Generation and Characterization of Human iPSC-Derived Astrocytes with Potential for Modeling X-Linked Adrenoleukodystrophy Phenotypes
Recommended Citation
Kaur N, and Singh J. Generation and Characterization of Human iPSC-Derived Astrocytes with Potential for Modeling X-Linked Adrenoleukodystrophy Phenotypes. Int J Mol Sci 2025; 26(4).
Document Type
Article
Publication Date
2-13-2025
Publication Title
Int J Mol Sci
Abstract
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.
Medical Subject Headings
Humans; Induced Pluripotent Stem Cells; Adrenoleukodystrophy; Astrocytes; Male; Cell Differentiation; Phenotype; ATP Binding Cassette Transporter, Subfamily D, Member 1; Fibroblasts
PubMed ID
40004040
Volume
26
Issue
4
