Abstract Body: Type 2 diabetes mellitus (T2DM) induces chronic inflammation, which can worsen the secondary injury following ischemic stroke. Yet, whether and how T2DM-induced inflammation affects the production of bone marrow-derived immune cells and their transcriptome remains largely unexplored. Hypothesis: T2DM biases the immune system to a proinflammatory phenotype in the bone marrow, increases the transmigration of myeloid cells and compounds the secondary injury caused by stroke. Methods: We induced ischemic stroke by distal occlusion of the middle cerebral artery (MCAO) in T2DM mouse model db/db mice and normoglycemic control db/+ mice. Three days post-stroke, bone marrow (BM) cells and tissue were subjected to single-cell RNA sequencing (scRNAseq) and GeoMx digital spatial profiling (DSP). Myeloid cell populations were quantified by Fluorescent cell activated sorting (FACS). We used the NicheNet tool to analyze the cell-cell communication between BM populations. Results: We detected an increased frequency of hematopoietic precursor and myeloid progenitor cells in the BM of T2DM mice compared to control mice via FACS, although CD11b (+) cells were significantly increased only in control and not in T2DM mice after stroke. GeoMx DSP found that the upregulation of cd47, s100a9, cd177, pecam1 genes in both CD115 and Ly6G expressing cells were more pronounced in T2DM BM compared to control BM after stroke. Pathway enrichment analysis pointed to an increased activation of signals for myeloid cell activation and migration in T2DM stroke BM compared to control stroke BM, relative to their respective non-stroke counterpart. NicheNet integrated with single-cell RNA sequencing data corroborated with a differential increase of ccr2 and ccr3 interactions with a number of chemokine ligands in the BM of T2DM stroke mice compared to control stroke mice. Conclusion: our data suggest that T2DM enhances myeloid cell migration and chemotaxis after stroke. Ongoing studies will identify the tissue compartments to which increased myeloid cells transmigrate in T2DM mice after stroke and the effect on stroke outcomes.