BMP signaling pathway is required for commitment of C3H10T1/2 pluripotent stem cells to the adipocyte lineage
BMP signaling pathway is required for commitment of C3H10T1/2 pluripotent stem cells to the adipocyte lineage
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BMP 信号通路是 C3H10T1/2 多能干细胞分化为脂肪细胞谱系所必需的
DOI：
10.1073/pnas.0906266106
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发表时间：
2009-08-04
影响因子：
11.1
通讯作者：
Tang, Qi-Qun
中科院分区：
文献类型：
--
作者：
Huang, Haiyan;Song, Tan-Jing;Tang, Qi-Qun
肥胖伴随着脂肪细胞数量和大小的增加。脂肪细胞数量的增加是脂肪组织的血管基质中存在的多能干细胞向脂肪细胞谱系募集的结果。这些多能细胞具有经历定型然后分化成脂肪细胞以及肌细胞、骨细胞和软骨细胞的潜力。在这篇文章中，我们发现骨形态发生蛋白（BMP）2和BMP 4都可以诱导C3 H10 T1/2多能干细胞向脂肪细胞的定向分化。在增殖过程中用这些BMP处理C3 H10 T1/2干细胞，然后在生长停滞时暴露于分化诱导剂后，几乎所有细胞都进入脂肪发育途径，表达特异性脂肪细胞标志物，并获得脂肪细胞表型。组成型活性BMP受体（CA）-BMPr 1A或CA-BMPr 1B的过表达诱导承诺在BMP 2/4的情况下，而显性负性受体显性负性-BMPr 1A的过表达抑制BMP诱导的承诺。此外，用RNAi敲低Smad 4（BMP/Smad信号通路中的辅助调节因子）的表达破坏了BMP的定型。然而，用RNAi敲低p38 MAPK（BMP/MAPK信号通路中的中间体）的表达对BMP诱导的承诺几乎没有影响。总之，这些发现表明BMP/Smad信号通路在脂肪细胞谱系确定中具有主导作用。蛋白质组学分析鉴定了赖氨酰氧化酶（LOX），一个真正的BMP信号通路的下游靶基因。LOX的表达在脂肪细胞谱系定型过程中由BMP 2/4诱导，并且其表达的敲低破坏了定型过程。
Obesity is accompanied by an increase in both adipocyte number and size. The increase in adipocyte number is the result of recruitment to the adipocyte lineage of pluripotent stem cells present in the vascular stroma of adipose tissue. These pluripotent cells have the potential to undergo commitment and then differentiate into adipocytes, as well as myocytes, osteocytes, and chondrocytes. In this article, we show that both bone morphogenetic protein (BMP)2 and BMP4 can induce commitment of C3H10T1/2 pluripotent stem cells into adipocytes. After treatment of C3H10T1/2 stem cells with these BMPs during proliferation followed by exposure to differentiation inducers at growth arrest, nearly all cells enter the adipose development pathway, express specific adipocyte markers, and acquire the adipocyte phenotype. Overexpression of constitutively active BMP receptor (CA)-BMPr1A or CA-BMPr1B induces commitment in the absence of BMP2/4, whereas overexpression of a dominant-negative receptor dominant-negative-BMPr1A suppresses commitment induced by BMP. Also, knockdown of the expression of Smad4 (coregulator in the BMP/Smad signaling pathway) with RNAi disrupts commitment by the BMPs. However, knockdown of expression of p38 MAPK (an intermediary in the BMP/MAPK signaling pathway) with RNAi had little effect on BMP-induced commitment. Together, these findings indicate that the BMP/Smad signaling pathway has a dominant role in adipocyte lineage determination. Proteomic analysis identified lysyl oxidase (LOX), a bona fide downstream target gene of the BMP signaling pathway. Expression of LOX is induced by BMP2/4 during adipocyte lineage commitment, and knockdown of its expression disrupts the commitment process.