Abstract WMP119: Novel Therapeutic Potential Of Intestinal Stem Cell Transplants For Ameliorating The Long Term Effects Of Cerebrovascular Stroke

Background: Stroke is a leading cause of disability and dementia with limited treatment options. Evidence suggests that stroke rapidly dysregulates the intestinal epithelium, causing a ‘leaky gut’ and elevated blood levels of inflammatory cytokines. Hypothesis: In view of the emerging evidence of the gut-brain connection, we tested whether early repair of the gut after ischemic stroke would prevent stroke-induced cognitive impairment. Methods: Adult and middle-aged Sprague-Dawley female and male rats were used for this study and assigned to the following groups: Control (sham), stroke with sham transplant (vehicle), or stroke with IESC transplantation. Rats were subjected to stereotaxic middle cerebral artery occlusion (MCAo) using Endothelin-1 (vasoconstrictor). Primary IESCs were isolated from young female and male rats to prepare organoid cultures. Dispersed organoid cells were labeled with PKH67 and injected iv 4h/24h/48h to middle aged hosts after stroke. Behavioral assessments were performed before stroke and 4 weeks after stroke. This included tests for depressive-like behaviors(Burrowing test and the Social Interaction test). Cognitive performance (Novel object Recognition test and Barnes maze test), which assess declarative and visuospatial memory respectively. Results: Vehicle-treated MCAo animals displayed depressive-like behaviors compared to their pre-stroke performance. In contrast, stroke animals that received IESC transplants showed were no different from their pre-stroke performance and no different from sham (no-stroke animals). A similar pattern was seen in tests of cognition. MCAo+vehicle animals showed poor ability to discriminate the novel object and displayed impaired learning and recall on the Barnes maze. In both tests, MCAo animals + IESC transplants animals were not impaired and had similar performance to the Sham (no stroke) group. MCAo caused a persistent elevation of the gut metabolite LPS and the inflammatory cytokine IL-17A, which was abated by IESC treatment. Conclusion: Overall, these data show that an intestinal stem cell population derived from a healthy young animal transferred to an older host after stroke can significantly improve long term behavior stroke outcomes.