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Remote Control of Heterodimeric Magnetic Nanoswitch Regulates the Adhesion and Differentiation of Stem Cells Heemin Kang, Hee Joon Jung, Dexter Siu Hong Wong, Sung Kyu Kim, Sien Lin, Kai Fung Chan, Li Zhang, Gang Li, Vinayak P. Dravid, and Liming Bian J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b03001 • Publication Date (Web): 22 Apr 2018 Downloaded from http://pubs.acs.org on April 22, 2018

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Journal of the American Chemical Society

Remote Control of Heterodimeric Magnetic Nanoswitch Regulates the Adhesion and Differentiation of Stem Cells Heemin Kang,†,⊥ Hee Joon Jung,‡,§,∥,⊥ Dexter Siu Hong Wong,† Sung Kyu Kim,‡,§,∥ Sien Lin,# Kai Fung Chan,¶ Li Zhang,¶ Gang Li,# Vinayak P. Dravid,‡,§,∥ and Liming Bian□,†,⌠,* †

Department of Biomedical Engineering, The Chinese University of Hong Kong, Hong Kong,

China. ‡

Department of Materials Science and Engineering, Northwestern University, Evanston, IL, USA.

§

International Institute for Nanotechnology, Evanston, IL, USA.

∥NUANCE #

Center, Northwestern University, Evanston, IL, USA.

Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of

Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, PR China. □

Translational Research Centre of Regenerative Medicine and 3D Printing Technologies of

Guangzhou Medical University, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China. Department of Mechanical and Automation Engineering and ⌠Shenzhen Research Institute, The

¶

Chinese University of Hong Kong, China.

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ABSTRACT Remote, non-invasive, and reversible control over the nanoscale presentation of bioactive ligands, such as Arg-Gly-Asp (RGD) peptide, is highly desirable for temporally regulating cellular functions in vivo. Herein, we present a novel strategy for physically uncaging RGD using a magnetic field that allows safe and deep tissue penetration. We developed a heterodimeric nanoswitch consisting of a magnetic nanocage (MNC) coupled to an underlying RGD-coated gold nanoparticle (AuNP) via a long flexible linker. Magnetically controlled movement of MNC relative to AuNP allowed reversible uncaging and caging of RGD that modulate physical accessibility of RGD for integrin binding, thereby regulating stem cell adhesion, both in vitro and in vivo. Reversible RGD uncaging by the magnetic nanoswitch allowed temporal regulation of stem cell adhesion, differentiation, and mechanosensing. This physical and reversible RGD uncaging utilizing heterodimeric magnetic nanoswitch is unprecedented and holds promise in the remote control of cellular behaviors in vivo. KEYWORDS: heterodimer, magnetic nanoswitch, remote control, in vivo cell adhesion, stem cell differentiation


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Cell adhesion is regulated by the interactions between cells and adhesive ligand, such as RGD sequences in the extracellular matrix in vivo, and mediates various cellular functions, such as stem cell differentiation.1 Dynamic binding between integrin and adhesive ligand mediates the formation of focal adhesions (FAs) that trigger mechanotransduction signaling.2 Designing materials with adhesive ligand whose presentation can be remotely controlled, is an attractive approach for non-invasive and temporal control of cellular adhesion and functions in vivo. Remote manipulation of cell-material interactions has been predominantly demonstrated with light-responsive molecules, such as photolabile molecules3 for uncaging RGD,3a and photoisomerizable molecules4 for cyclically uncaging RGD.4a In particular, transdermal uncaging of RGD via ultraviolet light, was shown to regulate cellular adhesion to implant in vivo.3a However, in vivo application of light exhibits limited tissue penetration and potential cytotoxicity. Developing materials that allow reversible RGD uncaging via penetrative stimuli, offers alternative strategy to control cellular adhesion in vivo. Magnetic field exhibits excellent penetration of living tissues with minimal cytotoxicity, thus suitable for clinical applications.5 Magnetic field was used for remotely controlling the motion of magnetic nanoparticles,6 and in vivo applications.7 Our own study showed that magnetic field tuned the tether compliance of RGD-bearing magnetic nanoparticles to modulate cell adhesion in vitro.8 Various RGD-coated static nanoparticles has been conjugated to substrate to investigate the effect of coupling strength,9 micro/nanospacing and density,10 and order/disorder

