Endogenous Stem Cells in Homeostasis Thiab Aging Part 2

 3.2 Oxytocin Cov

Oxytocin yog cov tshuaj hormones thiab neuropeptide uas nws cov ntshav plasma poob qis nrog kev laus. Cov nqaij ntshiv hauv cov tsiaj hluas tau txo qis thaum oxytocin raug txwv, thiab kev tswj hwm ntawm oxytocin txhim kho cov laus cov leeg qia hlwb ua haujlwm thiab kev loj hlob los ntawm kev ua kom muaj MAPK / ERK signaling pathway, uas ua rau cov nqaij ntshiv ntxiv [14]. Raws li FDA pom zoo tshuaj, oxytocin yog suav tias yog ib txoj hauv kev kho mob thiab muaj kev nyab xeeb los kho cov leeg nqaij laus. Tsis tas li ntawd, oxytocin raug tso tawm thaum khawm lossis sib txuas, uas tuaj yeem muaj txiaj ntsig los tiv thaiv kev laus.

Glycoside ntawm cistanche tuaj yeem ua rau muaj kev ua haujlwm ntawm SOD hauv plawv thiab daim siab cov ntaub so ntswg, thiab txo cov ntsiab lus ntawm lipofuscin thiab MDA hauv txhua cov ntaub so ntswg, tshem tawm ntau yam reactive oxygen radicals (OH-, H₂O₂, thiab lwm yam) thiab tiv thaiv DNA puas. los ntawm OH-radicals. Cistanche phenylethanoid glycosides muaj peev xwm tshem tawm cov dawb radicals, muaj peev xwm txo tau ntau dua li cov vitamin C, txhim kho cov haujlwm ntawm SOD hauv cov phev ncua, txo cov ntsiab lus ntawm MDA, thiab muaj qee yam kev tiv thaiv ntawm cov phev ua haujlwm. Cistanche polysaccharides tuaj yeem txhim kho kev ua haujlwm ntawm SOD thiab GSH-Px hauv erythrocytes thiab ntsws cov ntaub so ntswg ntawm cov nas senescent sim los ntawm D-galactose, nrog rau txo cov ntsiab lus ntawm MDA thiab collagen hauv lub ntsws thiab ntshav, thiab nce cov ntsiab lus ntawm elastin, muaj Cov nyhuv scavenging zoo ntawm DPPH, ncua lub sijhawm ntawm hypoxia hauv cov nas senescent, txhim kho cov haujlwm ntawm SOD hauv cov ntshav, thiab ncua lub physiological degeneration ntawm lub ntsws hauv kev sim cov nas nrog cellular morphological degeneration, kev sim tau pom tias Cistanche muaj peev xwm antioxidant zoo. thiab muaj peev xwm los ua ib qho tshuaj tiv thaiv thiab kho cov kab mob ntawm daim tawv nqaij laus. Nyob rau tib lub sijhawm, echinacoside hauv Cistanche muaj lub peev xwm tseem ceeb los tshem tawm DPPH dawb radicals thiab tuaj yeem tshem tawm cov pa oxygen reactive, tiv thaiv dawb radical-induced collagen degradation, thiab kuj muaj kev kho zoo ntawm thymine dawb radical anion puas.

Nyem rau rou cong rong cov txiaj ntsig

【Yog xav paub ntxiv:george.deng@wecistanche.com / WhatApp:86 13632399501 】

3.3 Bursicon

Bursicon yog cov tshuaj tua kab thiab cov tshuaj neuroendocrine. Neurotransmitters tso tawm los ntawm paj hlwb txhawb cov hlwb neuroendocrine tso tawm bursicon rau hauv cov hlab ntsha. Enteroendocrine hlwb nyob rau hauv lub plab zom mov secrete bursicon, uas khi rau nws receptor DLGR2 thiab inhibits epidermal loj hlob yam (EGF) qhia. Kev sib cuam tshuam ntawm bursicon thiab DLGR2 nyob rau hauv cov hnyuv Drosophila tuav lub quiescence ntawm txoj hnyuv qia hlwb [52]. Bursicon yog suav tias yog ib qho kev tswj hwm hauv zos rau kev saib xyuas cov kab mob hauv plab hnyuv hauv homeostasis.

3.4 TSI HGFA

HGF, ib qho mesenchyme-derived heparin-binding glycoprotein, khi rau c-Met receptor, thiab qhov kev sib cuam tshuam tswj cov cell proliferation, cell survival, cell motility, thiab cov ntaub so ntswg regeneration los ntawm tyrosine kinase txoj kev [53, 54]. Ntau qhov kev tshawb fawb yav dhau los tau pom tias HGF tau qhib qhov nkag ntawm cov cell quiescent satellite rau hauv lub voj voog ntawm tes. Nyob rau hauv 2014, Dr. Thomas Rando thiab nws pab pawg tau tshaj tawm tias satellite cell thiab extracellular matrix ntawm cov nqaij ntshiv puas secrete HGF, uas txhawb kev nkag mus ntawm quiescent satellite hlwb los ntawm lub xeev G0 mus rau GAlert theem los ntawm mTORC1 downstream. taw qhia txoj kev. GAlert hlwb yog primed rau proliferation thiab ua kom. Kev raug mob vim raug tso tawm ntawm qib qis ntawm HGF txhawb nqa quiescent satellite hlwb kom nkag mus rau theem GAlert, thaum lub sijhawm ntev raug mob vim HGF cov cim qhia sai sai txhawb kev loj hlob thiab ua kom kho [55]. Hauv xyoo 2017, pawg Rondo tau qhia tias kev txhaj tshuaj ntawm HGFA ua rau muaj kev ua haujlwm proteolytic rau HGF ua kom muaj zog thiab txhawb nqa lub xeev GAlert hauv cov leeg nqaij pob txha. Kev tswj hwm ntawm HGFA txaus ua tiav qia cell ua kom thiab kho cov ntaub so ntswg; Yog li, HGFA tau thov los ua tus neeg sib tw muaj peev xwm rau kev siv tshuaj kho mob hauv cov tshuaj regenerative [15].

