Abstract TMP33: Repair of Ischemic Intestinal Epithelial Stem Cells: Potential Therapy to Improve Stroke Outcomes

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Kathiresh Kumar Mani ◽  
Farida Sohrabji
Keyword(s):  
Stem Cells ◽  
Motor Function ◽  
Stroke Recovery ◽  
Female Rats ◽  
Stem Cell Marker ◽  
Left Middle Cerebral Artery ◽  
Intestinal Epithelial ◽  
Epithelial Stem Cells ◽  
Stroke Outcomes ◽  
Sensory Motor

Background: Nearly 50% of all stroke patients experience “leaky” gut, gut hemorrhage and gut epithelium damage. Gut leakiness may increase circulating inflammatory cytokines and other gut products such as endotoxins, which can impair stroke recovery. Here we tested the hypothesis that normalizing gut function via transplantation of intestinal epithelial stem cells (IESC) after stroke may stimulate repair of gut structures and improve stroke outcomes. Methods: Reproductive senescent female Sprague-Dawley rats used for this study and assigned to the following groups: Control (no stroke); stroke with sham transplant (vehicle); stroke with IESC transplantation. Rats were subjected to stereotaxic surgery to occlude the left middle cerebral artery by using Endothelin-1. Primary IECs were isolated from young female rats to prepare organoids cultures. Dissociated organoids were labeled with PKH26 and injected iv either once (48h after stroke) or 3 times (4h/24h/48h after stroke). Behavioral assays and saphenous blood draws were performed pre-stroke, 2d and 5d after stroke. Trunk blood, brain tissue and a segment of small intestine was collected at termination and processed for the expression of the stem cell marker Lgr5+, Na/K ATPase-α, and tight junction proteins. Results: Significant deterioration of the gut architecture was observed after stroke, including blunted or absent villi and irregular crypts. In animals that received PKH26-labeled organoid tranplants at 48h post stroke, labeled cells were seen in the center of the villus and a few organoid cells were immunositve for Lgr5+. Animals that received 3 organoid injections showed PKH26-labeled cells incorporated in both the villus and crypts. In these animals, villus were well formed and appeared no different from non-stroke controls. Sensory motor function assessed by adhesive removal test on the side contralateral to the infarction was severely impaired in the stroke/no transplant animals (120+secs/timed out), while this impairment was attenuated in the group that received 3 organoid injections (31±11 secs). Conclusion: These data suggest that transplantation of IESC after stroke may promote repair of gut villus and crypts, with a concomitant improvement in sensory motor function.

scholarly journals Stem cell treatment improves post stroke neurological outcomes: a comparative study in male and female rats

2021 ◽  
pp. svn-2020-000834
Author(s):  
Koteswara Rao Nalamolu ◽  
Bharath Chelluboina ◽  
Casimir A Fornal ◽  
Siva Reddy Challa ◽  
David M Pinson ◽  
...  
Keyword(s):  
Stem Cells ◽  
Sex Differences ◽  
Motor Function ◽  
Infarct Volume ◽  
Female Rats ◽  
Human Umbilical Cord ◽  
Male And Female ◽  
Post Stroke ◽  
Male And Female Rats ◽  
Males And Females

Background and purposeThe therapeutic potential of different stem cells for ischaemic stroke treatment is intriguing and somewhat controversial. Recent results from our laboratory have demonstrated the potential benefits of human umbilical cord blood-derived mesenchymal stem cells (MSC) in a rodent stroke model. We hypothesised that MSC treatment would effectively promote the recovery of sensory and motor function in both males and females, despite any apparent sex differences in post stroke brain injury.MethodsTransient focal cerebral ischaemia was induced in adult Sprague-Dawley rats by occlusion of the middle cerebral artery. Following the procedure, male and female rats of the untreated group were euthanised 1 day after reperfusion and their brains were used to estimate the resulting infarct volume and tissue swelling. Additional groups of stroke-induced male and female rats were treated with MSC or vehicle and were subsequently subjected to a battery of standard neurological/neurobehavioral tests (Modified Neurological Severity Score assessment, adhesive tape removal, beam walk and rotarod). The tests were administered at regular intervals (at days 1, 3, 5, 7 and 14) after reperfusion to determine the time course of neurological and functional recovery after stroke.ResultsThe infarct volume and extent of swelling of the ischaemic brain were similar in males and females. Despite similar pathological stroke lesions, the clinical manifestations of stroke were more pronounced in males than females, as indicated by the neurological scores and other tests. MSC treatment significantly improved the recovery of sensory and motor function in both sexes, and it demonstrated efficacy in both moderate stroke (females) and severe stroke (males).ConclusionsDespite sex differences in the severity of post stroke outcomes, MSC treatment promoted the recovery of sensory and motor function in male and female rats, suggesting that it may be a promising treatment for stroke.

