Enteric neuronal cell therapy reverses architectural changes in a novel diphtheria toxin-mediated model of colonic aganglionosis

Bhave, Sukhada; Arciero, Emily; Baker, Corey; Ho, Wing Lam N.; Stavely, Rhian; Goldstein, Allan M.; Hotta, Ryo

doi:10.1038/s41598-019-55128-4

Cited by 21 publications

(25 citation statements)

References 51 publications

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“…MAPK7 as an important member of the MAPK family, and could act as a mediator for some downstream signaling pathways that are involved in a number of cellular activities, including proliferation, differentiation, transcription regulation, and development (32). Diphtheria toxin receptor (DTR) plays a pivotal role in the function of dendritic cells (DCs) (33). IGFBP2 as a secreted protein is often overexpressed in tumors and could act as a biomarker for prognosis (34).…”

Section: Discussionmentioning

confidence: 99%

Helicobacter pylori-induced protein tyrosine phosphatase receptor type C as a prognostic biomarker for gastric cancer

Liu

et al. 2021

J Gastrointest Oncol

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Background: Helicobacter pylori (H. pylori) infection is closely associated with the tumorigenesis of gastric cancer. The aim of the present study was to identify the key regulator in H. pylori-related gastric cancer and to study the expression level and clinical value of the indicated key regulator in gastric cancer. Methods:The GSE6143 dataset was used to identify differentially expressed genes (DEGs) with limma R package, and enrichment analysis was done using the Metascape web-based portal. The protein-protein interaction analysis was done using Search Tool for the Retrieval of Interacting Genes/Proteins. Gastric adenocarcinoma AGS and BGC-823 cells were treated with H. pylori strain 26695 to construct the in vitro H. pylori infection model, and quantitative reverse transcription polymerase chain reaction was used to analyze the mRNA levels of indicated genes. The correlation analysis between two genes in gastric cancer was done by GEPIA. Furthermore, the PTPRC expression by pathological features analysis was conducted in UALCAN, an easy to use, interactive web-portal (http://ualcan.path.uab.edu). The survival analysis for gastric cancer, based on PTPRC expression levels, was done using the Kaplan-Meier plotter.Results: DEGs in gastric mucosa with or without H. pylori infection were identified and enriched in immune-related pathways and cancer pathways. The protein-protein interaction analysis confirmed the enrichment analysis of gene ontology. H. pylori strain 26695 exposure also confirmed the alteration of gene expression levels in AGS and BGC-823 cells. PTPRC was co-expressed with CSF2RB and TNFRSF7, indicating a significant positive correlation in gastric cancer. PTPRC was overexpressed in gastric cancer, and the overexpression of PTPRC was positively correlated with the progression of gastric cancer. Furthermore, the high expression of PTPRC could act as a poor prognostic factor for gastric cancer patients, especially for those at advanced stage. Conclusions: H. pylori-induced PTPRC is overexpressed in gastric cancer, and the overexpression of PTPRC is positively associated with the development of gastric cancer. The high expression of PTPRC could serve as poor prognostic biomarker for gastric cancer patients, especially for those at advanced stage. H. pylori-induced PTPRC is a prognostic biomarker for gastric cancer.

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Section: Discussionmentioning

confidence: 99%

Helicobacter pylori-induced protein tyrosine phosphatase receptor type C as a prognostic biomarker for gastric cancer

Liu

et al. 2021

J Gastrointest Oncol

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“…Nestin‐GFP mice were kindly gifted by Jorg Dietrich, MD, PhD, MGH 18 . Wnt1‐Cre mice were crossed with R26R‐tdT reporter mice to obtain Wnt1‐Cre;tdTomato (Wnt1‐tdT) mice in which all neural crest‐derived cells are fluorescently labelled as previously described 19,20 . For calcium imaging studies, Wnt1‐Cre were crossed with tdT‐GCaMP5 mice whereby all neural crest‐derived cells constitutively express tdTomato and the genetically encoded calcium indicator, GCaMP5 (Wnt1‐tdT‐GCaMP5) 21,22 .…”

Section: Methodsmentioning

confidence: 99%

Enteric mesenchymal cells support the growth of postnatal enteric neural stem cells

