Human IPSC-Derived Model to Study Myelin Disruption
Abstract
:1. Introduction
2. Results
2.1. Selection of Chemicals for Assay Development
2.1.1. Literature Review Results
2.1.2. Selection of Test Chemicals from Literature Review
2.2. Maturation of Oligodendrocyte and Expression of Myelin-Related Markers during BrainSphere Differentiation
2.3. Exposure to DNT Selected Compounds Alter Myelin in BrainSpheres
2.3.1. Cytotoxicity Assessment of Test Chemicals
2.3.2. Myelin Is Affected after Exposure of BrainSpheres to Chemicals Inducing DNT
3. Discussion
4. Materials and Methods
4.1. Literature Review to Identify Test Chemicals
Study Prioritization and Selection
4.2. Generation of Neural Progenitor Cells from Human Induced Pluripotent Stem Cells
4.3. Generation of the 3D Human Brain Model (BrainSpheres)
4.4. Chemical Exposure
4.5. Cell Viability Assessment
4.6. Immunocytochemical Staining and Confocal Imaging
4.7. Myelin Quantification
4.8. Gene Expression Analysis
4.9. Western Blot
4.10. Statistical Analyses
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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String | Combined with OR | Combined with OR | Combined with OR | ||
---|---|---|---|---|---|
1 | Embryonic and fetal development, embryonic structures, embryonic, embryo, embryos, embryology, fetal, fetus, pregnancy, gestation, gestational, in utero, prenatal neonatal, neonate, perinatal, postnatal, infant, adolescent, child, fetal brain, human development, developing brain, neurodevelopmental, neurodevelopment | AND | Pharmacological and toxicological phenomena and processes, toxicology, toxicity, toxicity tests, toxicant, toxicants, toxin, toxins, toxic actions, neurotoxicant, neurotoxicants, neurotoxin, neurotoxins, neurotoxins, pharmacology, pharmacologic actions, specialty uses of chemicals, organic chemicals, inorganic chemicals, environment and public health, exposure, exposures, environmental chemical, environmental chemicals, environmental health, hazard, hazards, hazardous, xenobiotics | AND | Myelin, oligodendroglia, myelin sheath, myelinogenesis, myelination, myelin proteins, oligodendrocyte, oligodendrocytes, oligodendrogenesis, white matter, dysmyelination, dysmyelinating, demyelination, demyelinating |
2 | Developmental neurotoxicant, developmental neurotoxicants, developmental neurotoxin, developmental neurotoxin, developmental neurotoxicity, neurodevelopmental toxicity, neurodevelopmental disorder, prenatal injuries, maternal exposure, teratogen, teratogens, teratogenic |
Inclusion Criteria | Exclusion Criteria |
---|---|
DNT is investigated with appropriate exposure scenarios (e.g., prenatal maternal, infant, or childhood exposure (in vivo), exposure during cell proliferation, differentiation, migration, myelination, or synaptogenesis (in vitro)) | DNT is not investigated |
A single chemical exposure is reported with a clearly identified chemical name or CAS number, or a chemical mixture is reported with human relevance | A chemical exposure is not reported, a mixture of chemicals is reported without human relevance, chemicals are not clearly identified, or exposures are psychosocial (e.g., stress or socioeconomic status), physical (e.g., radiation, particulate matter, or nanomaterials), or intrinsic biological traits (e.g., genetic mutations) |
At least two dose or concentration levels are tested or a single dose is tested but was chosen based on previous experience with multiple doses or on human exposure levels | One dose or concentration is tested but was not chosen based on previous experience with multiple doses or on human exposure levels |
DNT was evident at doses or concentrations lower than those which cause maternal toxicity (in vivo), general toxicity (in vivo), or cytotoxicity (in vitro) | The relationship between DNT and other forms of toxicity were not described or DNT was only evident at doses that also caused maternal toxicity (in vivo), general toxicity (in vivo), or cytotoxicity (in vitro) |
A chemical was characterized as a developmental neurotoxicant using endpoints associated with myelination in the central nervous system (e.g., markers or levels of oligodendrocyte differentiation or MBP gene expression), or a chemical was tested using endpoints associated with myelination during neurodevelopment but found to have no effect | A chemical was not characterized as a developmental neurotoxicant or was characterized using endpoints not associated with myelination, or only with peripheral nervous system myelination |
Studies with appropriate negative and solvent controls or control groups | Studies without appropriate negative and solvent controls or control groups |
Name | Abbreviation | Brand | Reference |
---|---|---|---|
Neurofilament 200 | NF | Sigma | N4142 |
Myelin basic protein | MBP | BioLegend | 808402 |
Proteolipid protein 1 | PLP1 | Biorad | MCA839G |
Oligodendrocyte marker 4 | O4 | R&D systems | MAB1326 |
Glial fibrillary acidic protein | GFAP * | Sigma | G9269 |
S100 calcium-binding protein B | S100B * | Abcam | ab52642 |
Gene Name | Abbreviation | Taqman® Assay ID |
---|---|---|
Neural-glial antigen 2 (chondroitin sulfate proteoglycan 4) | NG2 (CSPG4) | Hs00361541_g1 |
Oligodendrocyte transcription factor 1 | OLIG1 | Hs00744293_s1 |
Oligodendrocyte transcription factor 2 | OLIG2 | Hs00300164_s1 |
SOX-10 transcription factor | SOX10 | Hs00366918_m1 |
Adenomatous polyposis coli | APC | Hs01568269_m1 |
Proteolipid protein 1 | PLP1 | Hs00166914_m1 |
2′,3′-Cyclic-nucleotide 3′-phosphodiesterase | CNP | Hs00263981_m1 |
Myelin oligodendrocyte glycoprotein | MOG | Hs01555268_m1 |
Myelin basic protein | MBP | Hs00921945_m1 |
Housekeeping Genes | Abbreviation | Taqman® Assay ID |
β-actin | ACTB | Hs01060665_g1 |
18S | 18S | Hs999999_01 |
Glyceraldehyde 3-phosphate dehydrogenase | GAPDH | Hs02786624_g1 |
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Chesnut, M.; Paschoud, H.; Repond, C.; Smirnova, L.; Hartung, T.; Zurich, M.-G.; Hogberg, H.T.; Pamies, D. Human IPSC-Derived Model to Study Myelin Disruption. Int. J. Mol. Sci. 2021, 22, 9473. https://doi.org/10.3390/ijms22179473
Chesnut M, Paschoud H, Repond C, Smirnova L, Hartung T, Zurich M-G, Hogberg HT, Pamies D. Human IPSC-Derived Model to Study Myelin Disruption. International Journal of Molecular Sciences. 2021; 22(17):9473. https://doi.org/10.3390/ijms22179473
Chicago/Turabian StyleChesnut, Megan, Hélène Paschoud, Cendrine Repond, Lena Smirnova, Thomas Hartung, Marie-Gabrielle Zurich, Helena T. Hogberg, and David Pamies. 2021. "Human IPSC-Derived Model to Study Myelin Disruption" International Journal of Molecular Sciences 22, no. 17: 9473. https://doi.org/10.3390/ijms22179473