Abstract
Myelin is the lipidic insulating structure enwrapping axons and allowing fast saltatory nerve conduction. In the central nervous system, myelin sheath is the result of the complex packaging of multilamellar extensions of oligodendrocyte (OL) membranes. Before reaching myelinating capabilities, OLs undergo a very precise program of differentiation and maturation that starts from OL precursor cells (OPCs). In the last 20 years, the biology of OPCs and their behavior under pathological conditions have been studied through several experimental models. When co-cultured with neurons, OPCs undergo terminal maturation and produce myelin tracts around axons, allowing to investigate myelination in response to exogenous stimuli in a very simple in vitro system. On the other hand, in vivo models more closely reproducing some of the features of human pathophysiology enabled to assess the consequences of demyelination and the molecular mechanisms of remyelination, and they are often used to validate the effect of pharmacological agents. However, they are very complex, and not suitable for large scale drug discovery screening. Recent advances in cell reprogramming, biophysics and bioengineering have allowed impressive improvements in the methodological approaches to study brain physiology and myelination. Rat and mouse OPCs can be replaced by human OPCs obtained by induced pluripotent stem cells (iPSCs) derived from healthy or diseased individuals, thus offering unprecedented possibilities for personalized disease modeling and treatment. OPCs and neural cells can be also artificially assembled, using 3D-printed culture chambers and biomaterial scaffolds, which allow modeling cell-to-cell interactions in a highly controlled manner. Interestingly, scaffold stiffness can be adopted to reproduce the mechanosensory properties assumed by tissues in physiological or pathological conditions. Moreover, the recent development of iPSC-derived 3D brain cultures, called organoids, has made it possible to study key aspects of embryonic brain development, such as neuronal differentiation, maturation and network formation in temporal dynamics that are inaccessible to traditional in vitro cultures. Despite the huge potential of organoids, their application to myelination studies is still in its infancy. In this review, we shall summarize the novel most relevant experimental approaches and their implications for the identification of remyelinating agents for human diseases such as multiple sclerosis.
Highlights
Myelin is a very specialized lipidic insulating structure that allows rapid and efficient conduction of nerve impulses
Neurotransmitters, axonal signals, morphogens, cytokines, and extracellular matrix (ECM) proteins can all contribute to changing the fate of OL precursor cells (OPCs), modulating their maturation timing, promoting their local migration, or keeping them undifferentiated to maintain a pool of slowly proliferating cells (Nishiyama et al, 2021a)
This study revealed that both axon diameter and ligand type can play a role in OL response in the presence of axon-like mechanical stiffness and it may represent the basis for the generation of engineered environments that reflect key pathophysiological, mechanical, geometric, and biochemical components of the glial microenvironment for myelination assays
Summary
Myelin is a very specialized lipidic insulating structure that allows rapid and efficient conduction of nerve impulses. OPCs, highly dividing cells during embryogenesis, become relatively quiescent (but not silent) during adulthood, when they still represent an important source of potential remyelinating OLs after injury (Nishiyama et al, 2021a) During their differentiation to mature myelinating cells, OPCs make contacts with other glial cells and neurons with which they can form synapses and gap junctions, and they continuously refine their intrinsic program based on extracellular cues and inputs received from contacted cells. Intrinsic differences in oligodendroglia biology between humans and rodents is reflected in differences in the OPC pool (Dietz et al, 2016) For this reason, cellular reprogramming from human derived cells (typically dermal fibroblasts) into induced pluripotent stem cells (iPSCs) and into terminally differentiated OLs is increasingly becoming an important means to assess the effect of pharmacological agents on OPC maturation and axonal myelination both in physiological conditions and after insults. We shall describe the classic methods used to study myelination and remyelination in vitro, we shall introduce some of the most recent methods, their limits, and their potential relevance in the field (Figure 1), and shall describe the most relevant implications in the identification of remyelinating agents for human diseases
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