Role of Wnt-5a in the Determination of Human Mesenchymal Stem Cells into Preadipocytes
Role of Wnt-5a in the Determination of Human Mesenchymal Stem Cells into Preadipocytes
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DOI：
10.1074/jbc.m109.054338
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发表时间：
2010-02-26
影响因子：
4.8
通讯作者：
Laudes, Matthias
中科院分区：
文献类型：
--
作者：
Bilkovski, Roman;Schulte, Dominik M.;Laudes, Matthias
增加脂肪细胞的大小以及数量在肥胖症和2型糖尿病的发展中是重要的，脂肪细胞由间充质前体细胞产生。这一过程包括确定间充质干细胞（MSC）为前脂肪细胞（PA）和PA分化为成熟脂肪细胞。虽然分化过程已被高度研究，但对人类的决定知之甚少。在这项研究中，我们比较了人MSC和人定向PA在细胞和分子水平上，以获得进一步了解在决定过程中的调节机制。两种细胞类型显示出相似的形态和常见的间充质和造血表面标志物的表达模式。然而，尽管MSC能够分化为脂肪细胞和骨细胞，PA只能进行脂肪形成，表明PA在测定过程中失去了其多能性。与PA相比，WNT-5a在MSC中的表达显示出显著更高的水平，这表明WNT-5a下调可能在确定过程中是重要的。事实上，在含有中和WNT-5a抗体的培养基中孵育人MSC消除了它们经历骨生成的能力，尽管脂肪生成仍然是可能的。使用重组WNT-5a蛋白实现了相反的效果。在分子水平上，发现WNT-5a促进MSC中的c-Jun N-末端激酶依赖性细胞内信号传导。这种非经典途径的激活导致骨桥蛋白表达的诱导，进一步表明WNT-5a的促成骨作用。我们的数据表明，WNT-5a是维持MSC的成骨潜力所必需的，因此，抑制WNT-5a信号传导在人类中确定为PA中起作用。
Increasing adipocyte size as well as numbers is important in the development of obesity and type 2 diabetes, with adipocytes being generated from mesenchymal precursor cells. This process includes the determination of mesenchymal stem cells (MSC) into preadipocytes (PA) and the differentiation of PA into mature fat cells. Although the process of differentiation has been highly investigated, the determination in humans is poorly understood. In this study, we compared human MSC and human committed PA on a cellular and molecular level to gain further insights into the regulatory mechanisms in the determination process. Both cell types showed similar morphology and expression patterns of common mesenchymal and hematopoietic surface markers. However, although MSC were able to differentiate into adipocytes and osteocytes, PA were only able to undergo adipogenesis, indicating that PA lost their multipotency during determination. WNT-5a expression showed significantly higher levels in MSC compared with PA suggesting that WNT-5a down-regulation might be important in the determination process. Indeed, incubation of human MSC in medium containing neutralizing WNT-5a antibodies abolished their ability to undergo osteogenesis, although adipogenesis was still possible. An opposite effect was achieved using recombinant WNT-5a protein. On a molecular level, WNT-5a was found to promote c-Jun N-terminal kinase-dependent intracellular signaling in MSC. Activation of this noncanonical pathway resulted in the induction of osteopontin expression further indicating pro-osteogenic effects of WNT-5a. Our data suggest that WNT-5a is necessary to maintain osteogenic potential of MSC and that inhibition of WNT-5a signaling therefore plays a role in their determination into PA in humans.