Mucosal repair in the gastrointestinal tract

Mammen, Joshua M.V.; Matthews, Jeffrey B.

doi:10.1097/01.ccm.0000081429.89277.af

Cited by 102 publications

(90 citation statements)

References 58 publications

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“…The ability of intestinal mucosal stem cells to divide and generate more mucosal surface area in response to either injury or to loss of mucosal surface area is well known. [19][20][21][22][23] There has been some thought that, perhaps, regeneration of intestinal mucosa on biopolymer scaffolds in this way can generate large amounts of mucosal surface area. However, there are limits to the amount of mucosal regeneration that can take place in response to mucosal injury or loss, and these repair mechanisms cannot replace larger stretches of lost intestine.…”

Section: Discussionmentioning

confidence: 99%

Intestinal Stem Cell Organoid Transplantation Generates Neomucosa in Dogs

Agopian

Chen

Avansino

et al. 2009

Journal of Gastrointestinal Surgery

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Background and Aims Intestinal stem cell organoid transplantation generates functional intestinal neomucosa and has been used therapeutically to improve nutrient absorption and cure bile acid malabsorption in rats. We hypothesized that intestinal organoids can be harvested and transplanted to generate intestinal neomucosa in a large animal model. Materials and Methods In group 1, 2-month old beagles (n=6) underwent autotransplantation of intestinal organoids prepared from a segment of their own ileum. In group 2, intestinal organoids were harvested from fetuses and allotransplanted into 10-month old mother animals (n=4). Tissues were harvested after 4 weeks and analyzed by hematoxylin and eosin histology and fluorescent microscopy. Results Large numbers of viable organoids were harvested in both groups. In group 1, no neomucosal growth was identified in any of the engraftment sites after autotransplantation of juvenile organoids. In group 2, neomucosal growth with large areas of crypts and villi was identified in 11 of 12 polyglycolic acid scaffolds after allotransplantation of fetal organoids. The neomucosa resembled normal canine mucosa in structure and composition. Conclusions Intestinal stem cell organoid transplantation can be used to generate neomucosa in dogs. This is the first report of successful generation of intestinal neomucosa using intestinal stem cell organoid transplantation in a large animal model.

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Section: Discussionmentioning

confidence: 99%

Intestinal Stem Cell Organoid Transplantation Generates Neomucosa in Dogs

Agopian

Chen

Avansino

et al. 2009

Journal of Gastrointestinal Surgery

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“…Laminin Enhances CXCL12-stimulated Migration-Focal adhesion proteins regulate cellular interactions with the extracellular matrix. We next asked if CXCL12-induced migration was modulated by extracellular matrix components known to play roles in restitution (57)(58)(59). Epithelial cell migration of cells cultured on the non-integrin substrate BSA was significantly increased by CXCL12 stimulation (Fig.…”

Section: E)mentioning

confidence: 99%

Calcium Mobilization Triggered by the Chemokine CXCL12 Regulates Migration in Wounded Intestinal Epithelial Monolayers