3.5 TSI 11

Xyoo 2011, Tony Wyss-Coray thiab nws pab pawg tau tshaj tawm tias qib CCL11 hauv cov ntshav ntshav tau nce ntxiv hauv cov nas muaj hnub nyoog thiab tib neeg. CCL11 inhibits neurogenesis thiab cuam tshuam kev kawm thiab kev nco, yog li nws tau npaj ua ib qho kev txhawb nqa kev laus siv cov kev sim heterochronic parabiosis [7]. Tib pab pawg tau tawm tsam los txiav txim siab txog cov txheej txheem cuam tshuam nrog kev laus thiab cov ntaub so ntswg degeneration siv txoj hauv kev proteomic. Rau caum-rau cytokines, chemokines, thiab secreted signaling proteins tau ntsuas nyob rau hauv lub plasma ntawm ib txwm laus nas siv standardized, multiplex sandwich enzyme-txuas immunosorbent assays (ELISAs; Luminex). Ntawm cov 66 cov proteins, CCL2, CCL11, CCL12, CCL19, haptoglobin, thiab b2-microglobulin (B2M) nce hauv cov nas muaj hnub nyoog thiab cov nas me me heterochronic parabiosis. CCL11 yog ib qho tshuaj chemokine koom nrog cov lus teb tsis haum uas tsis tau tshaj tawm tias yog ib qho kev laus. Txawm li cas los xij, qib siab ntawm CCL11 tau kuaj pom hauv cov neeg siv cannabis thiab cov neeg uas muaj kev mob schizophrenia tshwm sim los ntawm cannabis [56]. Txawm hais tias CCL11 zoo li yog ib qho kev laus uas muaj feem cuam tshuam nrog lub cev, raws nraim li cas nws txhawb txoj kev laus xav tau kev kawm ntxiv.

3.6 B2M

Pab pawg Wyss-Coray thiab Saul A Villeda kuj tau tshaj tawm B2M raws li qhov muaj feem cuam tshuam rau kev laus uas cuam tshuam kev paub txog kev ua haujlwm thiab neurogenesis hauv nas [57]. B2M yog ib feem ntawm qhov loj histocompatibility complex class I (MHC I) molecules, uas tau nce hauv cov ntshav thiab hippocampus ntawm cov neeg laus thiab cov nas. Exogenous txhaj ntawm B2M systemically los yog hauv zos mus rau lub hippocampus impairs hippocampal-nyob ntawm kev txawj ntse muaj nuj nqi thiab neurogenesis nyob rau hauv cov me nyuam nas, thiab tsis muaj endogenous B2M nyob rau hauv B2m-/- nas tshem tawm hnub nyoog txog kev txawj ntse tsis ua hauj lwm thiab txhim kho neurogenesis nyob rau hauv cov laus nas [57]. Tsis tas li ntawd, kev nce qib ntawm cov kua dej B2M tau raug kuaj pom hauv cov kua dej cerebrospinal ntawm cov neeg mob HIV dementia [58, 59] lossis Alzheimer's disease [60]. Lub koom haum muaj zog ntawm qib B2M systemic thiab kev paub txog kev ua haujlwm poob qis qhia tias B2M yog qhov muaj peev xwm tiv thaiv kev laus. Txawm hais tias pawg Wyss-Coray thiab Villeda tseem tsis tau cais tawm ib qho kev tiv thaiv kev laus los ntawm cov tub ntxhais hluas plasma, lawv tau pom tias cov ntshav cov menyuam yaus rov qab muaj hnub nyoog cuam tshuam txog kev ua haujlwm tsis zoo hauv kev txawj ntse thiab synaptic plasticity ntawm cov nas qub [61]. Tsis tas li ntawd, lawv tau ua qhov kev sim tshuaj rau tib neeg uas siv cov ntshav plasma los ntawm cov tub ntxhais hluas pub dawb (\30) rau cov neeg laus Alzheimer's [62]. Muaj cov lus cog tseg rau kev kho kom rov zoo dua qub uas tuaj yeem tig rov qab lub sijhawm rau cov neeg laus, tab sis cov xwm txheej zoo li no tsuas yog qhov pib ntawm kev nkag siab txog kev laus.

4 Stem cell niche ua tus tswj qhov zoo lossis tsis zoo

Nyob rau hauv cov pob txha pob txha, HSCs, BMSCs, thiab EPCs muaj nyob rau hauv ib tug nruj tswj microenvironment, ib tug niche, uas pab txhawb rau kev tswj ntawm quiescence, proliferation, self-renewal, thiab sib txawv. Cov qia cell niche no yog tsim los ntawm cov neeg tshwj xeeb ntawm cov hlwb uas suav nrog cov khoom soluble xws li cytokines, chemokines, thiab cov yam ntxwv loj hlob thiab tsim cov tshuaj lom neeg, lub cev, thiab cov khoom siv hluav taws xob rau oxygen nro, extracellular matrices, shear rog, kub, nyob ib puag ncig pH, thiab monoatomic ions, tag nrho cov uas tswj cov qia cell tus cwj pwm. Tshooj lus no txiav txim siab seb muaj pes tsawg hnub nyoog hloov pauv hauv cov cellular lossis microenvironmental Cheebtsam ntawm lub niche cuam tshuam rau kev ua haujlwm ntawm qia hlwb lossis qia cell niche nws tus kheej.

