Muscle Development and Regeneration Program, Sanford-Burnham Medical Research Institute, 10901 N Torrey Pines Rd, La Jolla, CA 92037, USA.
Circ Res. 2012 Sep 14;111(7):876-81. doi: 10.1161/CIRCRESAHA.112.270272. Epub 2012 Aug 7.
The transforming growth factor-β (TGFβ) family member Nodal promotes cardiogenesis, but the mechanism is unclear despite the relevance of TGFβ family proteins for myocardial remodeling and regeneration.
To determine the function(s) of TGFβ family members during stem cell cardiogenesis.
Murine embryonic stem cells were engineered with a constitutively active human type I Nodal receptor (caACVR1b) to mimic activation by Nodal and found to secrete a paracrine signal that promotes cardiogenesis. Transcriptome and gain- and loss-of-function studies identified the factor as TGFβ2. Both Nodal and TGFβ induced early cardiogenic progenitors in embryonic stem cell cultures at day 0 to 2 of differentiation. However, Nodal expression declines by day 4 due to feedback inhibition, whereas TGFβ persists. At later stages (days 4-6), TGFβ suppresses the formation of cardiomyocytes from multipotent Kdr(+) progenitors while promoting the differentiation of vascular smooth muscle and endothelial cells.
Nodal induces TGFβ, and both stimulate the formation of multipotent cardiovascular Kdr(+) progenitors. TGFβ, however, becomes uniquely responsible for controlling subsequent lineage segregation by stimulating vascular smooth muscle and endothelial lineages and simultaneously blocking cardiomyocyte differentiation.
转化生长因子-β（TGFβ）家族成员 Nodal 可促进心肌发生，但尽管 TGFβ 家族蛋白与心肌重塑和再生有关，其作用机制仍不清楚。
确定 TGFβ 家族成员在干细胞心肌发生过程中的功能。
通过工程改造使鼠胚胎干细胞表达组成型激活的人 I 型 Nodal 受体（caACVR1b），以模拟 Nodal 的激活，并发现其分泌一种旁分泌信号，可促进心肌发生。转录组和基因增益及缺失功能研究鉴定出该因子为 TGFβ2。Nodal 和 TGFβ 在胚胎干细胞分化的第 0 至 2 天均可诱导早期心肌发生前体细胞。然而，由于反馈抑制，Nodal 的表达在第 4 天下降，而 TGFβ 持续存在。在后期（第 4-6 天），TGFβ 抑制多能性 Kdr(+)祖细胞形成心肌细胞，同时促进血管平滑肌和内皮细胞的分化。
Nodal 诱导 TGFβ，两者均可刺激多能性心血管 Kdr(+)祖细胞的形成。然而，TGFβ 通过刺激血管平滑肌和内皮谱系并同时阻止心肌细胞分化，成为控制后续谱系分离的唯一因素。
