Wang Yi, Nakayama Naoki
Developmental Biology Laboratory, Australian Stem Cell Centre and Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC 3800, Australia.
Stem Cell Res. 2009 Sep-Nov;3(2-3):113-25. doi: 10.1016/j.scr.2009.06.001. Epub 2009 Jun 9.
Pluripotent human embryonic stem (hES) cells are capable of generating a variety of mature cell types, including hematopoietic cells in vitro. However, the precise signaling mechanisms that regulate hematopoietic cell development from hES cells are still poorly documented. Here we demonstrate that hemoangiogenic cells derived from hES cells are defined by their high-level expression of KDR and low-level expression of PDGFRalpha (KDR(+)PDGFRalpha(lo)), and that the generation of such cells from hES cells is significantly elevated by the addition of WNT3a or BMP4 during differentiation. The addition of WNT3a caused the induction of both hemogenic and angiogenic activities, and the addition of BMP4 preferentially increased angiogenic activity, all enriched in the KDR(+)PDGFRalpha(lo) cell fraction. Interestingly, WNT3a stimulation of hemoangiogenic cell genesis was virtually abolished in the presence of a BMP inhibitor. On the other hand, the BMP4-induced angiogenic cell genesis was suppressed by coaddition of a WNT inhibitor. Thus, WNT and BMP signaling coordinately direct the differentiation of hES cells into KDR(+)PDGFRalpha(lo) hemoangiogenic cells.
多能性人类胚胎干细胞（hES细胞）能够在体外生成多种成熟细胞类型，包括造血细胞。然而，调控hES细胞向造血细胞发育的精确信号机制仍鲜有记载。在此，我们证明源自hES细胞的血血管生成细胞由其高水平表达KDR和低水平表达PDGFRα（KDR(+)PDGFRα(lo)）所定义，并且在分化过程中添加WNT3a或BMP4可显著提高hES细胞生成此类细胞的能力。添加WNT3a可诱导造血和血管生成活性，添加BMP4则优先增加血管生成活性，所有这些活性均富集于KDR(+)PDGFRα(lo)细胞组分中。有趣的是，在存在BMP抑制剂的情况下，WNT3a对血血管生成细胞发生的刺激几乎被消除。另一方面，WNT抑制剂的共同添加可抑制BMP4诱导的血管生成细胞发生。因此，WNT和BMP信号协同指导hES细胞分化为KDR(+)PDGFRα(lo)血血管生成细胞。
