Biology subjects

Dhukhwa, A.

Publications and source records attributed to Dhukhwa, A..

3 recordsLinked to original sources

bioRxiv2026

Remodeling oligodendrocyte lipid metabolism via liver X receptors overcomes inflammatory blockade of remyelination

Multiple sclerosis is characterized by immune-mediated demyelination and inefficient remyelination, owing to impaired differentiation of oligodendrocyte precursor cells (OPCs) into myelinating oligodendrocytes (OLs). Inflammatory cytokines within multiple sclerosis lesions inhibit OPC maturation and induce an immune-like phenotype with antigen-presenting properties, but the underlying mechanisms remain poorly defined. Here, we show that inflammation reprograms OPC lipid metabolism, linking altered metabolism to remyelination failure. In cultured rodent OPCs, interferon-{gamma} (IFN-{gamma}) induced a switch from lipid synthesis to utilization, leading to reduced intracellular fatty acid levels and increased dependence on fatty acid oxidation. Transcriptional analyses confirmed similar lipid metabolic changes in OL-lineage cells cultured from human surgical specimens or isolated from mouse models of inflammatory demyelination and human multiple sclerosis lesions. Enhancing lipid availability in OPCs through oleic acid supplementation or inhibition of fatty acid oxidation attenuated immune-like functions and increased differentiation. Pharmacologic activation of liver X receptor (LXR) transcription factors rebalanced lipid metabolism, suppressed immune-like functions, and overcame IFN-{gamma}-induced differentiation blockade in both mouse and human-derived OPCs. In an adoptive transfer-cuprizone mouse model in which inflammation directly impairs remyelination, LXR activation increased mature OL generation and augmented myelin repair. Together, these findings identify lipid metabolic remodeling as a key mechanism by which inflammation impairs OPC differentiation and highlight LXR activation as a therapeutic approach to enhance remyelination in multiple sclerosis.

neuroscience↗

bioRxiv2025

Profiling miRNAs involved in Human Oligodendrocyte Precursor Cell Differentiation and Maturation

MicroRNAs (miRNAs) are evolutionarily conserved post-transcriptional regulators that play critical roles in cellular development and differentiation across species. Although the importance of miRNAs in oligodendrocyte lineage cell (OLLC) differentiation has been extensively studied in rodent models, their roles in human OL development remain less understood. To address this gap, we used a human embryonic stem cell (hESC) reporter system designed to study human OLs and OL progenitor cells (OPCs). Using an optimized differentiation protocol, we used the reporter hESCs to generate and isolate well-characterized OLLCs at specific developmental stages and performed next-generation sequencing-based miRNA profiling to identify stage-specific miRNAs enriched during OL lineage specification and maturation. In addition to canonical miRNAs known to be enriched at various stages of OL development, our study identified several lesser-known miRNAs with distinct stage-specific enrichment patterns that may serve as useful molecular markers for classifying human CNS cell types in future studies. Target analysis of OPC-and OL-enriched miRNAs revealed key genes, including transcription factors ZNF488 and DLX1, cytoskeletal regulator CSNK2B, and potassium channel gene KCNJ1, along with key signaling pathways such as AKT, SMAD2/3, estrogen receptor, and insulin signaling, which regulate OPC and OL lineage function. These findings advance our understanding of the OLLC-specific miRNAs, and miRNA-mediated regulatory networks governing human OL differentiation and maturation and provide promising therapeutic targets for future studies aimed at restoring myelin integrity and improving outcomes in demyelinating diseases.

neuroscience↗

bioRxiv2024

Restoring the Multiple Sclerosis Associated Imbalance of Gut Indole Metabolites Promotes Remyelination and Suppresses Neuroinflammation

In multiple sclerosis (MS) the circulating metabolome is dysregulated, with indole lactate (ILA) being one of the most significantly reduced metabolites. We demonstrate that oral supplementation of ILA impacts key MS disease processes in two preclinical models. ILA reduces neuroinflammation by dampening immune cell activation as well as infiltration; and promotes remyelination and in vitro oligodendrocyte differentiation through the aryl hydrocarbon receptor (AhR). Supplementation of ILA, a reductive indole metabolite, restores the gut microbiomes oxidative/reductive metabolic balance by lowering circulating indole acetate (IAA), an oxidative indole metabolite, that blocks remyelination and oligodendrocyte maturation. The ILA-induced reduction in circulating IAA is linked to changes in IAA-producing gut microbiota taxa and pathways that are also dysregulated in MS. Notably, a lower ILA:IAA ratio correlates with worse MS outcomes. Overall, these findings identify ILA as a potential anti-inflammatory remyelinating agent and provide insights into the role of gut dysbiosis-related metabolic alterations in MS progression. One Sentence SummaryIndole lactate, a postbiotic metabolite reduced in MS, corrects gut microbiome metabolic imbalances associated with remyelination and neuroinflammation.

neuroscience↗