scholarly journals Unveiling role of Sphingosine-1-phosphate receptor 2 as a brake of epithelial stem cell proliferation and a tumor suppressor in colorectal cancer

2020 ◽  
Author(s):  
Luciana Petti ◽  
Giulia Rizzo ◽  
Federica Rubbino ◽  
Sudharshan Elangovan ◽  
Piergiuseppe Colombo ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Proliferation ◽  
Normal Mucosa ◽  
Genetically Engineered ◽  
Colorectal Carcinogenesis ◽  
Intestinal Stem Cells ◽  
Cancer Information ◽  
Intestinal Epithelial ◽  
Epithelial Stem Cells ◽  
Mucosal Regeneration

Abstract BackgroundSphingosine-1-phosphate receptor 2 (S1PR2) mediates pleiotropic functions encompassing cell proliferation, survival, and migration, which become collectively de-regulated in cancer. Information onto whether S1PR2 participates in colorectal carcinogenesis/cancer is scanty, and we set out to fill the gap.MethodsWe screened expression changes of S1PR2 in human CRC and matched normal mucosa specimens [N = 76]. We compared CRC arising in inflammation-driven and genetically engineered models in wild-type (S1PR2+/+) and S1PR2 deficient (S1PR2−/−) mice. We reconstituted S1PR2 expression in RKO cells and assessed their growth in xenografts. Functionally, we mimicked ablation of S1PR2 in normal mucosa by treating S1PR2+/+ organoids with JTE013, and characterized intestinal epithelial stem cells isolated from S1PR2−/−Lgr5-EGFP- mice.ResultsS1PR2 expression was lost in 33% of CRC; in 55%, it was significantly decreased, only 12% retaining expression comparable to normal mucosa. Both colitis-induced and genetic Apc+/min mouse models of CRC showed a higher incidence in size and number of carcinomas and/or high-grade adenomas, with increased cell proliferation in S1PR2−/− mice compared to S1PR2+/+ controls. Loss of S1PR2 impaired mucosal regeneration, ultimately promoting the expansion of intestinal stem cells. Whereas its overexpression attenuated cell cycle progression, it reduced the phosphorylation of AKT and augmented the levels of PTEN.ConclusionsIn normal colonic crypts, S1PR2 gains expression along with intestinal epithelial cells differentiation, but not in intestinal stem cells, and contrasts intestinal tumorigenesis by promoting epithelial differentiation, preventing the expansion of stem cells and braking their malignant transformation. Targeting of S1PR2 may be of therapeutic benefit for CRC expressing high Lgr5.

scholarly journals Functional Assessment of Stroke-Induced Regulation of miR-20a-3p and Its Role as a Neuroprotectant

2021 ◽  
Author(s):  
Taylor E. Branyan ◽  
Amutha Selvamani ◽  
Min Jung Park ◽  
Kriti E. Korula ◽  
Kelby F. Kosel ◽  
...  
Keyword(s):  
Motor Behavior ◽  
Mitochondrial Dynamics ◽  
Infarct Volume ◽  
Neuron Specific Enolase ◽  
Cell Types ◽  
Female Rats ◽  
Therapeutic Window ◽  
Middle Aged ◽  
Stroke Outcomes ◽  
Sensory Motor

