iPSC-derived myelinoids to study myelin biology of humans

James, Owen G; Selvaraj, Bhuvaneish T.; Magnani, Dario; Burr, Karen; Connick, Peter; Barton, Samantha K.; Vasistha, Navneet A.; Hampton, David W.; Story, David; Śmigiel, Robert; Płoski, Rafał; Brophy, Peter; ffrench‐Constant, Charles; Lyons, David A.; Chandran, Siddharthan

doi:10.1016/j.devcel.2021.04.006

Cited by 51 publications

(60 citation statements)

References 84 publications

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“…In fact, the myelinic channel system, although not conceptualised as such in the respective publications, is visible throughout the recent literature by virtue of expression of fluorescent ‘reporter’ proteins and immunostaining. For example, in zebrafish myelin illuminated with soluble GFP (Almeida et al, 2011 ) or in human myelin following CNP staining of iPSC‐derived myelinoids (see Figure 2B in James et al, 2021 ). These data demonstrate that the drawings of Río Hortega, despite his own doubts, are not artefactual.…”

Section: Discussionmentioning

confidence: 99%

Río‐Hortega's drawings revisited with fluorescent protein defines a cytoplasm‐filled channel system of CNS myelin

et al. 2021

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A century ago this year, Pío del Río‐Hortega (1921) coined the term ‘oligodendroglia’ for the ‘interfascicular glia’ with very few processes, launching an extensive discovery effort on his new cell type. One hundred years later, we review his original contributions to our understanding of the system of cytoplasmic channels within myelin in the context of what we observe today using light and electron microscopy of genetically encoded fluorescent reporters and immunostaining. We use the term myelinic channel system to describe the cytoplasm‐delimited spaces associated with myelin; being the paranodal loops, inner and outer tongues, cytoplasm‐filled spaces through compact myelin and further complex motifs associated to the sheath. Using a central nervous system myelinating cell culture model that contains all major neural cell types and produces compact myelin, we find that td‐tomato fluorescent protein delineates the myelinic channel system in a manner reminiscent of the drawings of adult white matter by Río‐Hortega, despite that he questioned whether some cytoplasmic figures he observed represented artefact. Together, these data lead us to propose a slightly revised model of the ‘unrolled’ sheath. Further, we show that the myelinic channel system, while relatively stable, can undergo subtle dynamic shape changes over days. Importantly, we capture an under‐appreciated complexity of the myelinic channel system in mature myelin sheaths.

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Section: Discussionmentioning

confidence: 99%

Río‐Hortega's drawings revisited with fluorescent protein defines a cytoplasm‐filled channel system of CNS myelin

et al. 2021

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“…Human IPSC-derived models to study myelin disruption have been revised elsewhere [58]. Some new human models combining iPSC and novel in vitro cultures technologies [59][60][61][62][63] have emerged, but only two study showed quantitative assessment [63]. Here, we provide an extensive evaluation of myelin quantification and adequate reference compounds for the assessment of myelin disruption.…”

Section: Introductionmentioning

confidence: 99%

Human IPSC-Derived Model to Study Myelin Disruption

Chesnut

Paschoud

Repond

et al. 2021

IJMS

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Myelin is of vital importance to the central nervous system and its disruption is related to a large number of both neurodevelopmental and neurodegenerative diseases. The differences observed between human and rodent oligodendrocytes make animals inadequate for modeling these diseases. Although developing human in vitro models for oligodendrocytes and myelinated axons has been a great challenge, 3D cell cultures derived from iPSC are now available and able to partially reproduce the myelination process. We have previously developed a human iPSC-derived 3D brain organoid model (also called BrainSpheres) that contains a high percentage of myelinated axons and is highly reproducible. Here, we have further refined this technology by applying multiple readouts to study myelination disruption. Myelin was assessed by quantifying immunostaining/confocal microscopy of co-localized myelin basic protein (MBP) with neurofilament proteins as well as proteolipid protein 1 (PLP1). Levels of PLP1 were also assessed by Western blot. We identified compounds capable of inducing developmental neurotoxicity by disrupting myelin in a systematic review to evaluate the relevance of our BrainSphere model for the study of the myelination/demyelination processes. Results demonstrated that the positive reference compound (cuprizone) and two of the three potential myelin disruptors tested (Bisphenol A, Tris(1,3-dichloro-2-propyl) phosphate, but not methyl mercury) decreased myelination, while ibuprofen (negative control) had no effect. Here, we define a methodology that allows quantification of myelin disruption and provides reference compounds for chemical-induced myelin disruption.

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“…Similarly, organoids generated from the ventral spinal cord showed earlier myelination ( Figure 3F ). Moreover, electron microscopy revealed that in these organoids, called “myelinoids,” myelin thickness, compaction and assembly at the paranodal junction are comparable to those observed in vivo ( James et al, 2021 ), whereas forebrain-patterned organoids demonstrated sparse myelination and lacked the typical architecture of myelinated axons. These parameters are crucial to model myelin physiology and to recapitulate myelin function.…”

Section: Brain Organoids As New Experimental Systems For In Vitro Myelination Studiesmentioning

confidence: 77%

Novel in vitro Experimental Approaches to Study Myelination and Remyelination in the Central Nervous System

Marangon

Caporale

Boccazzi

et al. 2021

Front. Cell. Neurosci.

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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.

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iPSC-derived myelinoids to study myelin biology of humans

Cited by 51 publications

References 84 publications

Río‐Hortega's drawings revisited with fluorescent protein defines a cytoplasm‐filled channel system of CNS myelin

Río‐Hortega's drawings revisited with fluorescent protein defines a cytoplasm‐filled channel system of CNS myelin

Human IPSC-Derived Model to Study Myelin Disruption

Novel in vitro Experimental Approaches to Study Myelination and Remyelination in the Central Nervous System

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