Kostiuk S V, Malinovskaia E M, Ermakov A V, Smirnova T D, Kameneva L V, Chvartatskaia O V, Loseva P A, Ershova E S, Liubchenko L N, Veĭko N N
Biomed Khim. 2012 Nov-Dec;58(6):673-83. doi: 10.18097/pbmc20125806673.
Human mesenchymal stem cells (MSCs) are now widely adopted in regenerative medicine. However, many questions on the role of different signaling pathways in the regulation of stem cell (SC) functional activity within the organism remain unaswered. In damaged regions the level of cell death increases and DNA fragments from dead cells (cell-free DNA, cfDNA) are accumulated in blood. We showed that in adipose-derived MSCs exposed in vitro to cfDNA fragments the transcription level increased (the total amount of cellular RNA and the rRNA amount rose). GC-rich CfDNA fragments (GC-DNA) activated the TLR9-dependent signal pathway: the expression of TLR9 and of TLR9-signaling pathway adapter--MyD88--was up-regulated. AT-rich DNA fragments did not increase the TLR9 expression, though, the MyD88 expression level rose. So we suggest that AT-DNA acts via some other receptors that nevertheless activate MyD88-dependent signalling in MSCs. We also showed that cfDNA fragments decreased the activity of caspase, an apoptotic enzyme. So, ctDNA can significantly influence the functional activity ofMSC by activating TLR9- and MyD88-dependent signal pathways and lowering the apoptosis level.
人间充质干细胞（MSCs）目前在再生医学中被广泛应用。然而，关于不同信号通路在生物体内调节干细胞（SC）功能活性方面的作用，仍有许多问题尚未得到解答。在受损区域，细胞死亡水平升高，死细胞的DNA片段（游离DNA，cfDNA）在血液中积累。我们发现，体外暴露于cfDNA片段的脂肪来源间充质干细胞的转录水平升高（细胞总RNA量和rRNA量增加）。富含鸟嘌呤和胞嘧啶的cfDNA片段（GC-DNA）激活了依赖Toll样受体9（TLR9）的信号通路：TLR9和TLR9信号通路衔接蛋白——髓样分化因子88（MyD88）的表达上调。尽管富含腺嘌呤和胸腺嘧啶的DNA片段（AT-DNA）没有增加TLR9的表达，但MyD88的表达水平升高。因此，我们认为AT-DNA通过其他一些受体发挥作用，这些受体仍能激活间充质干细胞中依赖MyD88的信号传导。我们还发现，cfDNA片段降低了凋亡酶半胱天冬酶的活性。所以，cfDNA可通过激活依赖TLR9和MyD88的信号通路并降低凋亡水平，显著影响间充质干细胞的功能活性。
