Effect of TEAD4 on multilineage differentiation of muscle-derived stem cells.

TEAD4 is a member of transcriptional enhancer factor (TEF) family of transcription factors and plays a pivotal role in regulating embryonic development and muscle regeneration. Known previously, dysfunction of TEAD4 in mouse myoblasts impairs myotube development. However, the effects of TEAD4 on multipotency of muscle-derived stem cells (MDSCs) have not been clearly understood. Recently, bovine MDSCs (bMDSCs) were successfully isolated from adult bovine muscle. Our derived bMDSCs could differentiate into mesodermal cells, including myotubes, adipocytes, and osteoid cells. Our results also revealed that bMDSCs had the capacity to develop into ectodermal and endodermal lineages including neuron-like cells and insulin-secreting cells. After TEAD4 knock-down (TEAD4-KD), bMDSCs still kept the original capacity to differentiate into neuron-like cells and insulin-secreting cells, as shown by acquisition of both neuronal and pancreatic markers normally expressed in differentiated cells. However, up-regulation of CAV3 and βMHC failed during myogenesis of bMDSCs with TEAD4-KD, although TEAD4-KD in bMDSCs did not affect osteoid cells and myotube formation. More interestingly, adipogenic differentiation of TEAD4-KD bMDSCs was significantly suppressed. During adipogenic differentiation, TEAD4-KD systematically impaired upregulation of TEAD1, TEAD2, and TEAD3, as well as the activation of C/EBP2, ADD1, and PPARγ as the key transcription factors for adipogenic differentiation. Finally, TEAD4-KD led to the failure of adipogenesis from bMDSCs. Together, our results support that TEAD4 is essential during adipogenic differentiation of bMDSCs. It has little effect on myogenesis of bMDSCs, and does not affect ostegenesis, neurogenesis, or pancreatic differentiation of bMDSCs. Our findings will be helpful for future study on the roles of the TEAD family during differentiation of MDSCs, and for controlling MDSC differentiation for stem cell applications.