4.1 HSC Niche hauv cov pob txha hluas thiab laus

Lub qia cell niche rau HSCs, uas muaj ntau lub cellular Cheebtsam thiab lawv cov secretions, tswj HSC homeostasis thiab kev lag luam siv cov txheej txheem sib txawv. BMSCs, endothelial hlwb ntawm arterioles/capillaries/sinusoids, osteoblasts, lub sympathetic paj hlwb, T hlwb, thiab macrophages yog tag nrho cov lees paub raws li zoo regulators, whereas adipocytes thiab osteoclasts feem ntau paub tias tsis zoo regulators (Fig. 4). Puas yog Nestinmid PDGFa? CD51? perivascular hlwb nyob ze HSCs thiab cov hlab ntsha adrenergic thiab tswj lub quiescence ntawm HSCs los ntawm secreting cytokine chemokine (C–X–C motif) ligand 12 (CXCL12) thiab qia cell factor (SCF) [63]. CXCL12-abundant reticular (CAR) hlwb, uas yog Nestin? Mx -1? Lepr?Prx-1? MSC-zoo li cov hlwb nyob ze ntawm lub endosteum, tswj HSC tus kheej-renewal, proliferation, thiab mobilization [64]. Endothelial hlwb ntawm arteriole thiab sinusoid txhawb HSCs los ntawm secreting FGF, EGF, DLL1, IGFBP2, ANGPT1, DHH, pleiotrophin, thiab Jagged -2 [12, 65, 66].

Lub endosteal qia cell niche muaj qhov chaw tshwj xeeb hypoxic tiv thaiv kab mob los tiv thaiv HSCs los ntawm inflammatory insult. Kwv yees li 80 feem pua ​​​​ntawm Lin-Sca1?- KIT? CD41-CD150?CD48- HSCs tau pom nyob ze rau ntawm qhov chaw endosteal ntawm cov pob txha, thiab tsuas yog 20 feem pua ​​​​ntawm HSCs nyob ze ntawm lub hauv paus hlab ntsha ntawm cov pob txha chaw [12]. Nyob rau hauv lub endosteal niche, tshwj xeeb osteoblastic hlwb (SNO hlwb) muab quiescent signals rau HSC txij nkawm. SNO hlwb thiab HSCs tsim ib lub cell-cell junction nrog N-cadherin thiab induce b-catenin-mediated PTEN activation uas thaiv PI3K / Akt / mTOR-induced cell voj voog nkag. Ob leeg SNO hlwb thiab HSCs tsim ib qho kev sib txuas ntawm VCAM thiab VLA4 thiab nruab nrab ntawm fibronectin thiab VLA5. SNO hlwb inhibit HSC ua kom, sib txawv, thiab apoptosis los ntawm kev muab BMP, Jagged, thiab Ang-1 [67]. Treg hlwb, uas sib sau rau ntawm qhov chaw endosteal, muab kev tiv thaiv kev tiv thaiv kab mob rau HSCs los ntawm kev zais cov tshuaj tiv thaiv cytokine IL-10. HSCs zoo li nyob hauv 20 lm ntawm CD4.CD25?FoxP3? Qhov chaw [68]. Sympathetic paj hlwb nyob rau hauv cov pob txha pob txha kuj tiv thaiv HSCs los ntawm secreting TGF-b activator los ntawm non-myelinating Schwann hlwb, uas cuam tshuam nrog cov TGF-b receptor ntawm HSC nto kom qhib lub phosphorylation ntawm SMAD2/3 signaling thiab ua rau cov txij nkawm thiab quiescence. ntawm HSCs [69]. Adrenergic paj hlwb thiab Nestin? BMSCs qhia HSC cov noob tu, suav nrog CXCL12, ANGPT1, Cov Khoom Siv ligand, thiab VCAM{33}}, thaum ua kom cov adrenergic receptor downregulates cov noob qhia [70].

Tsis ntev los no, cov kws tshawb fawb tau pom tias macrophages ua lub luag haujlwm tseem ceeb hauv kev saib xyuas ntawm LT-HSCs, uas nws depletion los ntawm granulocyte-colony-stimulating factor (GCSF) ua rau lub paj hlwb ua rau cov norepinephrine secrete, uas ua rau HSC egress mus rau hauv cov ntshav [71]. CD82/KAI1, uas tau nthuav tawm heev ntawm qhov chaw ntawm LT-HSCs, txhawb nqa LT-HSC quiescence los ntawm kev cuam tshuam nrog DARC (CD234) ntawm cov macrophages tom qab TGF-b1 / Smad3 signaling pathway [72]. Tsawg CD82 qhia yog txuam nrog cov qog nqaij hlav. Endothelial DARC paub tias yuav ua rau muaj qhov tshwm sim ntawm CD82. qog nqaij hlav [72]. a-SMA?COX-2? monocytes thiab macrophages tuav hematopoietic qia progenitor hlwb (HSPCs) los ntawm kev tsim cov prostaglandin E2, uas inhibits zus tau tej cov ROS nyob rau hauv HSPCs los ntawm limiting stromal-cell qhia ntawm cov chemokine CXCL12 [73]. CD169? macrophages hauv pob txha pob txha yog txawv ntawm M1/M2 macrophage subtypes thiab nthuav qhia CD206, VCAM{25}}, thiab CCL22 [74]. CD169 (Sialo-adhesion) yog lub cell adhesion molecule nyob rau saum npoo ntawm macrophages. CD169? macrophages muaj kwv yees li 2.6 feem pua ​​​​ntawm tag nrho cov pob txha pob txha, txhawb nqa HSC niche, thiab txhawb nqa HSC tuav nrog Nestin. BMSCs thiab b-adrenergic neurons hauv pob txha pob txha [75].

