Polybrominated diphenyl ether congener 99 (PBDE 99) promotes adipocyte lineage commitment of C3H10T1/2 mesenchymal stem cells
Polybrominated diphenyl ether congener 99 (PBDE 99) promotes adipocyte lineage commitment of C3H10T1/2 mesenchymal stem cells
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多溴二苯醚同源物 99 (PBDE 99) 促进 C3H10T1/2 间充质干细胞的脂肪细胞谱系定型
DOI：
10.1016/j.chemosphere.2021.133312
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发表时间：
2021-12-17
期刊：
影响因子：
8.8
通讯作者：
Du，Yuguo
中科院分区：
文献类型：
--
作者：
Wen，Qing;Xie，Xinni;Du，Yuguo
肥胖原被定义为部分通过刺激脂肪生成而引发肥胖的化学物质。成脂包括两个连续的过程：多能干细胞的脂肪细胞谱系承诺和前脂肪细胞的分化。与前脂肪细胞的分化相比，大多数环境致病因素对脂肪细胞谱系承诺的影响仍然很大程度上是未知的。本研究以C3H10T1/2为基础，研究了PBDE 99对脂肪细胞向间充质干细胞(MSC)定向分化的影响。我们的结果表明，在承诺期暴露于PBDE 99可显著上调C3H10T1/2间充质干细胞随后的脂肪生成。有趣的是，PBDE 99不影响C3H10T1/2骨髓间充质干细胞的成骨，尽管骨髓间充质干细胞的成脂和成骨通常是相互的。PBDE 99进一步证实可显著降低Pref1及其下游效应因子Sox9的表达，Pref1是极早期脂肪间质前体的标志。这一结果有力地提示PBDE99促进脂肪细胞对C3H10T1/2 MSCs的成脂作用。机制研究表明，PBDE 99有效地抑制了Hedgehog信号转导，Hedgehog信号转导是脂肪细胞谱系承诺的保守负调节因子。此外，PBDE 99对脂肪细胞的作用可通过与刺激性信号激活剂SAG的共同处理而被消除，这表明抑制Hedgehog信号是PBDE 99影响脂肪细胞承诺的原因。综上所述，这些结果有力地表明，增强脂肪细胞的谱系承诺可能参与了PBDE 99的潜在致肥作用，可能是通过抑制承诺阶段的Hedgehog信号。此外，本研究结果表明，C3H10T1/2可以作为一种可行的MSCs细胞模型来评价潜在致肥者对脂肪细胞的趋化能力。
Obesogens are defined as chemicals that trigger obesity partially by stimulating adipogenesis. Adipogenesis consists of two successive processes: the adipocyte lineage commitment of pluripotent stem cells and the differentiation of preadipocytes. Compared with the differentiation of preadipocytes, the effects of most environmental obesogens on adipocyte lineage commitment remain largely unknown. In this study, investigations are performed to explore the influences of PBDE 99 on the adipocyte lineage commitment based on C3H10T1/2, which has been widely used as a mesenchymal stem cell (MSC) model. Our results indicated that exposure to PBDE 99 during commitment stage resulted in significant up-regulation of subsequent adipogenesis in C3H10T1/2 MSCs. Interestingly, PBDE 99 did not affect the osteogenesis of C3H10T1/2 MSCs, although the adipogenesis and osteogenesis of MSCs are typically reciprocal. PBDE 99 was further demonstrated to significantly decrease the expression ofPref1, the marker of very early adipose mesenchymal precursor, and its downstream effector,Sox9. This result strongly suggested that PBDE 99 facilitated adipocyte commitment to exert adipogenic effect on C3H10T1/2 MSCs. Mechanistic studies revealed that PBDE 99 efficiently inhibited Hedgehog signaling transduction, a conserved negative regulator of the adipocyte lineage commitment. Furthermore, the effects of PBDE 99 on adipogenesis were abrogated by the co-treatment with SAG, a specific Hedgehog signaling activator, suggesting inhibition of Hedgehog signaling is responsible for the effect of PBDE 99 on adipocyte commitment. Taking together, these results strongly suggested enhanced adipocyte lineage commitment was involved in potential obesogenic effect of PBDE 99, presumably through repressing Hedgehog signalling during commitment stage. Moreover, the results of this study indicated that C3H10T1/2 can be used as a feasible MSCs cell model to evaluate the capabilities of potential obesogens on adipocyte commitment.