AbstractMicroRNAs have gained popularity as a potential treatment for many diseases, including stroke. This study identifies and characterizes a specific member of the miR-17–92 cluster, miR-20a-3p, as a possible stroke therapeutic. A comprehensive microRNA screening showed that miR-20a-3p was significantly upregulated in astrocytes of adult female rats, which typically have better stroke outcomes, while it was profoundly downregulated in astrocytes of middle-aged females and adult and middle-aged males, groups that typically have more severe stroke outcomes. Assays using primary human astrocytes and neurons show that miR-20a-3p treatment alters mitochondrial dynamics in both cell types. To assess whether stroke outcomes could be improved by elevating astrocytic miR-20a-3p, we created a tetracycline (Tet)-induced recombinant adeno-associated virus (rAAV) construct where miR-20a-3p was located downstream a glial fibrillary acidic protein promoter. Treatment with doxycycline induced miR-20-3p expression in astrocytes, reducing mortality and modestly improving sensory motor behavior. A second Tet-induced rAAV construct was created in which miR-20a-3p was located downstream of a neuron-specific enolase (NSE) promoter. These experiments demonstrate that neuronal expression of miR-20a-3p is vastly more neuroprotective than astrocytic expression, with animals receiving the miR-20a-3p vector showing reduced infarction and sensory motor improvement. Intravenous injections, which are a therapeutically tractable treatment route, with miR-20a-3p mimic 4 h after middle cerebral artery occlusion (MCAo) significantly improved stroke outcomes including infarct volume and sensory motor performance. Improvement was not observed when miR-20a-3p was given immediately or 24 h after MCAo, identifying a unique delayed therapeutic window. Overall, this study identifies a novel neuroprotective microRNA and characterizes several key pathways by which it can improve stroke outcomes.

Biology of Intestinal Epithelial Stem Cells

2015 ◽  
pp. 55-99
Author(s):  
Noah F. Shroyer ◽  
Kristin Bell ◽  
Yuan-Hung Lo
Keyword(s):  
Stem Cells ◽  
Intestinal Epithelial ◽  
Epithelial Stem Cells

scholarly journals Aging effects on intestinal homeostasis associated with expansion and dysfunction of intestinal epithelial stem cells

Aging ◽  
2017 ◽  
Vol 9 (8) ◽  
pp. 1898-1915 ◽  
Author(s):  
Emily C. Moorefield ◽  
Sarah F. Andres ◽  
R. Eric Blue ◽  
Laurianne Van Landeghem ◽  
Amanda T. Mah ◽  
...  
Keyword(s):  
Stem Cells ◽  
Intestinal Epithelial ◽  
Aging Effects ◽  
Epithelial Stem Cells ◽  
Intestinal Homeostasis

scholarly journals Intestinal epithelial cell-specific IGF1 promotes the expansion of intestinal stem cells during epithelial regeneration and functions on the intestinal immune homeostasis

2018 ◽  
Vol 315 (4) ◽  
pp. E638-E649 ◽  
Author(s):  
Yu Zheng ◽  
Yongli Song ◽  
Qi Han ◽  
Wenjie Liu ◽  
Jiuzhi Xu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Epithelial Cell ◽  
Intestinal Epithelial Cell ◽  
High Throughput Sequencing ◽  
Secretory Cells ◽  
Intestinal Epithelial ◽  
Epithelial Stem Cells ◽  
Microbial Composition ◽  
Epithelial Regeneration

It is well known that insulin-like growth factor 1 (IGF1) acts as a trophic factor in small intestine under both physiological and pathophysiological conditions. However, it still lacks direct in vivo evidence of the functions of intestinal epithelial cell (IEC)-specific IGF1 under both normal and pathological conditions. Using IEC-specific IGF1-knockout (cKO) mice and Lgr5-eGFP-CreERT mice, we demonstrate that IEC-specific IGF1 can enhance nutrient uptake, reduce protein catabolism and energy consumption, and promote the proliferation and expansion of intestinal epithelial cells, including intestinal epithelial stem cells and intestinal secretory cells. Next, we showed that IEC-specific IGF1 renders IECs resistant to irradiation and promotes epithelial regeneration. Strikingly, transcriptome profiling assay revealed that many differentially expressed genes involved in the differentiation and maturation of lymphoid lineages were significantly suppressed in the cKO mice as compared with the control mice. We demonstrated that deletion of IGF1 in IECs enhances bacterial translocation to the mesenteric lymph nodes and liver. Furthermore, high-throughput sequencing of 16S ribosomal RNA genes of gut microbiota revealed that IEC-specific IGF1 loss profoundly affected the gut microbial composition at various levels of classification. Therefore, our findings shed light on the in vivo roles of IEC-specific IGF1 in intestinal homeostasis, epithelial regeneration, and immunity, broadening our current insights on IGF1 functions.