Dab tsi tsis zoo regulators cuam tshuam rau HSC niche? Tom qab irradiation thiab nyob rau hauv cov laus laus, BMSCs zoo li sib txawv rau hauv adipocytes thiab sau cov hlab ntsha qhov chaw, uas yog to taub inhibit HSC muaj nuj nqi. Inhibiting adipogenesis txhim kho pob txha pob txha rov qab [76]. Tsis tas li ntawd, hauv 2017, Ambrosi et al. [77] siv qhov kev sib tw rov ua dua tshiab tom qab ua kom tuag irradiation thiab tshaj tawm tias adipocytes tsub zuj zuj hauv cov pob txha pob txha thaum muaj rog thiab kev laus ua rau qia cell-based hematopoiesis thiab pob txha rov tsim dua tshiab. Raws li ib feem ntawm cov txheej txheem ntawd, lawv tau hais tias cov pob txha-neeg nyob hauv adipocytic kab mob ua rau ntau dhau ntawm dipeptidyl peptidase-4 (DPP-4), lub hom phiaj rau kev kho mob ntshav qab zib uas tuaj yeem ua rau HSC niche tsis zoo. Lwm yam khoom siv ntawm tes rau kev noj qab haus huv HSC niche yog cov pob txha-degrading osteoclast. Hauv tus qauv osteoprotegerin-defi-tus qauv nas, osteoclasts degrade lub endosteal niche thiab induce HSC mobilization [78, 79]. Hauv cov laus lub cev, kev qaug zog ntawm cov niche-txhawb hlwb thiab kev txhawb nqa ntawm adiposity hauv cov pob txha pob txha tuaj yeem tshwm sim tib lub sijhawm, uas ua rau HSC homeostasis tsis zoo.

4.2 BMSC/EPC niche

Tau ntau xyoo lawm, BMSC kev tshawb fawb tau hais txog lub luag haujlwm tseem ceeb ntawm BMSCs hauv kev kho qhov txhab thiab kho cov nqaij mos. Txawm li cas los xij, kev nkag siab tam sim no ntawm cov hlwb thiab cov cim qhia uas tsim los ntawm BMSC niche yog qhov tsawg heev. BMSCs feem ntau yog sib xyaw ntawm cov hlwb progenitor hauv cov pob txha pob txha. CD31? EPCs tau paub tias nyob ze ze los ntawm BMSCs thiab txhim kho tus kheej rov muaj peev xwm ntawm BMSCs hauv vivo thiab hauv vitro [80]. Tshwj xeeb, cov fibronectin nyob rau hauv EPCs, ib feem ntawm lub extracellular matrix rau HSC niche, yog paub los qhib lub integrin nyob rau hauv BMSCs thiab txhawb tus kheej-renewal [81, 82]. EPCs yog cov khoom siv roj ntsha tseem ceeb ntawm BMSC niche thiab cuam tshuam rau cov txheej txheem lom neeg ntawm BMSCs. IGF-1/IGF-2 khi rau IGF-1R/IGF-2R ntawm BMSCs thiab nce kev loj hlob thiab kev rov ua dua tshiab rau tus kheej [83]. CXCL12 txhim kho BMSC colony-forming muaj peev xwm, uas yog txhawb nqa los ntawm kev ua kom lub b3-adrenergic neuron thiab ua raws li kev txhawb nqa ntawm EPC colony-forming potency [84].

5 Epigenetic hloov nyob rau hauv qia hlwb thaum laus

Nyob rau hauv lub xyoo caum dhau los, accumulating pov thawj tau txhawb kev hloov nyob rau hauv cov ntaub ntawv epigenetic thaum lub sij hawm kev laus nyob rau hauv ob lub qia hlwb thiab somatic hlwb. Epigenetics yog hais txog txhua yam kev hloov pauv hauv cov noob caj noob ces uas tsis muaj kev ywj pheej ntawm DNA sequencing. Kev hloov pauv ntawm Epigenetic hauv cov genome thiab DNA-txuas nrog cov proteins yog xav tau rau kev saib xyuas ntawm cov kab mob lom xws li lub cev ntawm tes, nrog rau kev cuam tshuam tshwj xeeb rau cov qia hlwb. Ntau hom kev hloov pauv hauv epigenetic yog encoded nyob rau hauv lub epigenome, suav nrog txo cov tub ntxhais histones, histone posttranslational modifications, structural and functional variants of histones, DNA methylation, chromatin remodeling, and altered noncoding RNA expression during the aging and senescence. Cov kev hloov pauv ntawm epigenetic no ua rau muaj kev tsis txaus ntseeg ntawm cov noob caj noob ces, telomere shortening, thiab genomic instability [85]. Histone hloov kho xws li methylation, phosphorylation, ubiquitination, thiab acetylation tuaj yeem ua nyias los yog sib koom ua ke los tswj cov noob qhia los ntawm kev hloov pauv hauv chromatin qauv. Histone methylation yog ib qho kev tshwm sim ntawm epigenetic uas ua rau muaj qhov sib txawv ntawm cov transcriptional outputs nyob ntawm cov lysine (K) residue, xws li K4, K9, K20, K27, K36, thiab K79. Piv txwv li, histone H3 methylated ntawm K4 los yog K36 feem ntau yog txuam nrog cov active genes, whereas methylation ntawm K9 thiab K27 yog feem ntau txuas rau gene repression.

DNA methylation yog ib qho kev hloov kho epigenetic ruaj khov txwv rau cytosine residues hauv CpG dinucleotides los ntawm DNA methyl transferase enzymes (DNMTs). Chromatin remodeling yog ib qho kev tshwm sim muaj protein ntau uas ua rau chromatin rearrangements thiab pab nkag mus rau cov nucleosomal DNA siv SWITch/sucrose non fermentation (SWI/SNF), polycomb pawg (PcG), thiab Trithorax pawg (TrxG) proteins. Tsis yog-coding RNAs, suav nrog microRNAs (miRNAs, * 20 nucleotides) thiab ntev-tsis-coding RNAs (lncRNAs, * 200 nucleotides), uas tsis tau muab txhais ua cov protein, koom nrog cov kev cai posttranscriptional ntawm noob qhia.

