The effect of YAP signaling on tenogenic differentiation

Abstract

Hippo signaling is one of the powerful pathways that regulate numerous biological processes, and it is involved in various physiological functions such as cellular proliferation, organ formation, tissue regeneration, and wound healing. Yes-associated protein (YAP) is a downstream effector of the Hippo pathway, and it is known to impact the tenogenic differentiation of mesenchymal stem cells significantly. In this research, we set the conditions for tenogenic differentiation of BMSCs (Bone Marrow Mesenchymal Stem Cells) and determine whether YAP influences this tenogenic differentiation. We could confirm that tenogenic differentiation did not proceed appropriately under Verteporfin-treated conditions, which inhibit the nuclear localization of YAP/TAZ. During the tenogenic differentiation of BMSC, mature tenocyte marker Col1a1 is significantly decreased in the Verteporfin-treated condition compared with CTL. However, expression levels of tenocyte progenitor markers like Scx and Tnmd did not decrease but increase when treated with Verteporfin. And XMU-MP1, YAP signaling activator is also affects to tenogenic differentiation process in a different way. FAT Atypical Cadherin (FAT) is a well-known upstream regulator of YAP/TAZ signaling. During the tenogenic differentiation process, FAT2 expression level significantly increases compared with other FAT genes. This result suggests that FAT2 has crucial roles in the tenogenic differentiation process. We performed a cross-check of BMSC data with the Xenopus laevis embryo. In drug treatment conditions, the tenocyte progenitor marker Tnmd is deceased in YAP inhibition status and has increased in YAP activation status. Also, when we induce YAP activation by knock-out the FAT family at the Xenopus laevis embryo, Tnmd expression level decrease is observed. Based on these results, YAP signaling may play a key role in switching between tenocyte progenitor cells and mature tenocytes. Also, by studying the impact of YAP signaling on tenogenesis, we expect to reveal that YAP could play a key role in tendon regeneration research.