Figure 8. Potential mechanotransduction mechanisms in cellular responsiveness to nanotopographical biomaterials.

(left) On pro-integrin clustering surfaces, which could be either smooth or composed of certain nanotopographical features, integrins could undergo free lateral recruitment and ligation with ECM proteins, and thus cluster and form mature, stable FAs together with the unhindered recruitment of FA adaptor proteins. This process initiates signals from plasma membrane, enhancing FAK/ERK signaling, as well as RhoA activity, which further promoting CSK contractility (through RhoA/ROCK) as well as stress fiber formation. CSK contractility, as an important mediator of mechanotransduction, could provide positive feedback to the FAs. In addition, CSK force could also induce phosphorylation of emerin, a nuclear envelope-located protein, and thus initiate nuclear mechanotransduction through enhanced nuclear actin polymerization and subsequent nuclear translocation of MAL, a transcription cofactor of SRF. In the meantime, prominent stress fibers formed in cells on smooth surfaces could promote the nuclear translocation of YAP/TAZ, a transcription co-factor of TEAD. Nuclear shuttling of SMAD 2/3 (R-SMAD), the transcription factor downstream of TGFβ signaling, is also controlled by YAP/TAZ translocation. (right) On surfaces containing anti-integrin clustering nanotopographical cues, although integrins could still freely diffuse laterally, the nanoscale surface features restrict the ligation of additional integrins to the ECM proteins, which further restrict successful recruitment and clustering of integrins and other FA proteins, resulting in smaller, less stable FAs. Such process disrupts the activation of RhoA and therefore limits the formation of stress fibers and might induce high cytoplasmic G-actin level, which inhibits the nuclear translocation of MAL and thus SRF signaling. Unlike nanotopographical surfaces that promote integrin clustering, anti-integrin clustering surfaces containing different types of nanoscale structures could not sustain FAK activation and downstream signaling. Last but not the least, compromised stress fibers and FAs on nanotopographical substrates could potentially intersect with Hippo/YAP pathway by enhancing YAP/TAZ phosphorylation via either Lats-dependent or –independent mechanisms, resulting in cytoplasmic retention of YAP/TAZ.