Developing a human iPSC-derived three-dimensional myelin spheroid platform for modeling myelin diseases

Recognizing the Beauty of Myelination through Identifying Sites of Phospholipid, Protein, and RNA Syntheses and Characterizing Their Movements in Myelin Internodes

“…3) Use other bio-orthogonal precursors to identify sites where other phospholipids, cholesterol, galactocerebroside and sulfatide are synthesized in CNS and PNS and characterize movements from these sites into and through myelin. 4) Use these precursors in vitro settings, e.g., neuron-Schwann cell co-cultures [116][117][118][119][120], oligodendrocyte-neuron co-cultures [121][122][123][124][125], brain and spinal cord slice preparations and brain and spinal cord organoids [126][127][128]. Improved resolution will enable these expansions.…”

Induced Pluripotent Stem Cells and Organoids in Advancing Neuropathology Research and Therapies

“…Another study involved engrafting mice with wild-type ASPA gene iPSCs [122] but did not specifically target CD as a study model. Notably, only one study developed a 3D culture protocol specifically tailored for CD, a rare leukodystrophy resulting from the loss of function in the aspartoacylase (ASPA) gene, which affects altered ASPA-expressing mature oligodendrocytes of the CNS [123]. Despite the limited number of articles, all of them have demonstrated promising results in treatment, modeling, and potentially translational studies.…”

Myelin organoids for the study of Alzheimer's disease

“…Human iPSCs can be differentiated into oligodendrocytes by mimicking the in vivo developmental trajectory of oligodendroglia (Douvaras and Fossati, 2015 ; Li et al, 2018 ; Liu et al, 2023 ). Similarly, exposure of differentiating brain organoids to factors that promote oligodendrocyte fate, including thyroid hormone (T3), insulin-like growth factor 1 (IGF-1), and platelet-derived growth factor AA (PDGF-AA), yields oligodendrocyte-containing myelinoids (Madhavan et al, 2018 ; Kim et al, 2019 ; Marton et al, 2019 ; James et al, 2021 ; Feng et al, 2023 ). Accelerated differentiation of oligodendrocytes in neural spheroids can also be achieved by overexpression of master transcription factors involved in oligodendrogenesis, SOX10 and OLIG2 (Ma et al, 2022 ).…”

“…Moreover, varying observations of myelin dysfunction in AD mouse models across different studies (Zhang et al, 2020 ; Chen J. F. et al, 2021 ; Depp et al, 2023 ) further support the use of myelinoids to clarify disease-relevant phenotypes. Feng et al ( 2023 ), James et al ( 2021 ), and Madhavan et al ( 2018 ) have shown that myelinoids recapitulate key aspects of genetic myelin disorders, including Canavan disease (CD) and Pelizaeus–Merzbacher disease. For example, exposure of aspartoacylase (ASPA)-deficient myelinoids derived from iPSCs of CD patients to N-acetyl-aspartate (NAA) induces extensive damage to myelin sheaths, mimicking spongy degeneration of the white matter in CD patients (Feng et al, 2023 ).…”

“…Feng et al ( 2023 ), James et al ( 2021 ), and Madhavan et al ( 2018 ) have shown that myelinoids recapitulate key aspects of genetic myelin disorders, including Canavan disease (CD) and Pelizaeus–Merzbacher disease. For example, exposure of aspartoacylase (ASPA)-deficient myelinoids derived from iPSCs of CD patients to N-acetyl-aspartate (NAA) induces extensive damage to myelin sheaths, mimicking spongy degeneration of the white matter in CD patients (Feng et al, 2023 ). Furthermore, myelinoids are responsive to pharmacological intervention; for example, pro-myelinating drugs ketoconazole and clemastine promote oligodendrogenesis in myelinoids (Madhavan et al, 2018 ).…”