5.1 Kev tshawb fawb Epigenetic hauv ntau hom thiab cov qauv progeria

Invertebrates yog cov qauv nrov rau kev tshawb fawb kev laus vim tias lawv muaj lub neej luv luv thiab muab cov caj ces yooj yim thiab kev tswj hwm ib puag ncig. Tsis tas li ntawd, cov qauv vertebrate xws li nas, nas, thiab zebrafish feem ntau yog siv. Hauv cov poov xab, tshem tawm cov chromatin remodeler SWI / SNF (ISW2) tau nthuav tawm qhov txuas ntxiv ntawm kev ua neej nyob thiab ua raws li kev txwv caloric los ntawm kev hloov pauv hauv nucleosome qhov chaw tseem ceeb rau kev tswj cov noob qhia [86]. Hauv 10 xyoo dhau los, histone methylation regulators xws li H3K4me3, H3K27me3, thiab H3K36me3 tau pom tias muaj kev koom tes hauv kev tswj lub neej ntawm C. elegans [87–89]. Tsis tas li ntawd, nce qib ntawm cov metabolites tseem ceeb, xws li acetyl CoA, thiab nce thoob ntiaj teb histone acetylation, suav nrog acetylated lysine 12 ntawm histone H4 (H4K12ac), tau lees paub thaum lub sijhawm kev laus. H4K12ac kev hloov pauv txuas ntxiv lub neej ntawm Drosophila [90]. Feem ntau hauv cov metabolism thiab kev laus, cov tsiaj nyeg sirtuin protein tsev neeg (SIRT1-SIRT7) tswj mitochondrial muaj nuj nqi thiab txhim kho qia cell ciaj sia. Sirtuins deacetylate histones thiab ob peb transcriptional regulators nyob rau hauv lub nucleus hauv cellular compartments [91]. Hauv cov nas, kev tshawb fawb txog qhov ua rau kev laus tau ua los ntawm kev tshuaj xyuas kev laus ntxov ntxov (progeria), xws li hauv Werner's syndrome thiab Hutchinson-Gilford progeria syndrome (HGPS), kab mob caj dab uas ua rau lub neej luv luv thiab tshwm sim los ntawm kev hloov pauv ntawm cov kab mob. Lamin A gene, uas ua rau chromatin hloov kho, metabolic tsis xws luag, qia cell qaug zog, cell voj voog deregulation, thiab o [92, 93].

5.2 Epigenetic hloov pauv hauv cov laus qia hlwb

Kev hloov kho rau DNA / histones thiab tsis-coding RNA-mediated mechanisms yog cov xwm txheej epigenetic uas ua lub luag haujlwm tseem ceeb hauv kev tswj cov qia / progenitor cell functions los ntawm kev hloov cov qauv chromatin. Kev hloov pauv ntawm Epigenetic hauv cov neeg laus qia hlwb yog qhov tseem ceeb thaum lub sijhawm laus vim tias lawv hloov pauv txoj haujlwm, clonal muaj pes tsawg leeg, thiab kab mob txoj hmoo ntawm cov qia hlwb uas tau tswj hwm los ntawm kev hloov pauv hauv nruab nrab thiab extrinsic epigenetic. Lub cim ua kom H3K4me3 thiab qhov kev tawm tsam H3K27me3 yog ob qhov chaw xav tias yuav cuam tshuam rau kev loj hlob ntawm noob caj noob ces. Cov thawj bivalent no kuj tso cai rau kev ua kom raws sijhawm thiab kev tsim txom thaum tsis muaj cov cim sib txawv [94]. Lub cim H3K27me3 yog qhov tseem ceeb rau kev tswj hwm daim ntawv txwv ntawm cov noob no, thaum H3K4me3/1 lub cim tuaj yeem ua rau muaj kev ua kom muaj kev cuam tshuam ntawm kev sib txawv ntawm cov cim sab nraud.

5.3 Epigenetic hloov pauv ntawm HSCs hauv kev laus thiab qia cell hierarchy

Interdependency ntawm histone hloov kho thiab DNA methylation tuaj yeem cuam tshuam rau HSC kev laus. Hauv cov qia hlwb, qhov kev txwv tsis pub H3K27me3 cim nyob rau hauv cov tub ntxhais hluas thiab hnub nyoog HSCs, ua ke nrog ob lub chromatin cim ntsig txog kev ua haujlwm nquag, H3K4me3, thiab H3K36me3, tau raug epigenetically profiled los ntawm ChiP-seq. Lub xub ntiag ntawm H3K4me3 thaum HSC laus tuaj yeem ua rau nws tus kheej rov ua dua tshiab hauv HSCs qub [95]. Nyob rau hauv sib piv, nyob rau hauv cov neeg laus skeletal leeg qia hlwb los yog satellite hlwb, lub xub ntiag ntawm H3K4me3 cov cim qhia me ntsis los yog tsis muaj qhov sib txawv nyob rau hauv cov hluas thiab laus nas [96]. Qhov kev tsis sib haum xeeb no tuaj yeem qhia tau tias kev tsim txom H3K4me3 cov cim yog qhov ua rau ntawm lwm cov txheej txheem, tsis yog transcription suppression, ntawm cov qia hlwb sib txawv. Tsis tas li ntawd, HSCs txuas nrog qhov poob ntawm H4K16ac ua kom lub cim thaum muaj hnub nyoog [27]. Ntxiv mus, Kdm3a thiab Kdm5b tau raug tshaj tawm los tswj cov qia cell laus vim tias lawv cov qib txo qis thaum lub sijhawm laus [97, 98]. Knockdown ntawm lysine demethylase Kdm5b (Jarid1b) txhim kho qhov kev nthuav dav hauv vitro ntawm HSCs thiab lawv hauv vivo lymphomyeloid sib txawv muaj peev xwm [99]. Tsis tas li ntawd, histone methylation ntawm H3K27me3 yog ib qho tseem ceeb regulator ntawm hematopoiesis. Cov kev tshawb fawb tsis ntev los no tau tshaj tawm tias cov tub ntxhais hluas HSCs tau pom qhov qis methylation hauv cheeb tsam genomic cuam tshuam nrog cov ntshav cell, thaum muaj hnub nyoog HSCs pom DNA hypermethylation hauv thaj chaw genomic cuam tshuam nrog cov kab mob lymphoid / erythroid [100].

