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Single nuclei transcriptomics reveals altered endothelial cell function, permeability, and cognition in diabetic mice.

ABSTRACT: Diabetes (DM) increases cardiovascular and cerebrovascular disease risk. However, the mechanism of DM-associated microvascular dysfunction and neuroinflammation remain unknown. We present a global assessment of endothelial cell-specific gene expression and integrated transcriptomics directly addressing hippocampal endothelium in diabetic mice, with the goal of determining the effect of DM in endothelial cell function and potential implications to vascular dementia. We observe for the first-time differential gene expression with strong signatures of cell signaling, activation of pathways for endothelial dysfunction, and neurodegeneration. Moreover, we identified that the integrated transcriptomic changes associate with blood brain barrier disruption by magnetic resonance imaging, and behavioral alterations, and correlate with the clinical gene profile of dementia patients, revealing opportunities for treatments with specificity for molecular pathology.

ORGANISM(S): Mus musculus

PROVIDER: GSE241142 | GEO | 2024/01/22

REPOSITORIES: GEO

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Project description:Diabetes mellitus [DM], with its burden of premature morbidity and mortality, represents one of the major threats to human health in the 21st century (Zimmet 2001). Accelerated atherosclerosis affecting arteries that supply the heart, brain and lower extremities is responsible for an increased risk of acute ischemic events. DM is also associated with microvascular disease, which is a leading cause of blindness, renal failure and debilitating neuropathies. Endothelial dysfunction, increased vascular permeability and microvascular cell loss by apoptosis are all hallmarks of diabetic microangiopathy. Diabetic patients not only incur cardiovascular complications more frequently, but also experience worse outcomes due to attenuation of vascular repair mechanisms. This impairment includes quantitative and qualitative abnormalities of bone marrow [BM]-derived progenitor cells (Emanueli 2002&2004; Loomans 2004; Krankel 2005; Fadini 2006). The mechanisms underlying BM dysfunction remain however enigmatic, especially when considering the privileged location that protects stem cells [SC] and progenitor cells [PC] of the marrow from external insults (Kopp 2008 and Kiel 2008). BM endothelial cells [EC] are instead an obvious target of DM, because they are directly exposed to blood glucose and incapable to regulate glucose influx. Strangely enough, little is known about the impact of diabetes on BM microvasculature. We hypothesize that damage induced by DM might start at the microvascular level, in a similar fashion to microangiopathy, which occurs in kidney, retina, heart and brain. We also propose that enduring microvascular cell loss might result in marrow hypo-perfusion and destabilization of SC homeostasis. In order to test this hypothesis, we studied streptozotocin-induced (STZ) type-1 DM and age-matched non-DM mice (n=6 to 10 per group in each experiment). Histological examination of femurs, collected from STZ-mice at 28-30 weeks from induction of DM or controls, showed remarkable differences in bone density and marrow composition. Bone marrow cells from healthy and diabetic animals were next selected for endothelial progenitors and cultured for 10 days under endothelial cell growth conditions. Next RNA was isolated and analysed by Illumina Sentrix Beadarrays.

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Single nuclei transcriptomics reveals altered endothelial cell function, permeability, and cognition in diabetic mice.

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