Topological cues of microparticles train stem cells for tissue repair via mechanotransduction

Microspheres (MPs) and porous microspheres (PMPs) are the two most widely used microparticles in tissue engineering and stem cell therapy. However, how stem cells perceive the topological differences between them to regulate cell function remains to be unclear. Here, we systematically studied the changes in stem cell function under the action of MPs and PMPs and elucidated the related mechanisms. Our findings show that the porous structure of PMPs can be sensed by focal adhesions (FAs), which triggers the synthesis of F-actin to inhibit the phosphorylation and degradation of Yes-associated protein (YAP), while also transmitting stress to the nucleus through the contraction of F-actin, thereby enhancing the nuclear translocation of YAP protein. The activation of YAP significantly enhances the proliferation, osteogenesis, paracrine and glucose metabolism of BMSCs, making them exhibit stronger bone repair ability in both in vivo and in vitro experiments. In summary, this study provides a comprehensive and reliable understanding of the behavior of BMSCs in response to MPs and PMPs. It also deepens our understanding of the association between microparticles’ topological cues and biological functions, which will provide valuable guidance for the construction of bone tissue engineering (BTE) scaffolds. • Our study explored the effects of topographical differences in commonly used microparticles on the functions of BMSCs from various angles, enriching our understanding of the cellular interactions between microparticle systems and BMSCs. •We have verified that the three-dimensional porous structure promotes the nuclear entry of YAP through the cytoskeleton remodeling mediated by the FA signaling pathway, and subsequently triggers the functional alterations of BMSCs.