hauv vitro raws li BM-hMSCs senescence phenotype [21]. Ntau qhov kev tshawb fawb tau tshawb fawb txog kev laus txog kev cuam tshuam rau hMSCs raws li kev tswj hwm ntawm TFs [22-27] thiab kev siv tshuaj sib txawv [10. 13,17,28,29].Txawm li cas los xij, peb yog thawj zaug uas tau soj ntsuam xyuas cov txiaj ntsig tiv thaiv kev laus ntawm cov tshuaj sib txawv ntawm BM-hMSCs los ntawm kev xav ntawm SA- -gal kev ua haujlwm thiab kev ua haujlwm sib txawv. Rapamycin, oltipraz, metformin, thiab vitamin C yog plaub yam tshuaj thawj zaug siv rau hMSCs kev cuam tshuam kev laus. Txawm hais tias tag nrho plaub cov tshuaj tiv thaiv BM-MSC senescence, cov teebmeem tshwm sim thiab cov txheej txheem ntawm plaub cov tshuaj hauv kev txhawb nqa kev sib txawv ntawm tes sib txawv. Qhov tseem ceeb tshaj plaws, peb kuj tsim kom muaj kev ntsuam xyuas tag nrho ntawm kev cuam tshuam tshuaj los ntawm kev txheeb xyuas ntawm transcriptomics thiab lipidomics profiles hauv cell supernatants thiab lysates. Hauv kev nthuav dav, cov ntaub ntawv transcriptomics tau soj ntsuam tag nrho nrog rau cov phenotype ntawm qia hlwb tom qab kev kho tshuaj los tshawb txog cov kev hloov pauv thiab cov txheej txheem hauv qab uas cuam tshuam los ntawm kev kho tshuaj. Ntxiv mus, cov qauv hloov lipid ntawm cov hlwb kho nrog cov tshuaj sib txawv ntawm lub sijhawm sib txawv tau txiav txim los ntawm LC-MS. Tsis tas li ntawd, los ntawm kev sib koom ua ke cov ntaub ntawv ntawm transcriptomics thiab lipid metabonomic, cov tshuaj tshwj xeeb metabolic txoj hauv kev thiab tshuaj cuam tshuam txog kev hloov lipid tau txheeb xyuas thiab sau cov ntsiab lus.

Oltipraz yog cov tshuaj zoo tshaj plaws los txhim kho lub peev xwm sib txawv ntawm BM-hMSCs ntawm plaub cov tshuaj. Cov DEGs cuam tshuam los ntawm kev kho oltipraz feem ntau ua rau cov cellular senescence, cell voj voog, thiab cellular teb rau cov tshuaj, cAMP, thiab lwm yam. Cov kev hloov pauv no ua lub luag haujlwm tseem ceeb hauv kev laus ntawm cellular Txawm li cas los xij, oltipraz thiab metformin, Nrf2 txoj hauv kev inhibitors, cuam tshuam rau txoj kev tswj hwm [30], uas feem ntau txhawb kev sib txawv ntawm tes, txoj hmoo ntawm tes, thiab cov metabolism hauv cell. Raws li ib qho inhibitor ntawm txoj kev mTOR, rapamycin tuaj yeem tiv thaiv cellular senescence [31, 32] Ib yam nkaus, peb kuj pom tias rapamycin ua lub luag haujlwm zoo tshaj plaws hauv kev txhawb kev sib txawv ntawm osteogenic uas feem ntau yog los ntawm kev tswj cov phosphate-muaj cov txheej txheem metabolic txoj hauv kev, cellular tivthaiv lub koom haum, Kev sib txuas lus ntawm tes, teeb liab hloov, macromolecule biosynthetic txheej txheem, cellular protein metabolic txheej txheem, thiab skeletal system kev loj hlob. Vitamin C yog ib tug paub zoo reductant thiab nws plays lub luag hauj lwm zoo tshaj plaws nyob rau hauv kev txhawb cell proliferation piv nrog rau lwm yam peb cov tshuaj, tab sis tsis muaj ib tug tseem ceeb nyhuv nyob rau hauv lub trilineage sib txawv peev xwm txhim kho MSC. Cov phenotypes no tuaj yeem tshwm sim los ntawm cov lus teb rau cytokine / lipid / oxidative kev nyuaj siab, thiab kev tswj hwm kev ua haujlwm catalytic zoo (Cov duab ntxiv 4).

Lipids tau pom los ua lub luag haujlwm tsis tuaj yeem hloov pauv hauv kev sib txawv ntawm cov qia hlwb [33]. Peb yav dhau los tau pom tias qhov nce ntawm daim nyias nyias glycerophospholipids suav nrog PCs thiab PEs, lub cim ntawm kev laus, tau pom thoob ntiaj teb hauv cov laus MSCs [18]. Hauv txoj kev tshawb fawb tam sim no, kev txo qis hauv PCs thiab PEs tau pom nyob rau hauv cov hlwb kho nrog oltipraz uas ua tau zoo tshaj plaws hauv kev ncua sijhawm ntawm MSCs PCs thiab PEs yog cov lipids uas muaj ntau tshaj plaws hauv kev tsim kho ntawm eukaryotic membranes 34]. Kev nce qib ntawm PCs thiab PEs hauv sera tau pom hauv cov neeg laus piv nrog cov neeg hluas [34]. Qhov zoo siab, PIs yog cov GPLs tsawg tsawg hauv MSCs hnub nyoog hauv peb qhov kev soj ntsuam dhau los. Hauv txoj kev tshawb no, PIs tau nce siab heev hauv txhua lub hlwb induced. Mechanically, txoj kev tsom xam pom tias qhov nce hauv PIs tuaj yeem cuam tshuam nrog lub tshuab ua haujlwm CDS1.CDS1 kinase tau raug pov thawj los koom nrog kev tswj hwm ntawm ROS signaling thiab ntxiv cuam tshuam rau kev qhia cov noob uas ua haujlwm hauv oxidative resistance [35]. Lwm qhov cuam tshuam loj heev hauv metabolic flux yog kev hloov pauv ntawm SFA rau MUFA kho los ntawm SCD. Raws li biobarometer ntawm lipogenesis, lub tshuab txais SFA / MUFA tau pom nyob rau hauv ib pawg kab mob xws li mob qog noj ntshav thiab kab mob uas tsis yog-coholic fatty siab (NAFLD) [36,37] Cov txiaj ntsig zoo sib xws kuj tau pom nyob rau hauv cov nas muaj hnub nyoog, uas qhia txog cov metabolism hauv lub cev tsis zoo. Lipids hauv daim siab thaum laus [38] Ua ke, peb lub tswv yim tuaj yeem siv rau hauv kev tshuaj xyuas tshuaj tiv thaiv kev laus thiab kev tshawb nrhiav molecular mechanism tom qab kev kho tshuaj hauv cov qia hlwb thiab mob qog noj ntshav. Los ntawm kev sib txuas cov tswv yim nrog cov kev ntsuam xyuas, peb tuaj yeem ua qhov kev soj ntsuam ntawm lub sijhawm raws li qhov kev laus ntawm cov qia hlwb kom pom cov tshuaj tshiab uas yuav siv los kho cov qia cell.

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