Abstract LB-200: IL-1beta promotes the development of intestinal epithelial stem cells

2012 ◽  
Author(s):  
Jishu Shi ◽  
Lei Wang ◽  
Ziyan Liu ◽  
Yijing Li ◽  
Loretta Pappan
Keyword(s):  
Stem Cells ◽  
Intestinal Epithelial ◽  
Epithelial Stem Cells

scholarly journals Krüppel-like Factor 5 Regulates Stemness, Lineage Specification, and Regeneration of Intestinal Epithelial Stem Cells

2020 ◽  
Vol 9 (4) ◽  
pp. 587-609 ◽  
Author(s):  
Chang-Kyung Kim ◽  
Madhurima Saxena ◽  
Kasmika Maharjan ◽  
Jane J. Song ◽  
Kenneth R. Shroyer ◽  
...  
Keyword(s):  
Stem Cells ◽  
Intestinal Epithelial ◽  
Epithelial Stem Cells ◽  
Lineage Specification

scholarly journals Type 3 innate lymphoid cells maintain intestinal epithelial stem cells after tissue damage

2015 ◽  
Vol 212 (11) ◽  
pp. 1783-1791 ◽  
Author(s):  
Patricia Aparicio-Domingo ◽  
Monica Romera-Hernandez ◽  
Julien J. Karrich ◽  
Ferry Cornelissen ◽  
Natalie Papazian ◽  
...  
Keyword(s):  
Stem Cells ◽  
Tissue Damage ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Intestinal Damage ◽  
Intestinal Epithelial ◽  
Epithelial Stem Cells ◽  
Intestinal Tissue ◽  
Mucosal Surfaces ◽  
Type 3

Disruption of the intestinal epithelial barrier allows bacterial translocation and predisposes to destructive inflammation. To ensure proper barrier composition, crypt-residing stem cells continuously proliferate and replenish all intestinal epithelial cells within days. As a consequence of this high mitotic activity, mucosal surfaces are frequently targeted by anticancer therapies, leading to dose-limiting side effects. The cellular mechanisms that control tissue protection and mucosal healing in response to intestinal damage remain poorly understood. Type 3 innate lymphoid cells (ILC3s) are regulators of homeostasis and tissue responses to infection at mucosal surfaces. We now demonstrate that ILC3s are required for epithelial activation and proliferation in response to small intestinal tissue damage induced by the chemotherapeutic agent methotrexate. Multiple subsets of ILC3s are activated after intestinal tissue damage, and in the absence of ILC3s, epithelial activation is lost, correlating with increased pathology and severe damage to the intestinal crypts. Using ILC3-deficient Lgr5 reporter mice, we show that maintenance of intestinal stem cells after damage is severely impaired in the absence of ILC3s or the ILC3 signature cytokine IL-22. These data unveil a novel function of ILC3s in limiting tissue damage by preserving tissue-specific stem cells.

scholarly journals Type 3 innate lymphoid cells maintain intestinal epithelial stem cells after tissue damage

2015 ◽  
Vol 210 (7) ◽  
pp. 2107OIA193
Author(s):  
Patricia Aparicio-Domingo ◽  
Monica Romera-Hernandez ◽  
Julien J. Karrich ◽  
Ferry Cornelissen ◽  
Natalie Papazian ◽  
...  
Keyword(s):  
Stem Cells ◽  
Tissue Damage ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Intestinal Epithelial ◽  
Epithelial Stem Cells ◽  
Type 3
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