![\"\"](\"https:\/\/blog.ulubat.org\/wp-content\/uploads\/2019\/04\/photo-1469276093774-c273601c8b02-2-1024x1024.jpg\")
<\/figure>\n\n\n\n\u0130nsan kemik ili\u011finden elde edilen MSC\u2019lerin farkl\u0131la\u015fmas\u0131 s\u0131ras\u0131nda\ntranskriptomun ge\u00e7ici profili<\/strong><\/p>\n\n\n\n \u00d6l\u00e7\u00fcmler sonras\u0131nda anla\u015f\u0131ld\u0131 ki adipogenesis\ns\u0131ras\u0131nda osteogeneze g\u00f6re gen ekspresyonu(upregulasyon ve downregulasyon)daha\nb\u00fcy\u00fck oranlarda de\u011fi\u015fti. Dolay\u0131s\u0131yla adiposit olu\u015fumuyla alakal\u0131 genlerdeki gen\naktivasyonu osteoblast\u0131nkilere g\u00f6re daha fazlayd\u0131. Bunun sebeplerinden biri\nfarkl\u0131la\u015fmam\u0131\u015f MSC\u2019lerde de osteoblastla ba\u011flant\u0131l\u0131 genlerin daha fazla\neksprese ediliyor olmas\u0131d\u0131r. Di\u011fer \u00f6nemli bir bulgu da farkl\u0131la\u015fman\u0131n 7.\ng\u00fcn\u00fcnde osteoblast olu\u015fumu adiposit olu\u015fumuna g\u00f6re daha \u00e7ok h\u00fccrede bir anda\nba\u015fl\u0131yor. <\/p>\n\n\n\n Osteogenez MSC\u2019nde zaten aktif olan genlerin\nind\u00fcksiyonuyla ba\u011flant\u0131l\u0131yken, adipogenez MSC\u2019deki aktif genlerin\ndownreg\u00fclasyonu ve aktif olmayan genlerin upreg\u00fclasyonunu i\u00e7eriyor. <\/p>\n\n\n\n MSC\u2019ler \u00e7al\u0131\u015f\u0131lan\nh\u00fccre modeline ba\u011flant\u0131l\u0131 olmaks\u0131z\u0131n osteoblastlara adipositlere k\u0131yasla daha\n\u00e7ok benziyor<\/strong><\/p>\n\n\n\n <\/strong>Transkriptom veri analizi;\ninsan kemik ili\u011finden elde edilen MSC\u2019lere, insan derisinden elde edilmi\u015f\nbirincil doku h\u00fccrelerine, in-vitro farkl\u0131la\u015ft\u0131r\u0131lm\u0131\u015f fare kemik ili\u011finden elde\nedilmi\u015f birincil MSC\u2019lere ba\u011fl\u0131 olmaks\u0131z\u0131n g\u00f6sterdi ki osteoblastlar\u0131n\ntranskriptomu adipositlere g\u00f6re MSC\u2019lerin transkriptomuna daha \u00e7ok benziyor. <\/p>\n\n\n\n Verilerle ba\u011flant\u0131l\u0131 olarak kemik ili\u011finden ya da ya\u011f\ndokusundan izole edilmi\u015f MSC\u2019ler adipogenesis s\u0131ras\u0131nda geldikleri yerlere\nba\u011flant\u0131l\u0131 olmaks\u0131z\u0131n osteogenesise g\u00f6re daha \u00e7ok genetik de\u011fi\u015fim g\u00f6zlemlenmi\u015f.\nBu da bir bak\u0131ma osteoblastlar\u0131n farkl\u0131la\u015fm\u0131\u015f fibroblastlar oldu\u011fu \u00f6nerisiyle\nuyumludur.<\/p>\n\n\n\n Osteogenesis ve\nAdipogenesis enhancer aktivasyonu bak\u0131m\u0131ndan birbirlerinden farkl\u0131la\u015f\u0131r<\/strong><\/p>\n\n\n\n <\/strong>Enhancer belirli h\u00fccre\ntipine \u00f6zel transkripsiyonu sa\u011flamak ad\u0131na olduk\u00e7a \u00f6nemli genomik d\u00fczenleyici\nfakt\u00f6rd\u00fcr. MSC\u2019den adiposit olu\u015fumu s\u0131ras\u0131nda osteoblast olu\u015fumuna g\u00f6re enhancer\naktivitesinde artma ya da azalma olarak daha belirgin bir fark g\u00f6zlemliyoruz. \u0130kinci olarak adipogenesis s\u0131ras\u0131nda enhancer\naktivitesi ve kromatin eri\u015filebilirli\u011fi(chromatin accessibility) de\u011fi\u015fimi\nbenzerken, osteoblast olu\u015fumu s\u0131ras\u0131nda enhancer aktivitesi de\u011fi\u015fimi kromatin\neri\u015filebilirli\u011finkine g\u00f6re daha hareketliydi. Kromatin eri\u015filebilirli\u011fi;\ngenomun belirli b\u00f6lgelerine d\u00fczenleyicilerin(promoter, enhancer, silencer,\ninsulator) ba\u011flanabilmesi dolay\u0131s\u0131yla DNA\u2019n\u0131n reg\u00fclasyona a\u00e7\u0131k hale gelmesi olay\u0131d\u0131r.