Rajashekhar Gangaraju, Traktuev Dmitry O, Roell William C, Johnstone Brian H, Merfeld-Clauss Stephanie, Van Natta Bruce, Rosen Elliot D, March Keith L, Clauss Matthias
Indiana Center for Vascular Biology and Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
Stem Cells. 2008 Oct;26(10):2674-81. doi: 10.1634/stemcells.2008-0277. Epub 2008 Jul 31.
Adipose stromal cells (ASC) are multipotential mesenchymal progenitor cells that are readily induced to undergo adipogenic differentiation, and we have recently demonstrated them to have functional and phenotypic overlap with pericytes lining microvessels in adipose tissues. In this study we addressed the hypothesis that modulation of ASC fate within this perivascular niche can occur via interaction with endothelial cells (EC), which serve to modulate the adipogenic potential of ASC. To this end, we investigated contact as well as paracrine effects of EC on ASC adipogenesis, in two-dimensional coculture and via conditioned medium and analyzed mutual gene expression changes by real-time reverse transcription polymerase chain reaction (PCR). A significant decrease in adipogenic differentiation was observed in ASC when they were cocultured with EC but not control fibroblasts. This endothelial cell-specific effect was accompanied by increased expression of factors involved in Wnt signaling, most prominently Wnt1, Wnt4, and Wnt10a, which are well-known inhibitors of adipogenesis. Suppression of Wnt1 but not Wnt 10a or scrambled control short interfering RNA in cocultures partially reversed the endothelial cell effect, thus increasing adipogenic differentiation, suggesting a plausible role of Wnt1 ligand in modulation of adipogenesis by the vasculature. Furthermore, addition of recombinant Wnt ligand or the Wnt signaling agonist inhibited adipogenic differentiation of ASC in the absence of EC. In conclusion, these data define the relationship in adipose tissue between ASC and EC in the perivascular niche, in which the latter act to repress adipogenesis, thereby stabilizing vasculature. It is tempting to speculate that abnormal endothelial function may be associated with pathologic derepression of adipogenesis. Disclosure of potential conflicts of interest is found at the end of this article.
脂肪基质细胞（ASC）是多能间充质祖细胞，易于被诱导进行脂肪生成分化，并且我们最近证明它们在功能和表型上与脂肪组织中微血管周围的周细胞存在重叠。在本研究中，我们探讨了一种假说，即在这个血管周围微环境中，ASC命运的调节可通过与内皮细胞（EC）相互作用来实现，而内皮细胞可调节ASC的脂肪生成潜能。为此，我们在二维共培养中以及通过条件培养基研究了EC对ASC脂肪生成的接触效应和旁分泌效应，并通过实时逆转录聚合酶链反应（PCR）分析了相互的基因表达变化。当ASC与EC共培养而非对照成纤维细胞共培养时，观察到脂肪生成分化显著降低。这种内皮细胞特异性效应伴随着参与Wnt信号通路的因子表达增加，最显著的是Wnt1、Wnt4和Wnt10a，它们是众所周知的脂肪生成抑制剂。在共培养中抑制Wnt1而非Wnt10a或 scrambled对照短干扰RNA可部分逆转内皮细胞的效应，从而增加脂肪生成分化，这表明Wnt1配体在血管系统对脂肪生成的调节中可能发挥合理作用。此外，在没有EC的情况下添加重组Wnt配体或Wnt信号激动剂可抑制ASC的脂肪生成分化。总之，这些数据定义了血管周围微环境中脂肪组织内ASC与EC之间的关系，其中后者起到抑制脂肪生成的作用，从而稳定血管系统。很容易推测异常的内皮功能可能与脂肪生成的病理性去抑制有关。潜在利益冲突的披露见本文末尾。
