Scientists at the University of Kyoto have linked Vinculin, a focal adhesion protein, with the famous YAP/TAZ pathway: its a mechanosensor that dictates cell fate based on the rigidity of the substrate
Noriyuki Kioka’s team have provided a new window of understanding on how mechanical forces influence cell differentiation.
They found that vinculin, a protein involved with adhesions, is able to control transcription factors YAP (Yes-associated protein) and TAZ (transcriptional co-activator with PDZ-binding motif) to regulate fat cell differentiation. By growing mesenchymal stem cells (MSCs) on stiff or soft matrices, the team demonstrated that only those growing on soft matrices differentiated into adipocytes – fat cells. Soft matrix was also associated with lower levels of activated vinculin. This seemed to exclude YAP and TAZ – two well known mechanical sensors – from the nucleus.
This study has provided a possible explanation of how vinculin, in a new role as a mechanosensor, is able to regulate gene expression and cell differentiation by changing the cellular location of YAP and TAZ. It has long been recognized that the physical properties of the cellular environment are crucial in differentiating stem cells into different cell types. But it has been unclear until now how those mechanical cues are transduced to regulate gene expression in MSCs.
MSCs are multipotent stem cells found in the bone marrow. Being multipotent means they are capable of differentiating into a wide range of cell types. Stem cells can sense signals from their surrounding environment to regulate cell differentiation. It has become increasingly clear that the mechanical properties (such as the stiffness of the matrix) can promote a certain cell lineage over another. It is not surprising, therefore, that more emphasis recently has been placed on understanding how stem cells sense and respond specific stiffness and how such mechanical cues signal changes in gene expression that determine stem cell fate.
How they translate stiffness into a biological response that alters cell fate has been unclear, but answers can be found in focal adhesion (FA) proteins like vinculin. FAs are massive protein complexes that serve as mechanical linkages between the extracellular environment and the cell. By responding to the elasticity of the surrounding environment, focal adhesion proteins are able to influence cell differentiation – vinculin has already been shown to activate when cells are on rigid matrices.
In this study, researchers link vinculin’s ability to sense matrix stiffness with the regulation of YAP/TAZ – Hippo pathway members responsible for cell fate determination. Thus by its sensing of the substrate, vinculin transduces a signal that tells MSCs to differentiate into fat cells (adipocytes), or bone cells (osteoblasts).
By understanding how different physical signals affect stem cell fate, we can use these findings to develop more sophisticated ways to differentiate stem cells, which will be extremely useful for future stem cell-based regenerative therapies.
SEM bone cell image (right panel) kindly provided by Tim Arnett at UCL
Written by Grace Chan