Myelinoid
Due to the complex nature of the human brain, there is a need for model systems which can closely mimic complicated biological processes.
Myelinoids provide a unique in vitro model through which myelin pathology, neurodegenerative diseases, developmental processes and therapeutic screening can be accomplished.
Monolayers, or 2D cultures, have been widely used in the past, however, they are limited by their lack of complexity and fail to recapitulate tissue architecture involved in biological processes occurring in vivo.
[4] Model organisms, such as Mus musculus, Caenorhabditis elegans, Drosophila melanogaster, and Saccharomyces cerevisiae, recapitulate biological complexity better than 2D monolayer cultures.
[15] However, a major constraint of cerebral organoids is that they lack robust myelin formation and are therefore not well suited to studies investigating white matter.
The process of generating these myelinated brain organoids lasted 210 days and involved the addition of various growth factors and media at specific time points.
[2] Due to the prolonged duration of the 2018 protocol, there were efforts to speed up and streamline the differentiation and generation of these myelinated organoids.
[1] In 2021, a group of researchers aimed to address the fact that the lengthy differentiation protocols renders myelinoids less practical for high throughput experimentation such as drug screening.
[19] To do this, scientists developed a human induced pluripotent stem cell (hiPSC) line that relies on early expression of an oligodendroglial gene which enabled the accelerated generation of myelinated organoids in just 42 days.
[2] A well established method used to efficiently differentiate hPSC into neural cells is by dual inhibition of SMAD signaling using dorsomorphin (also known as compound C) and SB431542.
The fundamentals of this workflow are generally used to obtain myelin organoids; however, various protocols that rely on it have introduced multiple modifications for different purposes.
[2] The generation of myelin organoids generally relies on neurocortical patterning factors that establish the structural and cellular framework necessary for the induction of oligodendrogenesis later on in the differentiation protocol.
[2] Therefore, the properties and components of myelin organoids in the early stages of differentiation are very similar to that observed in cerebral organoids where populations of neural progenitor cells, precursors of neurons and glial cells, start to emerge and self-organize into distinct layers that recapitulate features of the cortex during early embryogenesis.
[3] At such early stages, myelin organoids start to form large continuous neuroepithelial that encompass a fluid filled cavity representative of a brain ventricle.
[1][2] Further myelin maturation leads to distinct axonal subdomains with a paranodal axo-glial junction (PNJ) and node of Ranvier.
[2] Their results demonstrated that the myelinating oligocortical spheroids generated recapitulated the degrees of cellular pathology associated with the genetic variants, therefore can serve as models for understanding the relationships between PMD genotypes and phenotypes, which have not been fully characterized yet, therefore can serve as models for understanding the relationships between PMD genotypes and phenotypes, which have not been fully characterized yet.
[2][28][29] Clemastine and ketoconazole are promyelinating drugs that function as potent stimulators of oligodendrocyte generation and myelination in rodent models.
[30] Perinuclear retention of misfolded proteins is a hallmark of endoplasmic reticulum (ER) stress, which might be implicated in the pathology observed in PMD.
[32] The heterogeneity of oligodendrocytes was previously thought to be functionally homogeneous; however, distinct cell populations can be characterized through specific transcriptional signatures and gene ontology profiles.
[33] In 2020, researchers described an approach to obtain meaningful scRNA seq and assay for transposase-accessible chromatin using sequencing (ATAC-seq) data from brain organoids.
[34] Using the Orgo-Seq framework, three datasets (bRNA-seq from donor derived organoids, scRNA-seq data from cerebral organoids and fetal brains in precious studies, and bRNA-seq from the BrainSpan Project of human post-mortem brains) were used to study copy number variants in autism spectrum disorder.
Brain organoids serve as a human-derived model through which genetic variation and its impact on cell specific processes and association with neurodevelopmental and neurodegenerative disorders can be studied.
[34] With the absence of human brain tissue, myelinoids offer unprecedented opportunities for studying oligogenesis and myelination.
[2][3] While cerebral organoids form the brain cytoarchitecture and composition, they generally lack oligodendrocytes, the cells responsible for myelination in the central nervous system.
[2][19] Finally, the ability to generate myelinoids from patient derived hPSCs (induced-PSCs) offer major advantages and opportunities to explore patient-specific pathogenesis over the developmental and maturation stages of oligodendrocytes.
