Ptpn11D61G-+激活突變協(xié)同電離輻射對(duì)小鼠骨髓間充質(zhì)干細(xì)胞生物學(xué)行為的影響

Ptpn11D61G-+激活突變協(xié)同電離輻射對(duì)小鼠骨髓間充質(zhì)干細(xì)胞生物學(xué)行為的影響摘要：

本研究旨在探討體內(nèi)Ptpn11D61G/+激活突變與電離輻射對(duì)小鼠骨髓間充質(zhì)干細(xì)胞生物學(xué)行為的影響。我們發(fā)現(xiàn)，與野生型小鼠相比，Ptpn11D61G/+小鼠骨髓間充質(zhì)干細(xì)胞具有更高的增殖能力和多向分化潛能。在單次或分次電離輻射后，Ptpn11D61G/+小鼠骨髓間充質(zhì)干細(xì)胞的增殖和多向分化潛能均顯著下降。此外，我們還發(fā)現(xiàn)Ptpn11D61G/+小鼠骨髓間充質(zhì)干細(xì)胞受電離輻射損傷后，基因轉(zhuǎn)錄組發(fā)生了顯著改變。綜上，我們的研究表明，Ptpn11D61G/+激活突變對(duì)小鼠骨髓間充質(zhì)干細(xì)胞生物學(xué)行為具有重要影響，并且電離輻射加重了此影響。

關(guān)鍵詞：Ptpn11D61G/+激活突變；骨髓間充質(zhì)干細(xì)胞；電離輻射；增殖能力；多向分化潛能

Introduction：

骨髓間充質(zhì)干細(xì)胞作為一種多潛能干細(xì)胞，可以分化為多種細(xì)胞類(lèi)型，如成骨細(xì)胞、軟骨細(xì)胞和脂肪細(xì)胞等。骨髓間充質(zhì)干細(xì)胞在體內(nèi)具有重要的作用，在維持骨骼結(jié)構(gòu)穩(wěn)定性、免疫調(diào)節(jié)、組織修復(fù)等方面發(fā)揮著不可或缺的作用。然而，電離輻射作為一種廣泛存在于自然環(huán)境和醫(yī)學(xué)診療中的物理因素，對(duì)人體健康產(chǎn)生了極大的危害。

普通型強(qiáng)生肌營(yíng)養(yǎng)不良癥（NS）是一種常見(jiàn)的遺傳性疾病，是由于胚胎發(fā)育期間突變的基因Ptpn11所致。目前已知有多種Ptpn11激活突變，其中D61G是最常見(jiàn)的一種。以往的研究表明，Ptpn11D61G/+激活突變對(duì)多種細(xì)胞的生物學(xué)功能具有重要影響，如造血干細(xì)胞、肌肉細(xì)胞等。然而，Ptpn11D61G/+激活突變對(duì)小鼠骨髓間充質(zhì)干細(xì)胞的影響尚未明確。

本研究旨在探討Ptpn11D61G/+激活突變與電離輻射對(duì)小鼠骨髓間充質(zhì)干細(xì)胞生物學(xué)行為的影響，并探討其可能的分子機(jī)制。

Methods：

實(shí)驗(yàn)使用Ptpn11D61G/+小鼠和野生型小鼠作為研究對(duì)象，分別從小鼠骨髓中分離純化骨髓間充質(zhì)干細(xì)胞培養(yǎng)。通過(guò)MTT法、流式細(xì)胞術(shù)和油紅O染色法等方法，對(duì)小鼠骨髓間充質(zhì)干細(xì)胞的增殖能力、多向分化潛能和脂肪樣細(xì)胞分化能力進(jìn)行評(píng)估。對(duì)小鼠骨髓間充質(zhì)干細(xì)胞進(jìn)行單次或分次電離輻射處理，評(píng)估其對(duì)骨髓間充質(zhì)干細(xì)胞生物學(xué)行為的影響。此外，通過(guò)全轉(zhuǎn)錄組測(cè)序技術(shù)和生物信息學(xué)分析，對(duì)小鼠骨髓間充質(zhì)干細(xì)胞受電離輻射后轉(zhuǎn)錄組的變化進(jìn)行分析。

Results：

與野生型小鼠相比，Ptpn11D61G/+小鼠骨髓間充質(zhì)干細(xì)胞具有更高的增殖能力和多向分化潛能。在單次或分次電離輻射后，Ptpn11D61G/+小鼠骨髓間充質(zhì)干細(xì)胞的增殖和多向分化潛能均顯著下降。此外，我們還發(fā)現(xiàn)Ptpn11D61G/+小鼠骨髓間充質(zhì)干細(xì)胞受電離輻射損傷后，基因轉(zhuǎn)錄組發(fā)生了顯著改變，包括基因表達(dá)水平的增加或減少以及基因通路的變化。

Conclusion：

本研究表明，Ptpn11D61G/+激活突變對(duì)小鼠骨髓間充質(zhì)干細(xì)胞生物學(xué)行為具有重要影響，并且電離輻射加重了此影響。這一結(jié)果為深入了解體內(nèi)Ptpn11D61G/+激活突變對(duì)小鼠骨髓間充質(zhì)干細(xì)胞生物學(xué)行為的影響提供了重要線(xiàn)索，并為進(jìn)一步探索Ptpn11D61G/+激活突變與電離輻射致病機(jī)制提供了新的思路Introduction:

Ptpn11D61G/+isamutationinthegeneencodingShp2,aproteintyrosinephosphatasethatplaysaroleincellsignaling.Mutationsinthisgenehavebeenassociatedwithdevelopmentaldisorders,includingNoonansyndromeandleukemia.Inthisstudy,weinvestigatedtheeffectofPtpn11D61G/+mutationonthebehaviorofmousebonemarrow-derivedmesenchymalstemcells(BM-MSCs)andtheimpactofionizingradiationonthemutantBM-MSCs.

Methods:

BM-MSCswereisolatedfrombothwild-typeandPtpn11D61G/+mice,andtheirproliferation,differentiationandadipogenicpotentialwereevaluated.ThemutantBM-MSCsweresubjectedtosingleorfractionatedionizingradiation,andtheirbiologicalbehaviorwasexamined.Inaddition,thechangesintranscriptomeofmutantBM-MSCsafterionizingradiationwereanalyzedusingRNAsequencingandbioinformaticsanalysis.

Results:

Comparedtowild-typemice,Ptpn11D61G/+mutantBM-MSCsexhibitedhigherproliferationandmulti-lineagedifferentiationpotential.Aftersingleorfractionatedionizingradiation,bothproliferationanddifferentiationpotentialofmutantBM-MSCsweresignificantlydecreased.Furthermore,wefoundthatthetranscriptomeofPtpn11D61G/+mutantBM-MSCswassignificantlyalteredafterionizingradiation,includingchangesingeneexpressionlevelsandpathways.

Conclusion:

ThisstudysuggeststhatPtpn11D61G/+activatingmutationhasasignificantimpactonthebehaviorofmouseBM-MSCs,andionizingradiationexacerbatesthiseffect.TheseresultsprovideimportantcluesforunderstandingtheeffectsofPtpn11D61G/+activatingmutationonthebehaviorofmouseBM-MSCsinvivoandprovidenewavenuesforfurtherinvestigationofthepathogenesisofPtpn11D61G/+activatingmutationandionizingradiationInconclusion,thePtpn11D61G/+activatingmutationhasbeenshowntohaveasignificantimpactonthebehaviorofmouseBM-MSCs.Thisstudyprovidesimportantinsightintotheeffectsofthismutationoncellularprocessessuchasdifferentiationandproliferation,aswellasongeneexpressionlevelsandpathways.Additionally,itisshownthationizingradiationexacerbatestheeffectsofthemutationoncellularbehavior,specificallyintermsofcolonyformationanddifferentiationpotential.

ThefindingsofthisstudyhaveimplicationsfortheunderstandingandpotentiallytreatmentofsyndromessuchasNoonansyndrome,whichisassociatedwithPtpn11mutations.FurtherinvestigationofthemechanismsunderlyingtheeffectsofthePtpn11D61G/+mutation,aswellasitsinteractionwithotherenvironmentalfactorssuchasionizingradiation,couldleadtothedevelopmentoftargetedtherapiesorinterventionstomitigateitseffects.

Overall,thisstudyhighlightstheimportanceofunderstandingtheeffectsofgeneticmutationsoncellularbehavior,aswellasthepotentialinteractionsbetweenthesemutationsandenvironmentalfactors.SuchknowledgehasthepotentialtoleadtonewinsightsandtherapiesforarangeofgeneticdisordersanddiseasesInadditiontogeneticmutationsandenvironmentalfactors,epigeneticmodificationsalsoplayasignificantroleincellularbehavioranddiseasedevelopment.Epigeneticmodifications,suchasDNAmethylationandhistonemodifications,caninfluencegeneexpressionandaltercellularfunctionwithoutchangingtheunderlyinggeneticcode.Thesemodificationscanbeinfluencedbyfactorssuchasdiet,lifestyle,andenvironmentalexposure,andcanbeheritableacrossgenerations.

Epigeneticmodificationshavebeenimplicatedinarangeofdiseases,includingcancer,autoimmunedisorders,andneurologicaldisorders.Forexample,aberrantDNAmethylationpatternshavebeenobservedincertaincancers,andhistonemodificationshavebeenlinkedtoneurologicaldisorderssuchasAlzheimer'sandParkinson'sdisease.Understandingepigeneticmodificationsindiseasedevelopmentcouldleadtotheidentificationofnewtherapeutictargetsandinterventions.

Furthermore,recentadvancementsintechnologyhaveallowedforthestudyofthemicrobiome,acollectionofmicroorganismsthatliveinandonthehumanbody.Themicrobiomehasbeenimplicatedinarangeofdiseases,includinginflammatoryboweldiseaseandobesity.Additionally,researchhasshownthatthemicrobiomecaninfluenceepigeneticmodificationsandgeneexpression,suggestingapotentialroleindiseasedevelopment.

Inconclusion,thestudyofgenetics,environment,epigen