11

of

bioactive ligands on cellular adhesion and spreading. However, no prior studies have demonstrated physical and reversible uncaging and caging of nanoparticle-borne RGD. In this study, we conjugated magnetic nanoparticles as MNC to the underlying and RGDdecorated AuNP via long flexible linker, to form MNC-(AuNP-RGD) heterodimer on a substrate (Scheme 1). Under external magnetic field, MNC functioned as nanoswitch that reversibly uncaged and caged RGD to regulate stem cell adhesion, both in vitro and in vivo. Reversible RGD uncaging also temporally altered stem cell adhesion and differentiation. To our knowledge, this is the first demonstration of developing functional heterodimer-engineered substrate and the first example of physical and reversible ligand uncaging to regulate cellular adhesion, both in vitro and in vivo. 3 ACS Paragon Plus Environment


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Scheme 1. Summary of experiments in this study. Heterodimeric magnetic nanoswitch was remotely controlled to regulate in vivo adhesion and differentiation of stem cells on heterodimercoupled substrate by reversibly manipulating RGD ligand caging and uncaging. MNC-(AuNPRGD) heterodimer consists of magnetic nanocage (MNC) grafted to RGD-bearing gold nanoparticle (AuNP) via a long flexible linker on a substrate. To prepare MNC-(AuNP-RGD) heterodimer on a substrate, AuNP was first prepared.12 Transmission electron microscope (TEM) and dynamic light scattering (DLS) revealed uniform spherical morphology of AuNPs in 13 ± 2 nm (Figure S1). TEM and DLS showed spherical shape of citrate-capped MNC in 36 ± 6 nm (Figure S2). We prepared MNC larger than AuNP to allow sufficient caging of RGD-bearing AuNP by MNC without magnetic activation. X-ray diffraction revealed the diffraction peaks of MNC corresponded to those of magnetite (Fe3O4) (Figure S3A). Vibrating sample magnetometer showed superparamagnetic characteristics of MNC, which ensured their reversible uncaging and caging action upon switching on/off magnetic field (Figure S3B). To form heterodimer between MNC and AuNP and subsequently magnetically manipulate the motion of MNC, MNC was conjugated to AuNP with a long flexible thiol-poly(ethylene glycol) (thiol-PEG). Fourier transform infrared spectroscopy showed the characteristic bonds of thiol-PEGylated MNC with positive shift in zeta potential, compared with MNC, indicating the successful tethering of flexible linker to MNC (Figure S4A-B).


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Next, we fabricated the substrate coupled with MNC-(AuNP-RGD) heterodimers. AuNPs were first grafted to thiolated substrate and subsequently decorated with RGD peptide bearing thiol group (Figure S5). To minimize non-specific cellular adhesion, the area of substrate not covered by AuNPs, was passivated by PEG molecules.11 TEM and energy dispersive spectra (EDS) revealed monolayer of homogeneously distributed AuNPs at a density of 62 ± 15 particles/µm2 (Figure S6). Thiol-PEGylated MNC was then grafted to the underlying RGD-bearing AuNP (AuNP-RGD) to form heterodimer on the substrate. TEM and EDS revealed monolayer of homogeneously distributed heterodimeric nanoparticles with AuNP and MNC shown in dark and bright shades, respectively (Figure 1A-B). EDS mapping further confirmed direct coupling between AuNP and thiol-PEGylated MNC (Figure S7). Approximately 84% of AuNP was conjugated with MNC, suggesting efficient caging of AuNP by MNC. We then characterized reversible caging of AuNP-RGD by magnetically controlling the position of MNC. To turn magnetic nanoswitch “ON”, we placed magnet below and on one side of the heterodimeric substrate to attract MNC to downward direction, but away from AuNP-RGD, to laterally separate heterodimer, thereby uncaging RGD (Scheme 1). We placed magnet in this position because this allowed us to elucidate the effect of magnetic nanoswitching on regulating cellular adhesion. Conversely, to turn magnetic nanoswitch “OFF”, we removed magnet to restore proximate position of MNC to AuNP, thereby caging RGD. Magnetic field strength of the magnet, placed at approximately 1 cm distant from substrate for in vitro and in vivo experiments in this study, decreased with increasing distance from magnet and was 121 ± 6 mT at 1 cm (Figure S8). In situ atomic force microscopy (AFM) imaging was performed with magnetic nanoswitching to study the conformation of heterodimer. With magnetic nanoswitching on, AFM image revealed both larger MNC and smaller AuNP in heterodimer, shown by lateral size and height profile (Figure S9). This partitioned conformation of MNC-(AuNP-RGD) heterodimers suggested uncaging of AuNP-RGD. With magnetic nanoswitching on, partitioned heterodimer structure was maintained during serial AFM scanning, suggesting that AFM scanning minimally disrupted heterodimer conformation (Figure S10). However, with magnetic field off, MNC physically shielded underlying AuNP-RGD from AFM imaging, indicating effective caging of RGD (Figure 2C). Furthermore, magnetic switch was found to be reversible in RGD uncaging and caging. These show that MNC-(AuNP-RGD) heterodimers can function as an effective magnetic nanoswitch to reversibly modulate nanoscale RGD presentation. 5 ACS Paragon Plus Environment