\n<\/p>\n\n\n\n \u0130nsan kemik ili\u011finden elde edilmi\u015f MSC\u2019lerin ostegenezi\ns\u0131ras\u0131nda \u00f6nceden belirlenmi\u015f enhancer aktivasyonu gerekirken, adipogenezi\ns\u0131ras\u0131nda enhancer\u2019\u0131n de novo(kendili\u011finden olu\u015fan)ortaya \u00e7\u0131k\u0131p aktivasyonu\ngerekmektedir.<\/p>\n\n\n\n Quantitative\nexpression trait ve mezenkimal doku hastal\u0131klar\u0131yla ba\u011flant\u0131l\u0131 fonksiyonel dizi\nvaryasyonlar\u0131 i\u00e7in dinamik enhancer profilleri zenginle\u015ftirildi<\/strong><\/p>\n\n\n\n \u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 \u00a0Adiposit ve osteoblast farkl\u0131la\u015fmas\u0131 s\u0131ras\u0131nda reg\u00fcle edilen genlerle ili\u015fkili eQTL(Expression Quantitative Trait Locus)\u2019lar, benzer ge\u00e7ici aktiviteye sahip enhancer\u2019larla y\u00fcksek oranda zenginle\u015ftirildi. eQTL, bir genin ne kadar ekprese edildi\u011fini(mRNA seviyesini) d\u00fczenleyen genomik b\u00f6lgenin ad\u0131d\u0131r. Dinamik enhancer\u2019lar ya\u011f ve kemik doku fonksiyonuyla alakal\u0131 hastal\u0131k yap\u0131c\u0131 SNP(single nucleotide polymorphism)\u2019leri; inflamatuar ba\u011f\u0131rsak hastal\u0131\u011f\u0131, Alzheimer, ast\u0131m, menopozla ba\u011flant\u0131l\u0131 SNP\u2019lere g\u00f6re daha \u00e7ok bulunduruyor. <\/p>\n\n\n\n Tespit edilmi\u015f enhancer\u2019lar, MSC\u2019lerin in vitro farkl\u0131la\u015fmas\u0131 s\u0131ras\u0131nda\ntranskripsiyonel reg\u00fclasyonu i\u00e7in olduk\u00e7a \u00f6nemlidir. <\/p>\n\n\n\n Makine \u00f6\u011frenmesi\nstratejileri adipogenez ve osteogenezi tetikleyen a\u015famalar\u0131 \u00f6ng\u00f6r\u00fcyor<\/strong><\/p>\n\n\n\n <\/strong>Osteoblastlar\u0131n enhancer\naktivitesine en fazla katk\u0131da bulunan transkripsiyon fakt\u00f6rleri farkl\u0131la\u015fmam\u0131\u015f\nMSC\u2019lerde zaten y\u00fcksek bazal aktiviteye sahiptir ve sadece mRNA seviyesinde\nd\u00fczenlenmi\u015ftir. Adipositlerde ise\nenhancer aktiviteye en \u00e7ok katk\u0131da bulunan motifler MSC\u2019lerde nadiren aktiftir\nve transkripsiyonel olarak d\u00fczenlenmesi daha muhtemeldir.<\/p>\n\n\n\n Adipogenezi y\u00fcr\u00fcten\ntranskripsiyon fakt\u00f6rleri osteogenezi y\u00fcr\u00fctenlere g\u00f6re s\u00fcre\u00e7leri daha h\u0131zl\u0131 d\u00fczenliyor<\/strong><\/p>\n\n\n\n <\/strong>Farkl\u0131la\u015fma s\u0131ras\u0131nda her\niki grup i\u00e7in de birbirlerine yak\u0131n say\u0131da transkripsiyon fakt\u00f6r\u00fcn\u00fcn\nd\u00fczenleyici olarak rol ald\u0131\u011f\u0131 tahmin edilse de adipositlere \u00f6zg\u00fc transkripsiyon\nfakt\u00f6rlerinin birbirlerini d\u00fczenleyicilik ba\u011flam\u0131nda daha \u00e7ok etkiledi\u011fi ve\ndaha h\u0131zl\u0131 reg\u00fcle etti\u011fi g\u00f6r\u00fclm\u00fc\u015f. <\/p>\n\n\n\n <\/strong>Adipositlerle\nalakal\u0131 gen k\u00fcmeleri(bir dizi homolog gen) osteoblastla alakal\u0131 gen k\u00fcmelerine\ng\u00f6re birbirleriyle ba\u011flant\u0131lar\u0131 daha g\u00fc\u00e7l\u00fcd\u00fcr. Adipositlerin gen programlar\u0131\ndaha belirgindir ve rastgele da\u011f\u0131l\u0131m g\u00f6stermezler.