Biomechanical Strain Promotes the Differentiation of Murine Oogonial Stem Cells.

ABSTRACT

Cells within tissues are routinely subjected to physiological stress and strain, arising from direct interactions with neighboring cells as well as with extracellular matrix components. Accordingly, there is tremendous interest in deciphering how cells sense, and respond to, changes in biomechanical forces. In this study, we explored the effects of mechanostimulation on the differentiation of mouse female germline or oogonial stem cells (OSCs) as a model for adult stem cell function. We report that increasing levels, or repeated application of a subthreshold fixed level, of radial strain to OSCs in culture significantly increased rates of in vitro oocyte formation as a measure of stem cell differentiation. These responses involved changes in F-actin-mediated cytoskeletal tension as well as in activation of intracellular signaling by Rho-associated protein kinase (ROCK) and Yes-associated protein (YAP) phosphorylation. In addition, application of mechanical strain to OSCs enhanced association of YAP with muscle-specific cytidine-adenosine-thymidine (MCAT) response elements in the promoter stimulated by retinoic acid gene 8 (Stra8), the transcriptional activation of which is required for germline meiotic commitment. These data indicate that biomechanical strain directly promotes the differentiation of adult female germline stem cells through a signaling pathway involving F-actin, ROCK, YAP, and Stra8.