Engineering Photoresponsive Ligand Tethers for Mechanical Regulation of Stem Cells

Abstract

Regulating stem cell functions by precisely controlling the nanoscale presentation of bioactive ligands has a substantial impact on tissue engineering and regenerative medicine but remains a major challenge. Here it is shown that bioactive ligands can become mechanically “invisible” by increasing their tether lengths to the substrate beyond a critical length, providing a way to regulate mechanotransduction without changing the biochemical conditions. Building on this finding, light switchable tethers are rationally designed, whose lengths can be modulated reversibly by switching a light‐responsive protein, pdDronpa, in between monomer and dimer states. This allows the regulation of the adhesion, spreading, and differentiation of stem cells by light on substrates of well‐defined biochemical and physical properties. Spatiotemporal regulation of differential cell fates on the same substrate is further demonstrated, which may represent an important step toward constructing complex organoids or mini tissues by spatially defining the mechanical cues of the cellular microenvironment with light.

Multifunctional stimuli-responsive chemogenetic platform for conditional multicolor cell-selective labeling

“…Light activation as an external regulation and control means has been widely used in spatiotemporal controlled imaging due to its quick, straightforward, and precisely controllable properties. 38,39 Here, an optically controlled tagging system is explored as the preliminary attempt to achieve Please do not adjust margins Please do not adjust margins spatiotemporally selective labeling of cells. Here, the photoactivatable ligand photo-DOM containing a 2-nitrobenzyl group 39,40 was successfully synthesized through one-step nucleophilic reaction of HBR-3,5DOM and 1-(bromomethyl)-2nitrobenzene (Fig.…”

Static and photoresponsive dynamic materials to dissect physical regulation of cellular functions

“…197 Wang, Bian, and Cao have utilized a light-responsive protein, pdDronpa, as a linkage between a cell-adhesive ligand to the substrate for manipulating the ligand tethering. 198 Owing to the photo-reversibly dimerizing property of pdDronpa, the author have successfully controlled YAP nuclear translocation in response to blue/green irradiation, resulting in changes in adipogenic/osteogenic differentiation in MSCs. 198 In this way, the development of new tools as well as seeking adequate biological targets is crucial for the contribution of dynamic photoresponsive materials to fundamental biology.…”

Biophysical Approaches for Applying and Measuring Biological Forces

“…[ 174 ] On the other hand, with the development of molecular biology, MFP‐based approaches have been exploited to promote cell mechanotransduction and mechanically mediate the cell fate of stem cells. [ 175 ] Furthermore, a well‐designed optical sensor based on MFPs has been successfully employed to study abnormal nuclease spatial dynamics at the subcellular level on cancer cell membranes. [ 176 ] To conclude, despite the inevitable challenges, MFP‐based approaches provide new insight from the molecular view into how mechanical cues transduce and regulate cell fate.…”