Abstract
Cellular adhesion is regulated by the dynamic ligation process of surface receptors, such as integrin, to adhesive motifs, such as Arg-Gly-Asp (RGD). Remote control of adhesive ligand presentation using external stimuli is an appealing strategy for the temporal regulation of cell-implant interactions in vivo and was recently demonstrated using photochemical reaction. However, the limited tissue penetration of light potentially hampers the widespread applications of this method in vivo. Here, we present a strategy for modulating the nanoscale oscillations of an integrin ligand simply and solely by adjusting the frequency of an oscillating magnetic field to regulate the adhesion and differentiation of stem cells. A superparamagnetic iron oxide nanoparticle (SPION) was conjugated with the RGD ligand and anchored to a glass substrate by a long flexible poly(ethylene glycol) linker to allow the oscillatory motion of the ligand to be magnetically tuned. In situ magnetic scanning transmission electron microscopy and atomic force microscopy imaging confirmed the nanoscale motion of the substrate-tethered RGD-grafted SPION. Our findings show that ligand oscillations under a low oscillation frequency (0.1 Hz) of the magnetic field promoted integrin-ligand binding and the formation and maturation of focal adhesions and therefore the substrate adhesion of stem cells, while ligands oscillating under high frequency (2 Hz) inhibited integrin ligation and stem cell adhesion, both in vitro and in vivo. Temporal switching of the multimodal ligand oscillations between low- and high-frequency modes reversibly regulated stem cell adhesion. The ligand oscillations further induced the stem cell differentiation and mechanosensing in the same frequency-dependent manner. Our study demonstrates a noninvasive, penetrative, and tunable approach to regulate cellular responses to biomaterials in vivo. Our work not only provides additional insight into the design considerations of biomaterials to control cellular adhesion in vivo but also offers a platform to elucidate the fundamental understanding of the dynamic integrin-ligand binding that regulates the adhesion, differentiation, and mechanotransduction of stem cells.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 9636-9649 |
| Number of pages | 14 |
| Journal | ACS nano |
| Volume | 11 |
| Issue number | 10 |
| DOIs | |
| State | Published - Oct 24 2017 |
Funding
This work was supported by a General Research Fund grant from the Research Grants Council of Hong Kong (Project No. 14202215), the National Natural Science Foundation of China (Project No. 31570979), and the Health and Medical Research Fund, the Food and Health Bureau, the Government of the Hong Kong Special Administrative Region (Reference No. 03140056). This research was also supported by project BME-p3-15 of the Shun Hing Institute of Advanced Engineering and the Chow Yuk Ho Technology Centre for Innovative Medicine, The Chinese University of Hong Kong. This work was performed at the EPIC facility of Northwestern University’s NUANCE Center with the support from the Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource (NSF ECCS-1542205); the MRSEC program (NSF DMR-1121262) at the Materials Research Center; the International Institute for Nanotechnology (IIN); the Keck Foundation; and the State of Illinois, through the IIN.
Keywords
- SPION
- in vivo cell adhesion
- integrin ligand oscillations
- mesenchymal stem cells
- multimodal control
- stem cell differentiation
ASJC Scopus subject areas
- General Engineering
- General Physics and Astronomy
- General Materials Science