Intestinal epithelial stem cell transplants as a novel therapy for cerebrovascular stroke

• Published in: Brain, behavior, and immunity Vol. 107; pp. 345 - 360
• Main Authors: Mani, Kathiresh Kumar, El-Hakim, Yumna, Branyan, Taylor E., Samiya, Nadia, Pandey, Sivani, Grimaldo, Maria T., Habbal, Ali, Wertz, Anna, Sohrabji, Farida
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.01.2023
• Subjects: Animals; Disabled Persons; Humans; IL17; Intestinal epithelial stem cells; Lgr5; Motor Disorders; Organoids; Post stroke cognitive impairment; Rats; Stem Cell Transplantation; Stroke; Stroke - therapy; Transplant; Stroke; Organoids; Intestinal epithelial stem cells; Lgr5; Post stroke cognitive impairment; IL17; Transplant
• ISSN: 0889-1591; 1090-2139
• DOI: 10.1016/j.bbi.2022.10.015

•This study focuses on a novel preclinical therapy for stroke, using Intestinal Epithelial Stem Cells (IESCs).•Stroke rapidly results in a leaky gut and elevated blood levels of inflammatory cytokines and toxic gut metabolites.•IESCs from healthy young donors to older stroke animals repairs the gut and attenuates stroke-induced cognitive impairment.•IESC from older donor rats transplanted to young stroke animals do not improve stroke outcomes.•These data support the hypothesis that repairing the gut can improve stroke outcomes. Almost 2/3rds of stroke survivors exhibit vascular cognitive impairment and a third of stroke patients will develop dementia 1–3 years after stroke. These dire consequences underscore the need for effective stroke therapies. In addition to its damaging effects on the brain, stroke rapidly dysregulates the intestinal epithelium, resulting in elevated blood levels of inflammatory cytokines and toxic gut metabolites due to a ‘leaky’ gut. We tested whether repairing the gut via intestinal epithelial stem cell (IESC) transplants would also improve stroke recovery. Organoids containing IESCs derived from young rats transplanted into older rats after stroke were incorporated into the gut, restored stroke-induced gut dysmorphology and decreased gut permeability, and reduced circulating levels of endotoxin LPS and the inflammatory cytokine IL-17A. Remarkably, IESC transplants also improved stroke-induced acute (4d) sensory-motor disability and chronic (30d) cognitive-affective function. Moreover, IESCs from older animals displayed senescent features and were not therapeutic for stroke. These data underscore the gut as a critical therapeutic target for stroke and demonstrate the effectiveness of gut stem cell therapy.