TUhjnbcbe - 2020/12/30 13:10:00
TODAY今日发布StrokeEarlyRecent,Sept17,今日发布01篇CirculationResearchEarlyRecent,Sept17,今日发布01篇ATVBEarlyRecent,Sept17,今日发布06篇JAMAEarlyRecent,Sept16,今日发布04篇JAMACardiologyEarlyRecent,Sept16,今日发布09篇JIntervCardElectrophysiolEarlyRecent,Sept17,今日发布01篇CurrHeartFailRepEarlyRecent,Sept17,今日发布01篇NEJMSept17,:(12)今日发布23篇RECOMMEND推荐阅读01促炎性巨噬细胞分泌因子促进瓣膜间质细胞成骨样表型ATVBresearch-articleJosephC.Grim,BrianA.Aguado,etc.2小时前等28用户推荐阅读本文Objective:Residentvalvularinterstitialcells(VICs)activatetomyofibroblastsduringaorticvalvestenosisprogression,whichfurtherpromotesfibrosisorevendifferentiateintoosteoblast-likecellsthatcanleadtocalcificationofvalvetissue.Inflammationisahallmarkofaorticvalvestenosis,soweaimedtodetermineproinflammatorycytokinessecretedfromM1macrophagesthatgiverisetoatransientVICphenotypethatleadstocalcificationofvalvetissue.在主动脉瓣狭窄过程中，常驻瓣膜间质细胞（VICs）激活成肌成纤维细胞，进一步促进纤维化，甚至分化为成骨样细胞，导致瓣膜组织钙化。炎症是主动脉瓣狭窄的一个特征，因此我们的目标是确定M1巨噬细胞分泌的促炎细胞因子，这些细胞因子会导致短暂的VIC表型，从而导致瓣膜组织钙化。ApproachandResults:WedesignedhydrogelbiomaterialsasvalveextracellularmatrixmimicsenablingthecultureofVICsineithertheirquiescentfibroblastoractivatedmyofibroblastphenotypeinresponsetothelocalmatrixstiffness.WhenVICfibroblastsandmyofibroblastsweretreatedwithconditionedmediafromTHP-1-derivedM1macrophages,weobservedrobustreductionofαSMA(alphasmoothmuscleactin)expression,reducedstressfiberformation,andincreasedproliferation,suggestingapotentantifibroticeffect.Wefurtheridentifiedthat2cytokinesinM1mediaattributedtotheobservedantifibroticeffectswereTNF(tumornecrosisfactor)-α)andIL(interleukin)1β).After7daysofcultureinM1conditionedmedia,VICsbegandifferentiatingintoosteoblast-likecells,asmeasuredbyincreasedexpressionofRUNX2(runt-relatedtranscriptionfactor2)andosteopontin.WealsoidentifiedandvalidatedIL-6asacriticalmediatoroftheobservedpro-osteogeniceffect.我们设计了水凝胶生物材料作为瓣膜细胞外基质的模拟物，能够在其静止的成纤维细胞或激活的肌成纤维细胞表型中培养血管内皮细胞，以响应局部基质刚度。当VIC成纤维细胞和肌成纤维细胞被THP-1衍生的M1巨噬细胞的条件培养基处理时，我们观察到αSMA（α-平滑肌肌动蛋白）表达的强烈减少，减少应力纤维的形成，并增加增殖，这表明它有很强的抗纤维化作用。我们进一步证实，在M1培养基中，有2种细胞因子是TNF（肿瘤坏死因子）-α和IL（白细胞介素）1β。在M1条件培养基中培养7天后，通过RUNX2（runt相关转录因子2）和骨桥蛋白表达的增加，VICs开始分化为成骨样细胞。我们还确定并验证了IL-6是观察到的促成骨作用的关键介质。Conclusions:ProinflammatorycytokinesinM1conditionedmedia,notablyTNF-α,IL-1β,andIL-6,inhibitthemyofibroblastresponseinVICsandpromotetheirosteogenicdifferentiation.Together,ourworksuggestsinflammatoryM1macrophagesmaydriveamyofibroblast-to-osteogenicintermediateVICphenotype,whichmaymediatetheswitchfromfibrosistocalcificationduringaorticvalvestenosisprogression.M1条件培养液中的促炎性细胞因子，尤其是TNF-α、IL-1β和IL-6可抑制VICs的肌成纤维细胞反应，促进其成骨分化。总之，我们的研究表明，炎性M1巨噬细胞可能驱动肌成纤维细胞向成骨中间型VIC表型转化，这可能介导主动脉瓣狭窄进展过程中从纤维化到钙化的转变。扫描