In silico neuritogenesis model underpins mechanical interactionswith extracellular matrix as determinants of persistent axonal growthin stiffer microenvironments

Abstract

It has been broadly recognized that the crosstalk between cells and their extracellular matrix (ECM) is crucial for the proper function of biological tissues. Relatively recently the role of ECM came in focus in the context of neuronal development and regeneration, where the effects of the ECM mechanics on the migration of neurons and neurite growth are still incompletely understood. Here we present an in silico twin framework for neurite growth focusing on its biophysical interactions with the ECM. This coarsegrained model accounts for viscoelastic liquid- and solid-like ECMs and neurite growth by ECM-mediated traction forces. Resulting growth trajectories can be rationalized based on the theory of random walks and polymer physics. To critically assess models predictive power, we performed experiments on neurites of hippocampal rat neurons growing in 3D collagen gels and observed a more persistent axon outgrowth in denser matricies. The model fully recapitulated the effect, thereby underpinning the central role of mechanical interactions with ECM as guiding principle of axonal growth. We argue that a combination our model with optical microscopy may provide an is silico twin helping to disentangle the contributions of "passive" physics from more complex effects of chemical queues or an apparent mechanosensing.