Epigenetic regulators, xws li kaum-eleven translocation (Tet) enzymes uas tswj demethylation thiab DNMTs uas ua rau cov methylation ntawm CpG motifs, tshwm nyob rau hauv HSC compartment thaum laus. Cov theem sib txawv tau tshwm sim rau Tet2 thiab DNMTs hauv HSCs hluas thiab laus [95]. Kev tshawb nrhiav nas tsis ntev los no tau pom tias Tet2 poob ua rau kev hloov pauv myeloid thiab malignancies [101]. DNMT1 ua lub luag haujlwm hauv kev tswj cov tshuaj methylation, thiab DNMT1 qhov tsis txaus hauv HSCs tau pom tias myeloid skewing thiab cov txheej txheem rov ua dua tus kheej tsis zoo [102, 103]. Ntxiv mus, qhov poob ua haujlwm ntawm DNMT3A thiab DNMT3B ua rau tsis muaj HSC sib txawv [104].

LT-HSCs qhia txog kev hloov pauv hloov pauv miRNA pawg uas suav nrog miR-99b, let-7e, thiab miR-125a. miR- 125a yog koom nrog hauv kev nce tus naj npawb ntawm HSCs hauv vivo los ntawm yim npaug thiab txhawb nqa cov lymphoid-balanced HSCs [105, 106]. Lub lncRNA Xist yog qhov tseem ceeb rau HSC ciaj sia taus; Xist-deficient HSCs ua rau hematopoiesis txawv txav thiab muaj hnub nyoog poob [107].

5.4 Epigenetic hloov pauv ntawm BMSCs thaum ex vivo cell expansion thiab sib txawv

Cov txheej txheem epigenetic ntawm BMSCs kuj raug soj ntsuam zoo vim tias lawv cov kev siv kho mob hauv cov tshuaj kho dua tshiab. Kev hloov pauv ntawm Epigenetic pab tswj cov kev qhia ntawm ntau cov noob uas cuam tshuam nrog lub stemness ntawm BMSCs thiab kev sib txawv ntawm ntau hom cell uas muaj osteocytes, chondrocytes, lossis adipocytes.

Li et al. [108] piv cov kev hloov kho epigenetic ntawm histone H3 acetylation nyob rau hauv thaum ntxov- thiab lig-passage BMSCs. Histone H3 acetylation yog qhov tseem ceeb hauv kev tswj hwm BMSC kev laus thiab kev sib txawv. Piv txwv li, qib H3 acetylation coincides nrog gene qhia theem xws li K9 thiab K14 histone H3 acetylation tshwm sim nyob rau hauv ntau yam noob, xws li Oct4, Sox2, TERT, ALP, thiab Runx2, nyob rau hauv lub lig passage. Histone deacetylase inhibitors txhawb apoptosis thiab senescence hauv tib neeg BMSCs [109]. DNA methylation theem poob qis thaum lub sij hawm BMSC senescence, thiab inhibition ntawm DNMT1 thiab DNMT3b txhawb nqa cellular senescence nyob rau hauv umbilical qaum BMSCs los ntawm kev nthuav qhia ntawm p16INK4A thiab p21CIP1 / WAF1 [110].

Tsis ntev los no, kev tshawb fawb tau tshuaj xyuas cov txheej txheem epigenetic uas tswj BMSC sib txawv. Hauv osteogenesis ntawm BMSCs, chromatin hyperacetylation, histone methylation ntawm H3K4me3 ntawm promotor ntawm HOXA10 gene, thiab demethylation ntawm H3K27me3 pab txhawb kev txiav txim osteogenic ntawm BMSCs los ntawm inducing activation ntawm osteogenic transcription factor1, Runx121. Histone methylation ntawm H3K4 thiab H3K36 ntawm AP-2ib noob nce lub peev xwm osteogenic thiab odontogenic ntawm BMSCs [113]. Lub acetylation ntawm H3 thiab H4 ntawm osteocalcin noob los yog acetylation ntawm H3K9 induces osteogenic txawv ntawm BMSCs [114, 115]. DNA methylation ntawm tus txhawb nqa ntawm osteopontin txo qis thaum lub sij hawm induction ntawm osteogenic sib txawv hauv BMSCs [116]. Tsis tas li ntawd, miR-27a, miR-489, miR-204, thiab miR- 138 txo qis osteogenic sib txawv los ntawm kev txo qis kev qhia ntawm alkaline phosphatase, Runx2, lossis osterix [117, 118], thiab miRNA-20A, miR-148b, miRNA-2861, thiab miR-335 induce osteogenic differentiation by activating BMP/Runx2 [108, 119, 120].

Thaum lub sij hawm BMSC chondrogenesis, histone modifications thiab non-coding RNAs tuaj yeem koom nrog, tsis yog DNA methylation. Genes transcriptionally upregulated thaum lub sij hawm chondrogenesis yog cim los ntawm H3K36me3 ntawm lub cev noob, H3K4me3 thiab H3K9ac ntawm 50 kawg ntawm noob thiab txhawb nqa, thiab H3K4me1 thiab H3K27ac [121]. Kev nthuav qhia ntawm miR-130b, miR152, miR28, thiab miR26b nce hauv chondrogenesis [122], thiab miR{21}} kev qhia txo qis, uas ua rau muaj kev nthuav qhia ntau ntxiv ntawm SOX9 [123]. Ntxiv mus, miR-29 induces chondrogenesis los ntawm kev tswj FOXO3A [124], thiab miR{27}}p inhibits chondrogenesis [125].

Tsuas yog ob peb txoj kev tshawb fawb tau ua tiav ntawm BMSC adipogenesis. Histone methylation ntawm H3K4me2 tshwm sim ntawm tus txhawb nqa ntawm adipogenic noob xws li adiponectin, glut4, thiab leptin [126]. Tsis tas li ntawd, methyltransferase enhancer ntawm zest 2 (EZH2) induces adipogenesis los ntawm trimethylation ntawm H3K27, tab sis demethylase KDM6A ua rau osteogenesis los ntawm kev tshem tawm cov methylation ntawm H3K27me3. Knockdown ntawm EZH2 nce osteogenesis, thaum knockdown ntawm KDM6A nce adipogenesis [127].