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Figure 1. In situ imaging of reversible magnetic nanocaging of RGD-bearing AuNP. (A) Transmission electron micrograph and (B) energy dispersive spectrum of MNC-(AuNP-RGD) heterodimer-coupled substrate. Scale bar indicates 100 nm (High magnification: 10 nm). (C) In situ magnetic atomic force micrograph of heterodimer-coupled substrate to show reversible RGD caging by turning on and off magnetic nanoswitch. Blue dotted lines are drawn across the centers of AuNPs as non-magnetic reference. Scale bar represents 50 nm. Next, we investigated whether reversible RGD uncaging by heterodimeric magnetic nanoswitch could regulate integrin-RGD binding and thus adhesion and spreading of human mesenchymal stem cells (hMSCs). After 12 h in culture, magnetic switching “ON” that uncages RGD, significantly promoted cellular adhesion compared to switching “OFF” (Figure 2A and S11A). This finding demonstrates the efficacy of magnetic nanoswitch to regulate cellular adhesion by modulating physical accessibility of RGD for integrin ligation. In contrast, heterodimer-coupled substrate without grafted RGD, yielded minimal cellular adhesion regardless of switching “ON” or “OFF”, suggesting the efficient PEG blocking in preventing non-specific cellular adhesion (Figure S12A-B). Furthermore, the substrate coated with AuNP-RGD without MNC, yielded 6 ACS Paragon Plus Environment

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pronounced cellular adhesion under both switching “ON” and “OFF”, suggesting the necessity of MNC for magnetically regulating cellular adhesion (Figure S13A-B). Since integrin-RGD binding mediates FA formation and thus promotes cell spreading and mechanosensing, we further examined adherent cells. Switching “ON” significantly enhanced the spread area and FA formation, shown by robust staining against vinculin (key FA adaptor protein) of cells, compared to switching “OFF” (Figure 2A and S11B-D). These differential cell adhesion behaviors achieved by magnetic switching ON or OFF, were not observed without coupled RGD or MNC (Figure S12C and 13C-D).

Figure 2. Time-regulated heterodimeric magnetic nanoswitching regulates reversible adhesion and differentiation of stem cells. (A) Time-dependent immnuofluorescent staining micrographs against (A) vinculin or (B) RUNX2 or YAP (green) with actin (red) and nuclei (blue), and ALP staining in stem cells on heterodimer-coupled substrate by reversibly turning on and off magnetic nanoswitch. Scale bars represent 50 µm. Magnetic nanoswitch was turned continuously “ON” or “OFF”. Magnetic nanoswitch was also turned “OFF” for initial 12 h and 7 ACS Paragon Plus Environment


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“ON” for subsequent time (“OFF-ON”) or “ON” for initial 12 h and “OFF” for subsequent time (“ON-OFF”). We next examined whether temporal regulation of magnetic nanoswitch can reversibly regulate focal adhesion of stem cells during 24 h in culture. Consistent with the findings from 12 h in culture, switching “ON” at 24 h significantly enhanced focal adhesion of stem cells, compared to switching “OFF” (Figure 2A and S11B-D). Magnetic switching from “OFF” to “ON” (“OFFON”) induced focal adhesion and spreading of stem cells at 24 h that was inhibited at 12 h. Conversely, switching from “ON” to “OFF” (“ON-OFF”) suppressed focal adhesion of stem cells at 24 h that was established at 12 h. These findings indicate that magnetic nanoswitch temporally regulated cellular adhesion and spreading through physically and reversibly uncaging RGD, without chemical alterations of molecular structure with photochemical uncaging of RGD. This reversible cell adhesion was recently demonstrated by using light to mediate shrinkingswelling

of

RGD-bearing

hydrogel,13

disassembly

of

RGD-coupled

DNA,14

or

photoisomerization4b in vitro. Magnetic nanoswitching in the present study offers an alternative strategy using tissue-penetrative magnetic field for in vivo applications. The focal adhesion and spread morphology of stem cells regulate their mechanotransduction and differentiation15 that are required for regenerative therapies.16 We next evaluated whether reversible magnetic nanoswitch can regulate stem cell differentiation under osteogenic induction medium for 5 d under four conditions including “OFF”, “ON”, “OFF-ON”, and “ON-OFF”. Continuously switching “ON” induced higher nuclear localization of RUNX2 and ALP staining, key markers of osteogenic differentiation, as compared to switching “OFF” (Figure 2B and S14). The two alternating magnetic switching (“OFF-ON” and “ON-OFF”) exhibited the degree of differentiation comparable to switching “ON” and “OFF”, respectively. These data indicate that magnetic nanoswitch regulated stem cell differentiation that can be temporally suppressed or promoted. Switching “ON” and “OFF-ON” induced higher nuclear localization of YAP, mechanotransduction regulator, compared with switching “OFF” and “ON-OFF” (Figure 2B and S15). These suggest that magnetic nanoswitch-mediated stem cell differentiation involved mechanotransduction signaling.


