Generation and Characterization of Human iPSC-Derived Astrocytes with Potential for Modeling X-Linked Adrenoleukodystrophy Phenotypes
Open accessAbstract
X-adrenoleukodystrophy (X-ALD) is a peroxisomal metabolic disorder caused by mutations in the ABCD1 gene encoding the peroxisomal ABC transporter adrenoleukodystrophy protein (ALDP). Similar mutations in ABCD1 may result in a spectrum of phenotypes in males with slow progressing adrenomyeloneuropathy (AMN) and fatal cerebral adrenoleukodystrophy (cALD) dominating most cases. Mouse models of X-ALD do not capture the phenotype differences and an appropriate model to investigate the mechanism of disease onset and progress remains a critical need. Here, we generated induced pluripotent stem cell (iPSC) lines from skin fibroblasts of two each of apparently healthy control, AMN, and cALD patients with non-integrating mRNA-based reprogramming. iPSC lines expanded normally and expressed pluripotency markers Oct4, SOX2, NANOG, SSEA, and TRA-1–60. Expression of markers SOX17, Brachyury, Desmin, OXT2, and beta tubulin III demonstrated the ability of the iPSCs to differentiate into all three germ layers. iPSC-derived lines from CTL, AMN, and cALD male patients were differentiated into astrocytes. Differentiated AMN and cALD astrocytes lacked ABCD1 expression and accumulated saturated very long chain fatty acids (VLCFAs), a hallmark of X-ALD, and demonstrated differential mitochondrial bioenergetics, cytokine gene expression, and differences in STAT3 and AMPK signaling between AMN and cALD astrocytes. These patient astrocytes provide disease-relevant tools to investigate the mechanism of differential neuroinflammatory response in X-ALD and will be valuable cell models for testing new therapeutics.
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iPSC-derived astrocytes from two AMN and two cALD patients showed different mitochondrial bioenergetics.
“showed different mitochondrial bioenergetics”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [485]
iPSC-derived astrocytes from two AMN and two cALD patients accumulated VLCFAs.
“Those iPSC-derived astrocytes accumulated VLCFAs”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [485]
iPSC-derived astrocytes from two AMN and two cALD patients showed different cytokine-gene expression.
“cytokine-gene expression”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [485]
iPSC-derived astrocytes from two AMN and two cALD patients showed differences in STAT3- and AMPK signaling.
“differences in signal transducer and activator of transcription-3 (STAT3)- and AMP-activated protein kinase (AMPK) signaling between two AMN and two cALD patients [485].”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [485]
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Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy
Bougnères, P., & Le Stunff, C. (2025) · Genes · doi:10.3390/genes16050590 · Cited by 11 · see citing works
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- Authors
- Kaur, N., & Singh, J.
- Affiliations
- Henry Ford Health (US)
- Corresponding author
- Singh, Jaspreet
- ORCID
- Singh, Jaspreet
- Venue
- International Journal of Molecular Sciences
- Publisher
- MDPI AG
- Published
- 2025-02-13
- Volume
- 26
- Issue
- 4
- Pages
- 1576
- ISSN
- 1422-0067 (ISSN-L)
- PMC
- PMC11855073
- OpenAlex
- W4407557020
- Cited by
- 4
- References
- 68
- Citations by year
- 2025: 4
- FWCI
- 1.20
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- International Journal of Molecular Sciences (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institute of Health (NS114775, NS114245, A10263, A30973)
- Henry Ford Hospital (NS114775, NS114245, A10263, A30973)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Keywords
- X-linked adrenoleukodystrophy, iPSC-derived astrocytes, ABCD1, adrenomyeloneuropathy, cerebral adrenoleukodystrophy, peroxisomal disorders, very long chain fatty acids, mitochondrial bioenergetics, STAT3 signaling, AMPK signaling, neuroinflammation, disease modeling, iPSC differentiation
- MeSH terms
- ATP Binding Cassette Transporter, Subfamily D, Member 1, Adrenoleukodystrophy, Astrocytes, Cell Differentiation, Cells, Cultured, Fibroblasts, Humans, Male, Phenotype, Induced Pluripotent Stem Cells
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