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      Neural Crest Cell Implantation Restores Enteric Nervous System Function and Alters the Gastrointestinal Transcriptome in Human Tissue-Engineered Small Intestine

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          Summary

          Acquired or congenital disruption in enteric nervous system (ENS) development or function can lead to significant mechanical dysmotility. ENS restoration through cellular transplantation may provide a cure for enteric neuropathies. We have previously generated human pluripotent stem cell (hPSC)-derived tissue-engineered small intestine (TESI) from human intestinal organoids (HIOs). However, HIO-TESI fails to develop an ENS. The purpose of our study is to restore ENS components derived exclusively from hPSCs in HIO-TESI. hPSC-derived enteric neural crest cell (ENCC) supplementation of HIO-TESI establishes submucosal and myenteric ganglia, repopulates various subclasses of neurons, and restores neuroepithelial connections and neuron-dependent contractility and relaxation in ENCC-HIO-TESI. RNA sequencing identified differentially expressed genes involved in neurogenesis, gliogenesis, gastrointestinal tract development, and differentiated epithelial cell types when ENS elements are restored during in vivo development of HIO-TESI. Our findings validate an effective approach to restoring hPSC-derived ENS components in HIO-TESI and may implicate their potential for the treatment of enteric neuropathies.

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          Highlights

          • ENCC implantation restores enteric glial and neural subpopulations in HIO-TESI

          • ENCC differentiate into diverse neuronal subtypes and synapse with luminal ECC

          • ENCC-HIO-TESI demonstrates neuron-dependent contractility and relaxation

          • Early in vivo ENCC implantation alters the developing HIO-TESI transcriptome

          Abstract

          Human intestinal organoid and enteric neural crest cell co-culture restores enteric nervous system (ENS) function. Schlieve and colleagues developed an in vivo approach to establish ENS elements in tissue-engineered small intestine that demonstrates neuron-dependent functional integration. This method could be applied to other organ systems and represent a future cellular therapy for human enteric neuropathies.

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          Most cited references34

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          For the past 25 years NIH Image and ImageJ software have been pioneers as open tools for the analysis of scientific images. We discuss the origins, challenges and solutions of these two programs, and how their history can serve to advise and inform other software projects.
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            An in vivo model of human small intestine using pluripotent stem cells.

            Differentiation of human pluripotent stem cells (hPSCs) into organ-specific subtypes offers an exciting avenue for the study of embryonic development and disease processes, for pharmacologic studies and as a potential resource for therapeutic transplant. To date, limited in vivo models exist for human intestine, all of which are dependent upon primary epithelial cultures or digested tissue from surgical biopsies that include mesenchymal cells transplanted on biodegradable scaffolds. Here, we generated human intestinal organoids (HIOs) produced in vitro from human embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs) that can engraft in vivo. These HIOs form mature human intestinal epithelium with intestinal stem cells contributing to the crypt-villus architecture and a laminated human mesenchyme, both supported by mouse vasculature ingrowth. In vivo transplantation resulted in marked expansion and maturation of the epithelium and mesenchyme, as demonstrated by differentiated intestinal cell lineages (enterocytes, goblet cells, Paneth cells, tuft cells and enteroendocrine cells), presence of functional brush-border enzymes (lactase, sucrase-isomaltase and dipeptidyl peptidase 4) and visible subepithelial and smooth muscle layers when compared with HIOs in vitro. Transplanted intestinal tissues demonstrated digestive functions as shown by permeability and peptide uptake studies. Furthermore, transplanted HIO-derived tissue was responsive to systemic signals from the host mouse following ileocecal resection, suggesting a role for circulating factors in the intestinal adaptive response. This model of the human small intestine may pave the way for studies of intestinal physiology, disease and translational studies.
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              Translocation and dissemination of commensal bacteria in post-stroke infection.

              Bacterial infection is highly prevalent in patients who have had a stroke. Despite the potential contribution of micro-aspiration in post-stroke pneumonia, we found that the majority of the microorganisms detected in the patients who developed infections after having a stroke were common commensal bacteria that normally reside in the intestinal tracts. In a mouse model of ischemic stroke, post-stroke infection was only observed in mice that were born and raised in specific-pathogen-free facilities; this was not seen in mice that were born and raised in germ-free facilities. Using high-throughput 16S rRNA gene amplicon sequencing and bioinformatics analyses, we provide evidence demonstrating that the source of the bacteria forming the microbial community in the lungs of post-stroke mice was indeed the host small intestine. Additionally, stroke-induced gut barrier permeability and dysfunction preceded the dissemination of orally inoculated bacteria to peripheral tissues. This study identifies a novel pathway in which stroke promotes the translocation and dissemination of selective strains of bacteria that originated from the host gut microbiota.
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                Author and article information

                Contributors
                Journal
                Stem Cell Reports
                Stem Cell Reports
                Stem Cell Reports
                Elsevier
                2213-6711
                10 August 2017
                12 September 2017
                10 August 2017
                : 9
                : 3
                : 883-896
                Affiliations
                [1 ]Developmental Biology and Regenerative Medicine Program, The Saban Research Institute at Children's Hospital Los Angeles, 4650 W. Sunset Boulevard, MS#100, Los Angeles, CA 90027, USA
                [2 ]Department of Surgery, Division of Pediatric Surgery, Children's Hospital Los Angeles, Los Angeles, CA, 90027, USA
                [3 ]Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA, 90033, USA
                [4 ]Department of Internal Medicine, Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA
                [5 ]Center for Organogenesis, University of Michigan Medical School, Ann Arbor, MI, 48109, USA
                [6 ]Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA
                Author notes
                []Corresponding author tgrikscheit@ 123456chla.usc.edu
                Article
                S2213-6711(17)30327-2
                10.1016/j.stemcr.2017.07.017
                5599241
                28803915
                caa30c64-789e-4d25-8221-9807ba3db934

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 2 January 2017
                : 20 July 2017
                : 21 July 2017
                Categories
                Article

                tissue-engineered small intestine,human intestinal organoids,enteric neural crest,cells,enteric nervous system,human pluripotent stem cells

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