5.5 Epigenetic Hloov ntawm EPCs hauv Angiogenesis thiab Kev Laus

Kev txaus siab hauv EPCs tau nce siab vim tias lawv muaj peev xwm kho cov kab mob ntawm cov hlab ntsha rau kev raug mob ischemic los pab txhawb kev rov ua dua tshiab. Epigenetic regulators uas ua rau kom cov vascular kho muaj nuj nqi ntawm endothelial progenitor hlwb muaj peev xwm breakthroughs rau kev kho mob daim ntawv thov tswv yim. Kev siv tshuaj epigenetic los thim rov qab cov cim epigenetic thiab txhim kho revascularization yog raug kawm.

Hauv kev hloov kho histone ntawm EPCs, tag nrho ntawm cov noob bivalent ntawm qhov ua kom H3K4me3 cim thiab lub cim H3K27me3 tsis meej. H3K4 methylation yog qhov tseem ceeb rau angiogenesis vim tias lysine-specific demethylase 1 (LSD1) suppresses metastasis thiab angiogenesis los ntawm inducing H3K4 demethylation [128]. EZH2 yog tus tswj tsis zoo ntawm endothelial cell sib txawv uas yog overexpressed nyob rau hauv cov qog nqaij hlav cancer, represses txawv cov noob caj noob ces, thiab tswj stemness los ntawm deposition ntawm repressive H3K27me3 cim [129]. H3K36me3 methyltransferase yuav tsum muaj rau kev txhim kho vascular, endothelial cell sib txawv, thiab ua haujlwm [130]. Epigenetic kev hloov pauv hauv EPCs nrog nce H3K4m3 thiab txo H3K9me3 ua rau muaj kev tso tawm ntawm pro-inflammatory cytokines xws li MCP-1 thiab IL-6 thiab cuam tshuam cov angiopoietic phenotype, uas ua rau muaj kev pheej hmoo rau cov kab mob plawv [131] .

Kev koom tes ntawm DNA methylation / demethylation rau endothelial gene regulation tseem tsis to taub. Cov kev tshawb fawb tsis ntev los no tau tshaj tawm txog kev tsim txom H3K27me3 thiab DNA methylation cov cim hauv eNOS cov neeg txhawb nqa hauv EPC thaum ntxov, uas tuaj yeem thim rov qab rau hauv cov xwm txheej hypoxic kom nce eNOS qhia thiab yog li nce kev nrhiav neeg ua haujlwm endothelial thiab sib txawv [132]. Lub histone deacetylase enzyme HDAC1 kuj tau lees paub tias muaj ib feem tseem ceeb hauv inhibition ntawm endothelial proliferation thiab sib txawv [133].

Kev tshawb fawb txog cov tsis-coding RNAs hauv EPCs tau nce mus tas li. miR-21, miR-27a, miR-27b, miR-126, thiab miR-130a tau qhia hauv EPCs tab sis tau txo qis hauv EPCs. Hauv cov neeg mob ntshav qab zib, EPCs qhia qib qis ntawm miR-126 thiab miR-130. Inhibiting miR-126 txo qis kev loj hlob thiab kev tsiv teb tsaws, thiab inhibition ntawm miR-130 represses EPC sib txawv [134, 135]. miR-10A* thiab miR{13}} nce EPC kev laus, thiab thaiv cov miRNAs ua rau muaj kev tiv thaiv kev laus, txhim kho lub peev xwm angiogenic [136].

6 Kev mob thiab kev laus

Kev mob plab yog ib qho tseem ceeb ntawm cov txheej txheem pathophysiological uas tiv thaiv lub cev los ntawm kev kis kab mob thiab kho kev raug mob. Raws li cov neeg muaj hnub nyoog, lawv muaj ntau yam kab mob thiab kab mob thiab tsim kom muaj lub nra antigenic, uas tuaj yeem ua rau muaj qhov tsis sib haum xeeb. Thaum lub sij hawm kev laus, cov ntaub so ntswg adipose ntau ntxiv los ntawm kev noj zaub mov muaj suab thaj / rog, txo cov tshuaj hormones poj niam txiv neej, haus luam yeeb, thiab kev ntxhov siab ua ke ua rau mob ntev, qib qis, kab mob. Qhov hu ua mob [8, 9] ua rau muaj hnub nyoog txog cov kab mob xws li kab mob plawv, mob qog noj ntshav, ntshav qab zib, thiab osteoporosis [137]. Ntau qhov kev tshawb fawb txog kev sib raug zoo ntawm kev laus, kev mob, thiab kab mob tau ua. Cov qib ntawm pro-inflammatory cytokines thiab chemokines nce rau cov neeg laus. IL-6, TNF-a, IL-1b, thiab C-reactive protein (CRP), uas tawm hauv lub siab los teb rau IL-6, txhua qhov nce hauv cov ntshav ntawm cov neeg laus [137]. Pro-inflammatory markers raug suav hais tias yog cov kws tshaj lij ntawm cov kab mob uas muaj hnub nyoog xws li kab mob plawv, mob qog noj ntshav, ntshav qab zib mellitus, osteoporosis [137], thiab cov kab mob neurodegenerative xws li Alzheimer's disease [138]. Tsis tas li ntawd, cov neeg mob HIV tuaj yeem muaj kev laus ntxov ntxov los ntawm kev mob ntev thiab kev tiv thaiv kab mob, uas ua rau T-cell tsis ua haujlwm thiab progenitor cell qaug zog [139]. Kev mob ntev ua rau oxidative kev nyuaj siab, mitochondrial dysfunction, muaj hnub nyoog cov kab mob, myeloid-biased sib txawv, telomere shortening, epigenetic modifications, thiab lwm yam. [140]. Nws tseem yog qhov paub tsis meej seb qhov mob yog qhov ua rau lossis qhov tshwm sim ntawm kev laus.

