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Unraveling Single-Cell Regulatory Networks in iPSC-Derived Neurons from Veterans with Gulf War Illness

ABSTRACT: Gulf War Illness (GWI) is a complex condition affecting Veterans, and its underlying neuropathological mechanisms remain unclear. Patient-derived induced pluripotent stem cells (iPSCs) offer a platform to model the disease in vitro. Objective: To map transcriptomic landscapes and infer single-cell gene regulatory networks (scGRNs) in iPSC-derived neurons from symptomatic and non-symptomatic Gulf War Veterans to identify genes and pathways implicated in GWI pathophysiology and predisposition. Design, Setting, and Participants: This study utilized iPSCs generated from symptomatic GWI Veterans and non-symptomatic GWI Veteran controls. Neurons were differentiated from these iPSCs for analysis. Main Outcomes and Measures: Single-cell RNA sequencing (scRNAseq) was used to generate transcriptomic data. Machine learning algorithms were applied to infer and compare scGRNs between the symptomatic and non-symptomatic groups, identifying key regulatory differences. Results: Analysis of scRNAseq data revealed significant differences in gene expression profiles between neurons derived from symptomatic and non-symptomatic Veterans. scGRN inference identified distinct regulatory modules associated with GWI symptom status. Key transcription factors driving these differences were identified, along with target genes involved in neuroinflammatory responses, synaptic signaling, and stress response pathways. These findings point towards specific molecular dysregulations contributing to GWI neuropathology. Conclusions and Relevance: This study demonstrates the utility of iPSC-derived neurons coupled with single-cell transcriptomics and computational network inference for investigating GWI. The identified differences in scGRNs provide novel insights into the molecular underpinnings of the illness and highlight potential targets for future diagnostic and therapeutic strategies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE303735 | GEO | 2026/01/01

REPOSITORIES: GEO

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Project description:Background Gulf War Illness (GWI) is a severely debilitating condition with chronic symptoms affecting up to 30% of the veterans deployed to the 1990-91 Persian Gulf War. The symptoms associated with GWI include fatigue, musculoskeletal/joint pain and disturbances of multiple organ systems. The mechanisms of GWI are unknown, although the symptoms suggest that GWI is most likely caused by a combination of genetic predisposition and it’s interaction with environmental factors such as exposure to toxic chemicals. Objectives This research project aims to assess how sex differences in individuals with GWI impact their response to stress, specifically through an exercise challenge. Additionally, it highlights the importance of considering sex differences in the diagnosis and treatment of GWI. Methods We utilized RNA-seq to examine the differential gene expression (GE) in peripheral blood mononuclear cells of 24 female GWI patients, 20 male GWI patients, and 40 healthy controls (HC) who were matched in for sex, age, and BMI. We evaluated the gene expression changes at three time points: T0 (baseline), T1 (at maximal exertion), and T2 (4 hours into recovery after T1). To ensure consistency, we excluded genes located on the sex chromosomes and performed separate analyses for men and women. Our focus was to compare the response to exercise within each group (GWI patients and HC) between different time points. Results In the male GWI cohort, pathways associated with immune system process, particularly IL-12, and natural killer cell cytotoxicity were activated during exercise. The female GWI patients exhibited less significant changes in gene expression than men. During the recovery period, male GWI patients demonstrated distinct alterations in the regulation of innate immune responses. On the other hand, female GWI patients showed significant changes in genes related to regulation of intracellular signal transduction. These functional pathways and differentially expressed genes identified in this project provide valuable insights into the sex-specific pathophysiology of GWI. Conclusion The identification of sex-specific biomarkers and therapeutic targets in GWI holds great potential for understanding the distinct onset and progression of this disease in different sexes.

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Unraveling Single-Cell Regulatory Networks in iPSC-Derived Neurons from Veterans with Gulf War Illness

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