Mesenchymal Migration on Adhesive–Nonadhesive Alternate Surfaces in Macrophages

Mesenchymal migration usually happens on adhesive substrates, while cells adopt amoeboid migration on low/nonadhesive surfaces. Protein‐repelling reagents, e.g., poly(ethylene) glycol (PEG), are routinely employed to resist cell adhering and migrating. Contrary to these perceptions, this work discovers a unique locomotion of macrophages on adhesive–nonadhesive alternate substrates in vitro that they can overcome nonadhesive PEG gaps to reach adhesive regions in the mesenchymal mode. Adhering to extracellular matrix regions is a prerequisite for macrophages to perform further locomotion on the PEG regions. Podosomes are found highly enriched on the PEG region in macrophages and support their migration across the nonadhesive regions. Increasing podosome density through myosin IIA inhibition facilitates cell motility on adhesive–nonadhesive alternate substrates. Moreover, a developed cellular Potts model reproduces this mesenchymal migration. These findings together uncover a new migratory behavior on adhesive–nonadhesive alternate substrates in macrophages. Macrophages exhibit an exceptional mobility that they adopt a counterintuitive mesenchymal mode to migrate across the nonadhesive region on adhesive–nonadhesive alternate surfaces, which is insurmountable for other cell types. This motility is supported by podosomes formed on nonadhesive regions and can be enhanced by myosin IIA inhibition. This finding fills the void that mesenchymal migration can happen on nonadhesive surfaces.