Ptpn11D61G-+激活突变协同电离辐射对小鼠骨髓间充质干细胞生物学行为的影响

Ptpn11D61G-+激活突变协同电离辐射对小鼠骨髓间充质干细胞生物学行为的影响摘要：

本研究旨在探讨体内Ptpn11D61G/+激活突变与电离辐射对小鼠骨髓间充质干细胞生物学行为的影响。我们发现，与野生型小鼠相比，Ptpn11D61G/+小鼠骨髓间充质干细胞具有更高的增殖能力和多向分化潜能。在单次或分次电离辐射后，Ptpn11D61G/+小鼠骨髓间充质干细胞的增殖和多向分化潜能均显著下降。此外，我们还发现Ptpn11D61G/+小鼠骨髓间充质干细胞受电离辐射损伤后，基因转录组发生了显著改变。综上，我们的研究表明，Ptpn11D61G/+激活突变对小鼠骨髓间充质干细胞生物学行为具有重要影响，并且电离辐射加重了此影响。

关键词：Ptpn11D61G/+激活突变；骨髓间充质干细胞；电离辐射；增殖能力；多向分化潜能

Introduction：

骨髓间充质干细胞作为一种多潜能干细胞，可以分化为多种细胞类型，如成骨细胞、软骨细胞和脂肪细胞等。骨髓间充质干细胞在体内具有重要的作用，在维持骨骼结构稳定性、免疫调节、组织修复等方面发挥着不可或缺的作用。然而，电离辐射作为一种广泛存在于自然环境和医学诊疗中的物理因素，对人体健康产生了极大的危害。

普通型强生肌营养不良症（NS）是一种常见的遗传性疾病，是由于胚胎发育期间突变的基因Ptpn11所致。目前已知有多种Ptpn11激活突变，其中D61G是最常见的一种。以往的研究表明，Ptpn11D61G/+激活突变对多种细胞的生物学功能具有重要影响，如造血干细胞、肌肉细胞等。然而，Ptpn11D61G/+激活突变对小鼠骨髓间充质干细胞的影响尚未明确。

本研究旨在探讨Ptpn11D61G/+激活突变与电离辐射对小鼠骨髓间充质干细胞生物学行为的影响，并探讨其可能的分子机制。

Methods：

实验使用Ptpn11D61G/+小鼠和野生型小鼠作为研究对象，分别从小鼠骨髓中分离纯化骨髓间充质干细胞培养。通过MTT法、流式细胞术和油红O染色法等方法，对小鼠骨髓间充质干细胞的增殖能力、多向分化潜能和脂肪样细胞分化能力进行评估。对小鼠骨髓间充质干细胞进行单次或分次电离辐射处理，评估其对骨髓间充质干细胞生物学行为的影响。此外，通过全转录组测序技术和生物信息学分析，对小鼠骨髓间充质干细胞受电离辐射后转录组的变化进行分析。

Results：

与野生型小鼠相比，Ptpn11D61G/+小鼠骨髓间充质干细胞具有更高的增殖能力和多向分化潜能。在单次或分次电离辐射后，Ptpn11D61G/+小鼠骨髓间充质干细胞的增殖和多向分化潜能均显著下降。此外，我们还发现Ptpn11D61G/+小鼠骨髓间充质干细胞受电离辐射损伤后，基因转录组发生了显著改变，包括基因表达水平的增加或减少以及基因通路的变化。

Conclusion：

本研究表明，Ptpn11D61G/+激活突变对小鼠骨髓间充质干细胞生物学行为具有重要影响，并且电离辐射加重了此影响。这一结果为深入了解体内Ptpn11D61G/+激活突变对小鼠骨髓间充质干细胞生物学行为的影响提供了重要线索，并为进一步探索Ptpn11D61G/+激活突变与电离辐射致病机制提供了新的思路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