Modelling the central nervous system: tissue engineering of the cellular microenvironment

Abstract

With the increasing prevalence of neurodegenerative diseases, improved models of the central nervous system (CNS) will improve our understanding of neurophysiology and pathogenesis, whilst enabling exploration of novel therapeutics. Studies of brain physiology have largely been carried out using in vivo models, ex vivo brain slices or primary cell culture from rodents. Whilst these models have provided great insight into complex interactions between brain cell types, key differences remain between human and rodent brains, such as degree of cortical complexity. Unfortunately, comparative models of human brain tissue are lacking. The development of induced Pluripotent Stem Cells (iPSCs) has accelerated advancement within the field of in vitro tissue modelling. However, despite generating accurate cellular representations of cortical development and disease, two-dimensional (2D) iPSC-derived cultures lack an entire dimension of environmental information on structure, migration, polarity, neuronal circuitry and spatiotemporal organisation of cells. As such, researchers look to tissue engineering in order to develop advanced biomaterials and culture systems capable of providing necessary cues for guiding cell fates, to construct in vitro model systems with increased biological relevance. This review highlights experimental methods for engineering of in vitro culture systems to recapitulate the complexity of the CNS with consideration given to previously unexploited biophysical cues within the cellular microenvironment.

Keywords: astrocytes; hydrogel; induced pluripotent stem cells; neuron; neuronal differentiation; tissue engineering.

Figure 1.. The brain microenvironment.

Complex cell–cell and cell–matrix interactions drive tissue construction and network formation. Heterogeneous cellular interaction is simplified to show neuronal (grey) and non-neuronal (green), here limited to myelinating oligodendrocytes, astrocytes and microglia. (a) Paracrine cell signalling with soluble molecules (yellow). (b) Contact dependent cell–cell signalling requiring complementary ligands and receptors. (c) Neuronal signalling occurs via propagation of electrical signals within myelinated neurons and chemical neurotransmitter release across synapses. Dynamic cell–matrix interactions produce a tissue specific microenvironment with multiscale hierarchical features both biochemical and biophysical in nature. (d) Direct cell–matrix interaction modulates cellular behaviour via biochemical and mechanical stimuli-receptor interaction leading to induction of intracellular signalling cascades, with mechanosensing of matrix proteins often acting upon the internal cytoskeleton of the cell to evoke a biophysical response i.e. migration. Cells degrade matrix components e.g. collagen triple helices & branched proteoglycans, to remodel the local microenvironment. Created with BioRender.com.