Abstract
Little is known about how cells assemble as systems during corticogenesis to generate collective functions. We built a neurobiology platform that consists of fetal rat cerebral cortical cells grown within 3D silk scaffolds (SF). Ivermectin (Ivm), a glycine receptor (GLR) agonist, was used to modulate cell resting membrane potential (Vmem) according to methods described in a previous work that implicated Ivm in the arrangement and connectivity of cortical cell assemblies. The cells developed into distinct populations of neuroglial stem/progenitor cells, mature neurons or epithelial-mesenchymal cells. Importantly, the synchronized electrical activity in the newly developed cortical assemblies could be recorded as local field potential (LFP) measurements. This study therefore describes the first example of the development of a biologically relevant cortical plate assembly outside of the body. This model provides i) a preclinical basis for engineering cerebral cortex tissue autografts and ii) a biofidelic 3D culture model for investigating biologically relevant processes during the functional development of cerebral cortical cellular systems.
Highlights
IntroductionMitochondria, as the drivers of cellular metabolism, play dynamic roles in neuronal differentiation (Supplementary Figure S1) and activity[11]
Our study describes the changes in mitochondria shape and Δ Ψ m that occur during differentiation in rat E18 cerebral cortical cellular systems (Supplementary Data S2)
Co-cultures showed a significantly higher level of mitochondrial activity than the neuron or astrocyte cultures at both 1 wk and 3 wks, and there was no difference between the cells that were treated with induced cytotoxicity25. Unlike the Vmem (Ivm) and the control cells (Fig. 2A,B)
Summary
Mitochondria, as the drivers of cellular metabolism, play dynamic roles in neuronal differentiation (Supplementary Figure S1) and activity[11]. Vmem has been used as a physiological starting point for examining changes during the stages of cellular proliferation and differentiation[16] and it is required for persistent directional cell migration[17]. Both of these are fundamental biological processes during tissue development. We used Ivm (1 μ M) to control Vmem via GLR in the context of neuronal differentiation and growth (Supplementary Figure S3). In contrast to its specific activity on GLR, Ivm does not display agonist activity at the other mentioned receptors[20]
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