6.1 Kab mob thiab qia cell laus

Cov kab mob laus laus qhia txog kev txo qis ntawm cov colony-forming units thiab kev loj hlob zoo / cytokine / chemokine tso tawm. Quiescence thiab tuav ntawm HSCs yog ob qho tib si txhawb nqa los ntawm vascular endothelial kev loj hlob yam (VEGF), TGF-b1, thiab IL-10, uas txhua yam ua haujlwm raws li kev tiv thaiv kab mob [12]. Txawm li cas los xij, nyob rau hauv cov laus cov pob txha, cov yam tseem ceeb txo qis, thiab cov teeb meem inflammatory nce, uas induces immunogenicity. Inflammatory signals ua raws li kev hu xovtooj xwm ceev rau HSCs. Tsis pub dhau 1 teev ntawm kev kis kab mob los ntawm E. Coli-derived LPS txhaj tshuaj, LPS mus txog cov pob txha pob txha, cuam tshuam nrog TLR4 ntawm HSCs, thiab ua rau muaj kev loj hlob [10, 141]. IFNs xws li IFN-a thiab IFN-c ua ncaj qha rau HSCs kom txav HSCs quiescent mus rau theem kev loj hlob thiab kev sib txawv. Raws li kev ntxhov siab, xws li kab mob los yog kab mob, cytotoxic CD8? T hlwb thiab HSCs secrete IFN-c, uas ua rau kev qhia ntawm myeloid transcription yam C/EBPa thiab Runx1 hauv HSCs [142], thiab CD4. T hlwb tsim IFN-c los ntawm TLR / MyD88 txoj hauv kev [143]. Activated BMSCs thiab HSCs tsim IL-1, IL-6, TNF-a, G-CSF, thiab granulocyte-macrophage colony-stimulating factor (GM-CSF) [141], uas ua rau myeloid-biased. sib txawv, mobilization, thiab proliferation [141–144]. Cov txiaj ntsig no qhia tau tias cov kev kho mob tiv thaiv kab mob uas tswj cov kab mob inflammatory hauv cov pob txha pob txha microenvironment tuaj yeem hloov kho cov kab mob qia cell.

6.2 Anti-inflammatory tswj ntawm qia cell laus

Kaum xyoo dhau los, Bente K Pedersen tau luam tawm ib daim ntawv hu ua "Anti-inflammation-tsuas yog lwm lo lus los tiv thaiv kev laus?" [145]. Nws tau tshaj tawm tias, hauv cov hnub nyoog ntsig txog thiab mob ntev xws li atherosclerosis, ntshav qab zib, kab mob plawv, Alzheimer's kab mob, thiab mob qog noj ntshav, kev tswj hwm ntawm cov tshuaj uas tsis yog tshuaj steroidal los tiv thaiv kev mob ntawm cov kab mob hauv lub cev yuav txo qis qhov tshwm sim thiab tiv thaiv qhov mob tshwm sim. inhibition ntawm protein synthesis hauv cov neeg laus [145]. Piv txwv li, salsalate, tshuaj tiv thaiv kab mob uas inhibits NF-jB thiab dimer ntawm salicylic acid, txo cov kab mob hauv lub cev thiab tiv thaiv hom 2 mob ntshav qab zib hauv cov neeg laus rog [146]. Dr. Thomas von Zglinicki thiab nws pab pawg tau kawm qib qis inflammatory nfkb1-/- knockout nas, uas muaj hnub nyoog ntxov ntxov thiab muaj peev xwm rov tsim dua tshiab hauv daim siab thiab txoj hnyuv [147]. Cov kb-/- fibroblasts tau nce NF-kB, COX-2, thiab ROS los ntawm lub voj voog tawm tswv yim, ua rau DNA puas xws li telomere dysfunction thiab senescence. Txawm li cas los xij, kev siv tshuaj tiv thaiv kab mob los yog tshuaj tua kab mob antioxidant tau rov qab cov ntaub so ntswg rov qab los [147]. Tsis tas li ntawd, nws pab neeg ntsuas cov ntshav cov lej, cov metabolism, lub siab thiab lub raum ua haujlwm, telomere ntev, thiab theem ntawm kev mob ntawm Japanese centenarians [148]. Lawv tau tshaj tawm tias cov neeg centenarians pom ntev telomere ntev dua li cov pej xeem thiab tseem hais tias qhov mob yog ib qho tseem ceeb ua rau kev laus ntawm cov neeg laus heev. Kev tiv thaiv kab mob thiab cov tshuaj tiv thaiv kev nyab xeeb muaj peev xwm ua tau zoo tshaj plaws thiab yog cov kev kho mob zoo los txhawb kev noj qab nyob zoo [148].

7 Stem cell rov ua dua tshiab thiab kev lag luam: kev cia siab rau kev kho cov ntaub so ntswg thiab tiv thaiv kev laus

Cov qia hlwb uas muaj peev xwm sib txawv, xws li cov neeg laus qia hlwb, embryonic qia hlwb, thiab induced pluripotent qia hlwb, yuav tsum tau siv los kho cov ntaub so ntswg poob thiab raug mob rau kev ua haujlwm rov qab los ntawm ntau yam kab mob degenerative thiab raug mob. Ntau qhov teeb meem tseem ceeb, xws li kev tswj hwm kab lis kev cai tshwj xeeb sib txawv, kev tsim cov qia hlwb ntau, tus nqi siab ntawm ex vivo cell kab lis kev cai, tsis tshua muaj engraftment ntawm qhov chaw hloov, thiab luv luv ib nrab-lub neej ntawm cov tshuaj kho hlwb, yuav tsum tau daws rau kev kho mob. daim ntawv thov ua ntej. Ntawm qhov tod tes, cov neeg laus endogenous lossis cov ntaub so ntswg qia hlwb khaws tseg rau hauv cov ntaub so ntswg thiab cov kabmob ntawm lub cev tuaj yeem siv los kho cov ntaub so ntswg yam tsis muaj kev nthuav dav ex vivo cell kab lis kev cai yog tias cov molecules me me lossis loj hlob yam uas tswj cov qia cell nws tus kheej thiab kev lag luam tuaj yeem raug txheeb xyuas. .

【Yog xav paub ntxiv:george.deng@wecistanche.com / WhatApp:86 13632399501 】