How does BMP4 mediate mesodermal differentiation in human embryonic stem cells?
Bone morphogenetic proteins (BMPs) are one of the key members of the Transforming growth factor beta (TGFβ) superfamily that affects most cell types throughout the body and plays a crucial role in both self-renewal and differentiation of human embryonic stem cells (hESC). However, the exact mechanisms have not been fully elucidated. We reveal that BMP4 is a potent inducer of cardiomyocyte differentiation of hESC in comparison to TGFβ and ActivinA which had no effect on the number of beating cardiomyocytes compared to untreated cells. Our microarray expression analysis demonstrated that BMP4 induces differentiation of hESC by upregulating the well-known epithelial-mesenchymal transition (EMT) transcription factors SLUG and MSX2. The role of SLUG and MSX2 were examined during early hESC differentiation using lentiviral overexpression and knock-down constructs. We discovered that BMP4 induced MSX2 expression that mediated mesodermal differentiation. Moreover, knock-down of MSX2 in BMP4 treated hESC resulted in abolished expression of early mesodermal marker T-BRACHYURY and early cardiac marker ISLET-1.
Our results strongly indicate that BMP4 mediates early hESC commitment to the mesodermal lineages via the EMT mediators SLUG and MSX2.