title: Stochastic nanoroughness modulates neuron-astrocyte interactions and function via mechanosensing cation channels.
abstract: Extracellular soluble signals are known to play a critical role in maintaining neuronal function and homeostasis in the CNS. However, the CNS is also composed of extracellular matrix macromolecules and glia support cells, and the contribution of the physical attributes of these components in maintenance and regulation of neuronal function is not well understood. Because these components possess well-defined topography, we theorize a role for topography in neuronal development and we demonstrate that survival and function of hippocampal neurons and differentiation of telencephalic neural stem cells is modulated by nanoroughness. At roughnesses corresponding to that of healthy astrocytes, hippocampal neurons dissociated and survived independent from astrocytes and showed superior functional traits (increased polarity and calcium flux). Furthermore, telencephalic neural stem cells differentiated into neurons even under exogenous signals that favor astrocytic differentiation. The decoupling of neurons from astrocytes seemed to be triggered by changes to astrocyte apical-surface topography in response to nanoroughness. Blocking signaling through mechanosensing cation channels using GsMTx4 negated the ability of neurons to sense the nanoroughness and promoted decoupling of neurons from astrocytes, thus providing direct evidence for the role of nanotopography in neuron-astrocyte interactions. We extrapolate the role of topography to neurodegenerative conditions and show that regions of amyloid plaque buildup in brain tissue of Alzheimer's patients are accompanied by detrimental changes in tissue roughness. These findings suggest a role for astrocyte and ECM-induced topographical changes in neuronal pathologies and provide new insights for developing therapeutic targets and engineering of neural biomaterials.
authors.affiliation: Institute for Macromolecular Chemistry, BIOSS Centre for Biological Signalling Studies, and.
authors.forename: Nils R
authors.initials: NR
authors.lastname: Blumenthal
authors.affiliation: Department of Neuroscience, Karolinska Institutet, SE17177 Stockholm, Sweden.
authors.forename: Ola
authors.initials: O
authors.lastname: Hermanson
authors.affiliation: Department of Neuroanatomy, University of Freiburg, 79104 Freiburg, Germany; and.
authors.forename: Bernd
authors.initials: B
authors.lastname: Heimrich
authors.affiliation: Institute for Macromolecular Chemistry, BIOSS Centre for Biological Signalling Studies, and prasad.shastri@gmail.com.
authors.forename: V Prasad
authors.initials: VP
authors.lastname: Shastri
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000401:mortality; D000818:Animals; D001253:Astrocytes / Q000473:pathology; D015220:Calcium Channels / Q000378:metabolism*; D002450:Cell Communication; D002454:Cell Differentiation; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D040542:Mechanotransduction, Cellular; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D016716:PC12 Cells; D010455:Peptides / Q000494:pharmacology; D051381:Rats; D013111:Spider Venoms / Q000494:pharmacology
chemical_list: D015220:Calcium Channels; D036341:Intercellular Signaling Peptides and Proteins; C411249:MTx4 protein, Grammostola spatulata; D010455:Peptides; D013111:Spider Venoms
keywords: FAM38A; Piezo-1; mechanotransduction; polarization; stretch-activated channels