title: Engineering cortical neuron polarity with nanomagnets on a chip.
abstract: Intra- and extracellular signaling play critical roles in cell polarity, ultimately leading to the development of functional cell-cell connections, tissues, and organs. In the brain, pathologically oriented neurons are often the cause for disordered circuits, severely impacting motor function, perception, and memory. Aside from control through gene expression and signaling pathways, it is known that nervous system development can be manipulated by mechanical stimuli (e.g., outgrowth of axons through externally applied forces). The inverse is true as well: intracellular molecular signals can be converted into forces to yield axonal outgrowth. The complete role played by mechanical signals in mediating single-cell polarity, however, remains currently unclear. Here we employ highly parallelized nanomagnets on a chip to exert local mechanical stimuli on cortical neurons, independently of the amount of superparamagnetic nanoparticles taken up by the cells. The chip-based approach was utilized to quantify the effect of nanoparticle-mediated forces on the intracellular cytoskeleton as visualized by the distribution of the microtubule-associated protein tau. While single cortical neurons prefer to assemble tau proteins following poly-L-lysine surface cues, an optimal force range of 4.5-70 pN by the nanomagnets initiated a tau distribution opposed to the pattern cue. In larger cell clusters (groups comprising six or more cells), nanoparticle-mediated forces induced tau repositioning in an observed range of 190-270 pN, and initiation of magnetic field-directed cell displacement was observed at forces above 300 pN. Our findings lay the groundwork for high-resolution mechanical encoding of neural networks in vitro, mechanically driven cell polarization in brain tissues, and neurotherapeutic approaches using functionalized superparamagnetic nanoparticles to potentially restore disordered neural circuits.
authors: †Department of Bioengineering, ‡California NanoSystems Institute, and §Department of Neurobiology, University of California, Los Angeles, California 90095, United States.
authors: Anja
authors: A
authors: Kunze
authors: †Department of Bioengineering, ‡California NanoSystems Institute, and §Department of Neurobiology, University of California, Los Angeles, California 90095, United States.
authors: Peter
authors: P
authors: Tseng
authors: †Department of Bioengineering, ‡California NanoSystems Institute, and §Department of Neurobiology, University of California, Los Angeles, California 90095, United States.
authors: Chanya
authors: C
authors: Godzich
authors: †Department of Bioengineering, ‡California NanoSystems Institute, and §Department of Neurobiology, University of California, Los Angeles, California 90095, United States.
authors: Coleman
authors: C
authors: Murray
authors: †Department of Bioengineering, ‡California NanoSystems Institute, and §Department of Neurobiology, University of California, Los Angeles, California 90095, United States.
authors: Anna
authors: A
authors: Caputo
authors: †Department of Bioengineering, ‡California NanoSystems Institute, and §Department of Neurobiology, University of California, Los Angeles, California 90095, United States.
authors: Felix E
authors: FE
authors: Schweizer
authors: †Department of Bioengineering, ‡California NanoSystems Institute, and §Department of Neurobiology, University of California, Los Angeles, California 90095, United States.
authors: Dino
authors: D
authors: Di Carlo
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000737:chemistry / Q000494:pharmacology; D001696:Biomechanical Phenomena; D001921:Brain / Q000166:cytology*; D060846:Cell Engineering / Q000379:methods*; D016764:Cell Polarity / Q000187:drug effects; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D059346:Magnets; D053758:Nanoparticles; D036103:Nanotechnology / Q000379:methods*; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D016875:tau Proteins / Q000378:metabolism
chemical_list: D001672:Biocompatible Materials; D016875:tau Proteins
keywords: bipolar force interrogation; dissociated cortical neurons; functionalized superparamagnetic nanoparticles; magnetic BioMEMS; magnetic field gradients; protein polarization; tau