CircZMIZ1/miR-194/SOX9通路在脂肪间充质干细胞向髓核细胞转分化中的作用机制

Decreased number and compromised function of nucleus pulposus cells (NPCs) are paramount causes of intervertebral disc degeneration (IDD). Therefore, the strategy of tissue engineering aimed at regeneration of NPCs is the current research hotspot. Adipose-derived mesenchymal stem cells (ADSCs) can up-regulate the expression of SOX9 and differentiate into NPCs via TGF-β3 and IGF-1 treatment. However, the mechanisms by which TGF-β3 and IGF-1 regulate SOX9 expression remain unclear. CircRNAs have been shown to be involved in stem cell differentiation through epigenetic regulation in recent years. Our previous study also showed that circRNA plays an important role in IDD. Combined with circRNA chip, bioinformatics analysis, software prediction and preliminary experimental evidence, it is proposed that TGF-β3 and IGF-1 up-regulate the expression of SOX9 by activating the CircZMIZ1/miR-194/SOX9 pathway in ADSCs, Further enhance the synthesis of extracellular matrix, express NPCs specific phenotypic genes, and promote the differentiation of cells into NPCs. The revelation of this pathway is expected to specifically induce the differentiation of ADSCs and promote the regeneration of the nucleus pulposus cells, which hopefully provides a new strategy for the prevention and treatment of IDD.

髓核细胞（NPCs）数量减少和功能减退是椎间盘退变(IDD)发生的主要原因，故而以NPCs移植再生为手段的组织工程学策略是当今的研究热点。脂肪间充质干细胞(ADSCs)经TGF-β3和IGF-1处理可上调转录因子SOX9表达并使干细胞向NPCs分化，然而TGF-β3和IGF-1调控SOX9的机制尚未明确。CircRNA近来被证明通过表观遗传调控参与干细胞分化，本课题组的研究也表明circRNA在IDD中发挥重要作用。通过结合circRNA芯片、生物信息学分析、软件预测和预实验佐证，提出：TGF-β3和IGF-1通过激活ADSCs中的CircZMIZ1/miR-194/SOX9通路上调SOX9的表达，而表达上调的SOX9进而增强细胞外基质合成能力，表达NPCs特异性表型基因，促进细胞成NPCs定向分化。本通路的揭示可为特异性诱导ADSCs分化、促进NPCs再生移植及防治IDD提供新的策略。

髓核细胞（NPCs）数量减少和功能减退是椎间盘退变(IDD)发生的主要原因，故而以NPCs.移植再生为手段的组织工程学策略是当今的研究热点。脂肪间充质干细胞(ADSCs)经TGF-β3和IGF-1处理可上调转录因子SOX9表达并使干细胞向NPCs分化，然而TGF-β3和IGF-1调控SOX9的机制尚未明确。CircRNA近来被证明通过表观遗传调控参与干细胞分化，本课题组的研究也表明circRNA在IDD中发挥重要作用。通过结合circRNA芯片、生物信息学分析、软件预测和预实验佐证，提出：TGF-β3和IGF-1通过激活ADSCs中的CircZMIZ1/miR-194/SOX9通路上调SOX9的表达，而表达上调的SOX9进而增强细胞外基质合成能力，表达NPCs特异性表型基因，促进细胞成NPCs定向分化。本通路的揭示可为特异性诱导ADSCs分化、促进NPCs再生移植及防治IDD提供新的策略。