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Figure 3. Remote control of heterodimeric magnetic nanoswitching alters the adhesion and mechanosensing of stem cells in vivo. (A) Schematic representation of magnetic nanoswitching in vivo. (B) Immunofluorescent staining images against actin (red), nuclei (blue), and humanspecific nuclear antigen (HuNu), vinculin, or YAP (green), following in vivo injection of stem cells onto heterodimer-coupled substrate under in vivo magnetic nanoswitching. Scale bars represent 50 µm. Physical, non-invasive, tissue-penetrative, cytocompatible, and reversible uncaging of RGD via heterodimeric magnetic nanoswitch can offer advantages in regulating cellular adhesion in vivo. We subcutaneously implanted heterodimer-grafted substrate and injected hMSCs onto substrate. We applied magnet nanoswitching either “OFF” or “ON” and examined cellular adhesion in vivo after 4 h (Figure 3A). In vivo magnetic switching “ON” significantly enhanced cellular adhesion compared with switching “OFF” (Figure 3B and S16A). All of adherent cells after 4 h were human-specific nuclear antigen-positive injected human stem cells, and this could be due to limited time for recruitment and adhesion of host cells.3a Concomitantly, switching “ON” significantly promoted focal adhesion and spreading of in vivo adherent stem cells, compared with switching “OFF” (Figure 3B and S16B-D). Magnetic nanoswitch did not induce such distinct cell adhesion in vivo, without coupled RGD or MNC (Figure S17 and S18). Furthermore, switching “ON” induced pronounced nuclear localization of YAP, compared with switching 9 ACS Paragon Plus Environment


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“OFF” (Figure 3B and S16E). Collectively, these findings indicate that tissue-penetrative and cytocompatible magnetic nanoswitch with advantages over photochemical uncaging of RGD, effectively regulated physical uncaging of RGD, and cellular adhesion, spreading, and mechanosensing in vivo. These also suggest that magnetic nanoswitch could non-invasively and potentially modulate cellular function in deep tissues in vivo, such as stem cell differentiation, over prolonged periods. In summary, we developed MNC-(AuNP-RGD) heterodimeric nanoswitch, consisting of magnetic nanocage flexibly coupled to RGD-coated AuNP. This study provides the first evidence for physical and reversible ligand uncaging via magnetic nanoswitch to control stem cell adhesion, both in vitro and in vivo. Reversible magnetic nanoswitch allowed temporal regulation of RGD uncaging and thus focal adhesion, spreading, differentiation, and mechanosensing of stem cells. Modular nature of our heterodimeric nanoswitch can accommodate various bioactive motifs including receptors,17 antibodies,18 or antigens19. Therefore, our magnetic nanoswitch can be instrumental for in vivo temporal regulation of various cellular function. This physical, non-invasive, non-contact, and reversible nanoswitch can potentially enhance the performance of material implants and outcome of regenerative therapies involving stem cells.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Experimental methods and additional figures for detailed characterizations of heterodimeric nanostructure on the substrate, and analysis of stem cell adhesion, differentiation, and mechanosensing under the magnetic nanoswitching in vitro or in vivo (PDF)

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected].


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ORCID Vinayak P. Dravid: 0000-0002-6007-3063 Liming Bian: 0000-0003-4739-0918

Author Contributions ⊥Contributed

equally to this work.

Notes The authors declare no conflict of interest.

ACKNOWLEDGEMENTS Project 31570979 is supported by the National Natural Science Foundation of China. This work is supported by a General Research Fund grant from the Research Grants Council of Hong Kong (project no. 14202215, 14220716); the Health and Medical Research Fund, the Food and Health Bureau, the Government of the Hong Kong Special Administrative Region (reference no.: 02133356, 03140056); the project BME-p3-15 of the Shun Hing Institute of Advanced Engineering, The Chinese University of Hong Kong; the Chow Yuk Ho Technology Centre for Innovative Medicine, The Chinese University of Hong Kong. This work made use of the EPIC facility of Northwestern University’s NUANCE Center, which has received support from the Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource (NSF ECCS-1542205); the MRSEC program (NSF DMR-1720139) at the Materials Research Center; the International Institute for Nanotechnology (IIN); the Keck Foundation; and the State of Illinois, through the IIN.



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