Modulating motility of intracellular vesicles in cortical neurons with nanomagnetic forces on-chip

Abstract

Vesicle transport is a major underlying mechanism of cell communication. Inhibiting vesicle transport in brain cells results in blockage of neuronal signals, even in intact neuronal networks. Modulating intracellular vesicle transport can have a huge impact on the development of new neurotherapeutic concepts, but only if we can specifically interfere with intracellular transport patterns. Here, we propose to modulate motion of intracellular lipid vesicles in rat cortical neurons based on exogenously bioconjugated and cell internalized superparamagnetic iron oxide nanoparticles (SPIONs) within microengineered magnetic gradients on-chip. Upon application of 6–126 pN on intracellular vesicles in neuronal cells, we explored how the magnetic force stimulus impacts the motion pattern of vesicles at various intracellular locations without modulating the entire cell morphology. Altering vesicle dynamics was quantified using, mean square displacement, a caging diameter and the total traveled distance. We observed a de-acceleration of intercellular vesicle motility, while applying nanomagnetic forces to cultured neurons with SPIONs, which can be explained by a decrease in motility due to opposing magnetic force direction. Ultimately, using nanomagnetic forces inside neurons may permit us to stop the mis-sorting of intracellular organelles, proteins and cell signals, which have been associated with cellular dysfunction. Furthermore, nanomagnetic force applications will allow us to wirelessly guide axons and dendrites by exogenously using permanent magnetic field gradients.

Force-Mediating Magnetic Nanoparticles to Engineer Neuronal Cell Function

“…The advancement came through microfabricating up to 10,000 parallelized arrays of magnetic field gradient. The fabrication approach based on permalloy, borrowed from solid state devices, was integrated into cell culture chips of the size of few millimeters (Tseng et al, 2012 ; Kunze et al, 2015 , 2017 ; Murray et al, 2016 ; Tay et al, 2016a ). Acoustic tweezers are also used to move and modulate intracellular trafficking.…”

“…(Meister, 2016 ) (C) Overview of experimentally reported force ranges indicating significant changes in neuronal cell function and morphology induced through a force stimulus. The list highlights general reported mechanical sensitivity for neurons (GS), (Zablotskii et al, 2016a , b ) force mediated calcium induction (CI), (Calabrese et al, 2002 ; Matthews et al, 2010 ; Maneshi et al, 2014 ; Tay et al, 2016a ) force mediated cell migration/displacement (CM), (Kunze et al, 2015 ) force mediated modulation of vesicle motion (VM), (Kunze et al, 2017 ) force mediated protein positioning (PO), (Kunze et al, 2015 ) force mediated axon towing and stretching (AT), (Bray, 1984 ; Suter and Miller, 2011 ) and force mediated filopodia/growth cone stretching (FS). (Franze, 2013 ).…”

“…A comprehensive review about these approaches is provided by van Bergeijk et al ( 2016 ) A genetically, or chemically independent approach to vesicle transport is through the application of mechanical forces. Two distinct methods employ mechanical tension on transport dynamics of vesicles in neuronal cells (Siechen et al, 2009 ; Ahmed et al, 2012 , 2013 ; Kunze et al, 2017 ). The difference between the two methods are depicted in Figure 6 .…”

“…Forces inside a cell, called intracellular forces, play an important role during the regulation of a wide range of cellular processes like membrane protrusion, (Ji et al, 2008 ) cell migration and spreading, (Galbraith and Sheetz, 1998 ; Pita-Thomas et al, 2015 ), or transport of intracellular organelles (Svoboda and Block, 1994 ; Visscher et al, 1999 ; Klumpp and Lipowsky, 2005 ; Kunze et al, 2017 ). These forces can be generated by the cell itself or be imposed on the cell through a force-mediating object or changes in the extracellular environment.…”

“…In the brain, forces are widely associated with traumatic brain injury, where a physical change in the extracellular environment imposes sheer on the brain cells that can lead into damages at the neuronal cell network (Bigler, 2001 ; Matthew Hemphill et al, 2015 ), or induce inflammatory neurodegenerative signals (Maneshi et al, 2014 ). Recent technical advances in capturing mechanical aspects of brain cells in culture have revealed insights into different magnitudes of forces and their impact on regulating brain cell function like calcium signaling (Calabrese et al, 2002 ; Tay et al, 2016a ; Tay and Di Carlo, 2017 ), neurite elongation (Bray, 1984 ; Kunze et al, 2015 ; Pita-Thomas et al, 2015 ), or vesicle movement (Ahmed et al, 2012 ; Kunze et al, 2017 ). These force-mediated cell functions let us hypothesize that forces in the brain may not only cause lesions, far more, they may be used to our advantage in next-generation neurotherapeutic devices.…”