Stavely

Bhave

et al. 2021

Stem Cells

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Interplay between embryonic enteric neural stem cells (ENSCs) and enteric mesenchymal cells (EMCs) in the embryonic gut is essential for normal development of the enteric nervous system. Disruption of these interactions underlies the pathogenesis of intestinal aganglionosis in Hirschsprung disease (HSCR). ENSC therapy has been proposed as a possible treatment for HSCR, but whether the survival and development of postnatal-derived ENSCs similarly rely on signals from the mesenchymal environment is unknown and has important implications for developing protocols to expand ENSCs for cell transplantation therapy. Enteric neural crest-derived cells (ENCDCs) and EMCs were cultured from the small intestine of Wnt1-Rosa26-tdTomato mice. EMCs promoted the expansion of ENCDCs 9.5-fold by inducing ENSC properties, including expression of Nes, Sox10, Sox2, and Ngfr. EMCs enhanced the neurosphere-forming ability of ENCDCs, and this persisted after withdrawal of the EMCs. These effects were mediated by paracrine factors and several ligands known to support neural stem cells were identified in EMCs. Using the optimized expansion procedures, neurospheres were generated from small intestine of the Ednrb −/− mouse model of HSCR. These ENSCs had similar proliferative and migratory capacity to Ednrb +/+ ENSCs, albeit neurospheres contained fewer neurons. ENSCs derived from Ednrb −/− mice generated functional neurons with similar calcium responses to Ednrb +/+ ENSCs and survived after transplantation into the aganglionic colon of Ednrb −/− recipients. EMCs act as supporting cells to ENSCs postnatally via an array of synergistically acting paracrine signaling factors. These properties can be leveraged to expand autologous ENSCs from patients with HSCR mutations for therapeutic application.

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“…HSCR is an enteric neuropathy which occurs in 1:5000 live-births and is characterized by aganglionosis along variable lengths of the distal intestine [10,20]. In most cases (80-90%), aganglionosis is affecting the rectum and the distal part of the sigmoid colon [20,21,32]. HSCR is caused by the failing of ENCCs to colonize the distal part of the intestinal tract during gestation (weeks 4 to 12 of human embryonic development).…”

Section: Ens Development and Enteric Neuron Differentiationmentioning

confidence: 99%

“…A rare HSCR-variant, the so-called skip segment HSCR, contains an area within the aganglionated GI tissue in which the intestine shows the presence of ganglia, therefore containing enteric neurons and glial cells [24]. HSCR leads to functional obstruction and an impaired GI motility which is potentially fatal [10,32]. So far, the therapy applied consists of a surgical resection of the aganglionated GI tissue and anastomosis of healthy innervated tissue with the remaining part of the rectum [21,32,33].…”

Section: Ens Development and Enteric Neuron Differentiationmentioning

confidence: 99%

Differentiation and Subtype Specification of Enteric Neurons: Current Knowledge of Transcription Factors, Signaling Molecules and Signaling Pathways Involved

2022

Journal of Cellular Signaling

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The ENS contains a network of neurons and glial cells which are dispersed over two major ganglionated and interconnected plexuses, the myenteric (Auerbach) plexus, and the submucosal (Meissner) plexus. In larger mammals, the submucosal plexus is further subdivided into smaller plexuses [4,[6][7][8][9][10]. The neurons of the myenteric plexus are primarily involved in GI motility regulation, while the neurons of the submucosal plexus are involved in the regulation of secretion and vascular tone [3,6,11,12]. The ENS is a highly complex nervous system of which the functioning is dependent on many different neuronal subtypes. To keep an overview of the neuronal subtypes, they are categorized in different classes according to certain characteristics. Among these features are their morphology, electrical properties, chemical coding, and

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Enteric neuronal cell therapy reverses architectural changes in a novel diphtheria toxin-mediated model of colonic aganglionosis

Cited by 21 publications

References 51 publications

Helicobacter pylori-induced protein tyrosine phosphatase receptor type C as a prognostic biomarker for gastric cancer

Helicobacter pylori-induced protein tyrosine phosphatase receptor type C as a prognostic biomarker for gastric cancer

Enteric mesenchymal cells support the growth of postnatal enteric neural stem cells

Differentiation and Subtype Specification of Enteric Neurons: Current Knowledge of Transcription Factors, Signaling Molecules and Signaling Pathways Involved

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