Agle¹,

Vongsa²,

Dwinell

2010

Journal of Biological Chemistry

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Restitution of intestinal epithelial barrier damage involves the coordinated remodeling of focal adhesions in actively migrating enterocytes. Defining the extracellular mediators and the intracellular signaling pathways regulating those dynamic processes is a key step in developing restitution-targeted therapies. Previously we have determined that activation of the chemokine receptor CXCR4 by the cognate ligand CXCL12 enhances intestinal epithelial restitution through reorganization of the actin cytoskeleton. The aim of these studies was to investigate the role of calcium effectors in CXCL12-mediated restitution. CXCL12 stimulated release of intracellular calcium in a dose-dependent manner. Inhibition of intracellular calcium flux impaired CXCL12-mediated migration of IEC-6 and CaCo2 cells. Pharmacological blockade and specific shRNA depletion of the phospholipase-C (PLC␤3) isoform attenuated CXCL12-enhanced migration, linking receptor activation with intracellular calcium flux. Immunoblot analyses demonstrated CXCL12 activated the calcium-regulated focal adhesion protein proline-rich tyrosine kinase-2 (Pyk2) and the effector proteins paxillin and p130Cas . Interruption of Pyk2 signaling potently blocked CXCL12-induced wound closure. CXCL12-stimulated epithelial cell migration was enhanced on laminin and abrogated by intracellular calcium chelation. These results suggest CXCL12 regulates restitution through calcium-activated Pyk2 localized to active focal adhesions. Calcium signaling pathways may therefore provide a novel avenue for enhancing barrier repair.A battery of molecules stimulate epithelial restitution in vitro and in vivo, including cytokines, luminal peptides, probiotics, and as we have reported, chemokines (1-11). Restitution in vivo is dependent on several factors absent from cellculture model systems, including mucin-producing goblet cells, extracellular matrix-producing fibroblasts, immune cells, and the luminal microbiota. Within that complex environment, deletion of genes specifically within the intestinal epithelium has proven useful in deciphering roles for transforming growth factor-␤1 (TGF-␤1) 3 receptor, epidermal growth factor receptor, cadherin, laminin, and Vav in integrity and repair of the gut mucosa (12-16). More recent reports have begun to link mucosal fibroblasts and T cells with key roles in injury repair (17)(18)(19)(20)(21)(22). Despite these findings, the mechanisms by which those molecules elicit their functions, in either reductionist cell-culture models, or complex in vivo systems, remain incompletely characterized.Chemokines are abundantly and ubiquitously produced host defense molecules that participate in activation and directional trafficking of leukocytes. The chemokine receptors CXCR4, CCR5, CCR6, and CX 3 CR1 are expressed by the cells of the human intestinal epithelium (23-26). Chemokines produced by intestinal epithelial cells play an important role in orchestrating physiological and pathological inflammation, consistent with a role in amplifying intestinal inflamm...

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“…In general, the gastrointestinal mucosa has a remarkable ability to repair damage. When the integrity of the superficial mucosa is breached, ulcer healing, a complex and tightly regulated process of filling the mucosal defect, begins (Mammen and Matthews, 2003). Angiogenesis, the formation of new microvessels, is one of the critical components for repair of mucosal defect.…”

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confidence: 99%

Quercetin Activates an Angiogenic Pathway, Hypoxia Inducible Factor (HIF)-1-Vascular Endothelial Growth Factor, by Inhibiting HIF-Prolyl Hydroxylase: a Structural Analysis of Quercetin for Inhibiting HIF-Prolyl Hydroxylase

Jeon

Kim²,

Choi³

et al. 2007

Mol Pharmacol

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We investigated a molecular mechanism underlying quercetinmediated amelioration of colonic mucosal injury and analyzed chemical structure contributing to the quercetin's effect. Quercetin up-regulated vascular endothelial growth factor (VEGF), an ulcer healing factor, not only in colon epithelial cell lines but also in the inflamed colonic tissue. VEGF derived from quercetin-treated colon epithelial cells promoted tube formation. The VEGF induction was dependent on quercetin-mediated hypoxia-inducible factor-1 (HIF-1) activation. Quercetin delayed HIF-1␣ protein disappearance, which occurred by inhibiting HIF-prolyl hydroxylase (HPH), the key enzyme for HIF-1␣ hydroxylation and subsequent von Hippel Lindau-dependent HIF-1␣ degradation. HPH inhibition by quercetin was neutralized significantly by an elevated dose of iron. Consistent with this, cellular induction of HIF-1␣ by quercetin was abolished by pretreatment with iron. Two iron-chelating moieties in quercetin, -OH at position 3 of the C ring and/or -OH at positions 3Ј and 4Ј of the B ring, enabled the flavonoid to inhibit HPH and subsequently induce HIF-1␣. Our data suggest that the clinical effect of quercetin may be partly attributed to the activation of an angiogenic pathway HIF-1-VEGF via inhibiting HPH and the chelating moieties of quercetin were required for inhibiting HPH.

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Mucosal repair in the gastrointestinal tract

Abstract: Minor epithelial injuries are repaired with the complex process of epithelial restitution independent of cell proliferation.

Cited by 102 publications

References 58 publications

Intestinal Stem Cell Organoid Transplantation Generates Neomucosa in Dogs

Intestinal Stem Cell Organoid Transplantation Generates Neomucosa in Dogs

Calcium Mobilization Triggered by the Chemokine CXCL12 Regulates Migration in Wounded Intestinal Epithelial Monolayers

Quercetin Activates an Angiogenic Pathway, Hypoxia Inducible Factor (HIF)-1-Vascular Endothelial Growth Factor, by Inhibiting HIF-Prolyl Hydroxylase: a Structural Analysis of Quercetin for Inhibiting HIF-Prolyl Hydroxylase

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