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bioRxiv · 10.64898/2025.12.29.696958

Type 2 diabetes Reprograms Bone Marrow Hematopoiesis and Dysregulates Immune Signaling in Response to Stroke

Zhang, H.·Gu, W.·Yu, K.·Tu, C.-L.·Chang, W.·Liu, J.
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Abstract

Type 2 diabetes mellitus (T2DM) worsens stroke outcomes, but the underlying mechanisms linking T2DM to systemic immune dysfunction remain unclear. We investigated whether T2DM alters bone marrow (BM) hematopoiesis and dysregulate immune signaling following ischemic stroke in mice. Single-cell RNA sequencing, GeoMx digital spatial profiling (DSP), nCounter, and flow cytometry were used to analyze BM cells from control (db/+, Ctrl) and diabetic (db/db, T2DM) mice underwent experimental stroke or sham surgery. Diabetes caused marked structural remodeling of BM, with reduced cellularity and imbalance of hematopoietic lineages. Pseudotime trajectory analysis revealed impaired differentiation and maturation signatures of hematopoietic progenitor cells (HPC1) and granulocytes, and overactivation toward monocytes in diabetes after stroke. CellChat analysis demonstrated reorganization of intercellular communication, with hematopoietic progenitor cells (HPC1) and monocytes emerging as dominant signaling hubs through upregulated MIF, SIRP, and THBS pathways. AUCell enrichment indicated increased glycolysis and oxidative phosphorylation but reduced interferon-{gamma} (IFN-{gamma}) signaling, reflecting metabolic activation coupled with immune dysregulation. DSP and nCounter further confirmed upregulation of genes in the MIF, SIRP and THBS pathways in CD115 monocytes and Ly6G neutrophils, indicating proinflammatory and migratory activation in diabetic bone marrow. Our data suggest that T2DM reprograms hematopoiesis and signaling networks, leading to maladaptive myeloid responses and impaired immune regulation after stroke. This maladaptive BM environment amplifies inflammation and limits repair, linking diabetic metabolic stress to worsened ischemic outcomes. Targeting bone marrow immune dysfunction may offer a therapeutic strategy to improve stroke recovery in diabetic patients.

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Zhang, H., Gu, W., Yu, K., Tu, C.-L., Chang, W., Liu, J.. 2025-12-30. Type 2 diabetes Reprograms Bone Marrow Hematopoiesis and Dysregulates Immune Signaling in Response to Stroke. https://doi.org/10.64898/2025.12.29.696958

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