<\/p>\n\n\n\n MSC\u2019lerin transkripsiyon fakt\u00f6rlerinin\nbir alt k\u00fcmesi osteogenezi devam ettirirken adipogenezi durdurur<\/strong><\/p>\n\n\n\n <\/strong>Farkl\u0131la\u015fma s\u0131ras\u0131nda enhancer aktiviteyi d\u00fczenleyen transkripsiyon\nfakt\u00f6rlerinin b\u00fcy\u00fck bir k\u0131sm\u0131 MSC ve osteoblastlarda daha fazla aktif olmas\u0131na\nra\u011fmen, adiposit farkl\u0131la\u015fmas\u0131 s\u0131ras\u0131nda daha az aktiflik g\u00f6stermi\u015ftir.<\/p>\n\n\n\n Osteogenik k\u00f6k h\u00fccre fakt\u00f6rlerinin aktivite profiline\nkatk\u0131 sa\u011flayan 202 fakt\u00f6r \u00f6ng\u00f6r\u00fclmesine ra\u011fmen, fakt\u00f6rlerin teker teker\nknockdown edilmesi(ekspresyonunun azalt\u0131lmas\u0131)farkl\u0131la\u015fmay\u0131 engellemek i\u00e7in\nyeterli. Dolay\u0131s\u0131yla bu fakt\u00f6rler hem enhancer aktivitede hem de gen\nd\u00fczenlenmesinde \u00f6nemli i\u015flevleri var.<\/p>\n\n\n\n Osteogenik k\u00f6k h\u00fccre\nfakt\u00f6rleri insan mezenkimal biyolojisi taraf\u0131ndan kapsan\u0131yor<\/strong><\/p>\n\n\n\n <\/strong>Osteogenik k\u00f6k h\u00fccre\nfakt\u00f6rlerinden baz\u0131lar\u0131; osteoporoz, ya\u015fl\u0131l\u0131k, obezite, ins\u00fclin direnci\ndurumlar\u0131na g\u00f6re farkl\u0131la\u015fan ekspresyon g\u00f6sterdiler. \u00d6ng\u00f6r\u00fclen 202 k\u00f6k h\u00fccre\nfakt\u00f6r\u00fc di\u011fer transkripsiyon fakt\u00f6rlerine g\u00f6re daha farkl\u0131 eksprese edilmi\u015fti. <\/p>\n\n\n\n Sizin de g\u00f6rebilece\u011finiz gibi olduk\u00e7a kapsaml\u0131, bol metotlu ve \u00e7arp\u0131c\u0131 bir makaleyle kar\u015f\u0131 kar\u015f\u0131yay\u0131z. O zaman ben de makalenin son c\u00fcmlesiyle bitireyim. <\/p>\n\n\n\n MSC farkl\u0131la\u015fmas\u0131n\u0131n molek\u00fcler mekanizmalar\u0131n\u0131 tan\u0131mlamak, ya\u015flanma ve metabolik hastal\u0131klar s\u0131ras\u0131nda MSC fonksiyonunun s\u00fcrd\u00fcr\u00fclmesi bak\u0131m\u0131ndan etkili stratejiler geli\u015ftirmek i\u00e7in bir \u00f6nko\u015fuldur.<\/p>\n\n\n\n Yararlan\u0131lan Kaynaklar<\/p>\n\n\n\n 1.Rauch, A. Osteogenesis\ndepends on commissioning of a network of stem cell transcription factors that\nact as repressors of adipogenesis. Nature Genetics <\/em>51<\/strong>, 716 – 727 (2019).<\/p>\n\n\n\n 2.Kassem, M. & Marie, P. J. Senescence-associated\nintrinsic mechanisms of osteoblast dysfunctions. Aging Cell <\/em>10<\/strong>, 191\u2013197 (2011).<\/p>\n\n\n\n 3. Squillaro, T., Peluso, G. & Galderisi, U. Clinical\ntrials with mesenchymal stem cells: an update. Cell Transplant. <\/em>25<\/strong>, 829\u2013848 (2016).<\/p>\n\n\n\n 4. Liu,\nT. M. et al. Identification of common pathways mediating differentiation of\nbone marrow\u2013 and adipose tissue\u2013derived human mesenchymal stem cells into three\nmesenchymal lineages. Stem Cells <\/em>25<\/strong>,\n750\u2013760 (2007).<\/p>\n\n\n\n 5. Catarino, R., Stark, A. Assessing sufficiency and necessity of enhancer activities for gene\nexpression and the mechanisms of transcription activation. Genes & Dev<\/em>. 32, 202\n\u2013 223 (2018).<\/p>\n\n\n\n 6. Ducy, P., Schinke, T. &\nKarsenty, G. The osteoblast: a sophisticated fibroblast under central\nsurveillance. Science\n<\/em>289<\/strong>, 1501\u20131504 (2000).<\/p>\n\n\n\n![\"\"](\"https:\/\/blog.ulubat.org\/wp-content\/uploads\/2019\/04\/kemilk-1024x1024.jpg\")
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