Regulation of cell-cell fusion by nanotopography

Abstract

Cell-cell fusion is fundamental to a multitude of biological processes ranging from cell differentiation and embryogenesis to cancer metastasis and biomaterial-tissue interactions. Fusogenic cells are exposed to biochemical and biophysical factors, which could potentially alter cell behavior. While biochemical inducers of fusion such as cytokines and kinases have been identified, little is known about the biophysical regulation of cell-cell fusion. Here, we designed experiments to examine cell-cell fusion using bulk metallic glass (BMG) nanorod arrays with varying biophysical cues, i.e. nanotopography and stiffness. Through independent variation of stiffness and topography, we found that nanotopography constitutes the primary biophysical cue that can override biochemical signals to attenuate fusion. Specifically, nanotopography restricts cytoskeletal remodeling-associated signaling, which leads to reduced fusion. This finding expands our fundamental understanding of the nanoscale biophysical regulation of cell fusion and can be exploited in biomaterials design to induce desirable biomaterial-tissue interactions.

Development of fusogenic glass surfaces that impart spatiotemporal control over macrophage fusion: Direct visualization of multinucleated giant cell formation

“…However, the calculated roughness indicated that the surfaces were rather flat since adsorbed material was raised from the surface by ∼10 nm or less. Therefore, consistent with previous work [23, 30, 31], this study observed no clear connection between nanoscale (<100 nm) surface roughness and increased fusion. Although FD surface roughness was ∼2.5-fold higher than paraffin-adsorbed surfaces, the latter was significantly more active.…”

“…Interfacial processes driven by the physicochemical properties of the material are known to be important modulators of macrophage fusion [4, 23, 24]. In order to gain insight into the characteristics of the surface that might promote macrophage fusion, we employed atomic force microscopy (AFM) to directly visualize surface features.…”

“…Previous studies that investigated the effect of surface topology in a foreign body reaction model demonstrated that there was a 500 nm threshold for linear, parallel gratings of poly(∈-caprolactone), poly(lactic acid) and poly(dimethylsiloxane), below which macrophages did not respond [30]. Furthermore, bulk metallic glass nanowhiskers [31] reduced macrophage fusion [23]. Our AFM imaging data revealed the existence of linear arrays of material on both the FD and paraffin-adsorbed surfaces (Figures 2A and 6A).…”

Hydrophilic titanium surface‐induced macrophage modulation promotes pro‐osteogenic signalling

“…More recently, a hydrophilic titanium surface with nanotopography (modSLA) has been shown to modulate the early inflammatory response in vivo promoting polarization of macrophages to an M2-like phenotype, even in diabetic conditions where an exaggerated pro-inflammatory environment is a distinguishing feature (Lee et al, 2017). Titanium surface nanotopography has also been shown to regulate both macrophage cell shape (McWhorter, Wang, Nguyen, Chung, & Liu, 2013), the release of cytokines (Luu, Gott, Woo, Rao, & Liu, 2015) and restrict cytoskeletal remodelling-associated signalling by macrophages leading to reduced cell to cell fusion, potentially moderating the foreign body reaction (Padmanabhan et al, 2016).…”

Multicompartment Drug Release System for Dynamic Modulation of Tissue Responses

“…The FBR to implants begins immediately after injury to tissue and, in the case of most synthetic implants, results in a variety of tissue responses including: recruitment of inflammatory cells to the surface of the implant, macrophage fusion to form foreign body giant cells (FBGCs), and eventual encapsulation in an avascular, oriented collagenous capsule . Biomaterial‐host interfaces have been the subject of countless studies over decades of work, which have led to the development of promising technologies that are able to promote specific biological responses from a variety of implants . Nevertheless, implants that do not degrade rapidly are ultimately subject to the FBR and fibrotic encapsulation.…”