Using MS induced pluripotent stem cells to investigate MS aetiology

Fortune, Alastair J; Fletcher, Jessica L.; Blackburn, Nicholas B.; Young, Karen

doi:10.1016/j.msard.2022.103839

Cited by 9 publications

(7 citation statements)

References 130 publications

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“…Disruption of OL development and/or function is associated with a variety of disorders such as MS, LD, SCZ, and ASD ( Mighdoll et al, 2015 ; Birey et al, 2017 ; Inamura et al, 2018 ; Phan et al, 2020 ; Fortune et al, 2022 ). A major focus in the field is to model these disorders using hiPSC-derived OLs to inform us about disease mechanisms that can be targeted for therapeutic intervention and for screening compounds for promyelinating potential.…”

Section: The Use Of Ipsc-derived Oligodendrocytes To Study Demyelinat...mentioning

confidence: 99%

“…These demyelinated lesions cause inflammation which stimulates the cytotoxic T-cells to travel to the lesion and damage the neurons ( Hafler et al, 2005 ). A key pathology of MS is that the damaged myelin cannot be quickly re-myelinated, exposing the axons to attack by the immune system ( Fortune et al, 2022 ). Usually following demyelination events, resident OPCs regenerate myelination to restore the saltatory conduction and neurological function, but this process of remyelination declines with age and duration of illness ( Chari, 2007 ; Koutsoudaki et al, 2020 ; Mozafari et al, 2020 ).…”

Section: The Use Of Ipsc-derived Oligodendrocytes To Study Demyelinat...mentioning

confidence: 99%

“…A genome wide association study of MS identified 233 independent genetic variants associated with genetic risk for MS ( International Multiple Sclerosis Genetics Consortium (IMSGC), et al, 2013 ), and thus the polygenic nature of MS severely limits the generation of animal models based on genetic risk. However, these challenges are beginning to be addressed with the use of MS patient-derived hiPSCs models which contain each individual patient’s set of common variants of risk ( Fortune et al, 2022 ).…”

Section: The Use Of Ipsc-derived Oligodendrocytes To Study Demyelinat...mentioning

confidence: 99%

“…Demyelinating disorders are complex, multifactorial conditions that lead to profound nervous system dysfunction. Recently, the paradigm has shifted to studying the disruption of glial cells, such as oligodendrocytes and astrocytes, as potential causes of neurological dysfunction in several disorders, such as Multiple sclerosis (MS), Leukodystrophy (LD), Schizophrenia (SCZ), and Autism spectrum disorder (ASD), where dysmyelination is observed concomitantly or as the predecessor of neuronal dysfunction ( Mighdoll et al, 2015 ; Birey et al, 2017 ; Inamura et al, 2018 ; Phan et al, 2020 ; Fortune et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

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Utilizing hiPSC-derived oligodendrocytes to study myelin pathophysiology in neuropsychiatric and neurodegenerative disorders.

Shim,

Romero-Morales,

Sripathy

et al. 2024

Front. Cell. Neurosci.

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Oligodendrocytes play a crucial role in our central nervous system (CNS) by myelinating axons for faster action potential conduction, protecting axons from degeneration, structuring the position of ion channels, and providing nutrients to neurons. Oligodendrocyte dysfunction and/or dysmyelination can contribute to a range of neurodegenerative diseases and neuropsychiatric disorders such as Multiple Sclerosis (MS), Leukodystrophy (LD), Schizophrenia (SCZ), and Autism Spectrum Disorder (ASD). Common characteristics identified across these disorders were either an inability of oligodendrocytes to remyelinate after degeneration or defects in oligodendrocyte development and maturation. Unfortunately, the causal mechanisms of oligodendrocyte dysfunction are still uncertain, and therapeutic targets remain elusive. Many studies rely on the use of animal models to identify the molecular and cellular mechanisms behind these disorders, however, such studies face species-specific challenges and therefore lack translatability. The use of human induced pluripotent stem cells (hiPSCs) to model neurological diseases is becoming a powerful new tool, improving our understanding of pathophysiology and capacity to explore therapeutic targets. Here, we focus on the application of hiPSC-derived oligodendrocyte model systems to model disorders caused by oligodendrocyte dysregulation.

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Section: The Use Of Ipsc-derived Oligodendrocytes To Study Demyelinat...mentioning

confidence: 99%

Section: The Use Of Ipsc-derived Oligodendrocytes To Study Demyelinat...mentioning

confidence: 99%

Section: The Use Of Ipsc-derived Oligodendrocytes To Study Demyelinat...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Utilizing hiPSC-derived oligodendrocytes to study myelin pathophysiology in neuropsychiatric and neurodegenerative disorders.

Shim,

Romero-Morales,

Sripathy

et al. 2024

Front. Cell. Neurosci.

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“…iPSC-derived pericytes (iPericytes) are increasingly used in place of primary pericyte lines to model pericyte function in health and disease [ 6 – 11 ]. iPericytes have several advantages over primary pericyte lines, as they can be derived from iPSCs reprogrammed from individuals of various genetic backgrounds and disease diagnoses [ 12 ], allowing them to be used for basic biological studies as well as disease modelling or phenotyping. It is also possible to co-culture iPericytes with cells derived from the same iPSC line, to model the neurovascular unit (NVU) [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Induced pluripotent stem cell derived pericytes respond to mediators of proliferation and contractility

King,

Courtney,

Brown

et al. 2024

Stem Cell Res Ther

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Background Pericytes are multifunctional contractile cells that reside on capillaries. Pericytes are critical regulators of cerebral blood flow and blood–brain barrier function, and pericyte dysfunction may contribute to the pathophysiology of human neurological diseases including Alzheimers disease, multiple sclerosis, and stroke. Induced pluripotent stem cell (iPSC)-derived pericytes (iPericytes) are a promising tool for vascular research. However, it is unclear how iPericytes functionally compare to primary human brain vascular pericytes (HBVPs). Methods We differentiated iPSCs into iPericytes of either the mesoderm or neural crest lineage using established protocols. We compared iPericyte and HBVP morphologies, quantified gene expression by qPCR and bulk RNA sequencing, and visualised pericyte protein markers by immunocytochemistry. To determine whether the gene expression of neural crest iPericytes, mesoderm iPericytes or HBVPs correlated with their functional characteristics in vitro, we quantified EdU incorporation following exposure to the key pericyte mitogen, platelet derived growth factor (PDGF)-BB and, contraction and relaxation in response to the vasoconstrictor endothelin-1 or vasodilator adenosine, respectively. Results iPericytes were morphologically similar to HBVPs and expressed canonical pericyte markers. However, iPericytes had 1864 differentially expressed genes compared to HBVPs, while there were 797 genes differentially expressed between neural crest and mesoderm iPericytes. Consistent with the ability of HBVPs to respond to PDGF-BB signalling, PDGF-BB enhanced and a PDGF receptor-beta inhibitor impaired iPericyte proliferation. Administration of endothelin-1 led to iPericyte contraction and adenosine led to iPericyte relaxation, of a magnitude similar to the response evoked in HBVPs. We determined that neural crest iPericytes were less susceptible to PDGFR beta inhibition, but responded most robustly to vasoconstrictive mediators. Conclusions iPericytes express pericyte-associated genes and proteins and, exhibit an appropriate physiological response upon exposure to a key endogenous mitogen or vasoactive mediators. Therefore, the generation of functional iPericytes would be suitable for use in future investigations exploring pericyte function or dysfunction in neurological diseases.

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