Rho GTPases as Key Molecular Players within Intestinal Mucosa and GI Diseases

Pradhan, Rashmita; Ngo, Phuong A.; Martínez-Sánchez, Luz del Carmen; López-Posadas, Rocío

doi:10.3390/cells10010066

Cited by 18 publications

(19 citation statements)

References 189 publications

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“…For all 4 cell lines, we found at least 200 genes showing significant individual-specific expression levels (LRT-adjusted P value<.01). Although the focus of our study was determining the TGFb response in each line, we did observe differences in individual-specific baseline expression of various genes implicated in IBD such as several Rho and GTPase activity genes 37 in the 269i VEOIBD line ( Figure 4B ). To determine if our lines were suitable to assay individual-specific fibrotic responses, we fitted our RNA-Seq data to a model that included an interaction term between TGFβ treatment and individual gene expression to identify a set of 159 genes with a significant individual-specific response to TGFβ (LRT-adjusted P -value<.01).…”

Section: Resultsmentioning

confidence: 86%

Development of a Personalized Intestinal Fibrosis Model Using Human Intestinal Organoids Derived From Induced Pluripotent Stem Cells

Estrada

Patel

Rabizadeh

et al. 2021

Inflammatory Bowel Diseases

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Background Intestinal fibrosis is a serious complication of Crohn’s disease. Numerous cell types including intestinal epithelial and mesenchymal cells are implicated in this process, yet studies are hampered by the lack of personalized in vitro models. Human intestinal organoids (HIOs) derived from induced pluripotent stem cells (iPSCs) contain these cell types, and our goal was to determine the feasibility of utilizing these to develop a personalized intestinal fibrosis model. Methods iPSCs from 2 control individuals and 2 very early onset inflammatory bowel disease patients with stricturing complications were obtained and directed to form HIOs. Purified populations of epithelial and mesenchymal cells were derived from HIOs, and both types were treated with the profibrogenic cytokine transforming growth factor β (TGFβ). Quantitative polymerase chain reaction and RNA sequencing analysis were used to assay their responses. Results In iPSC-derived mesenchymal cells, there was a significant increase in the expression of profibrotic genes (Col1a1, Col5a1, and TIMP1) in response to TGFβ. RNA sequencing analysis identified further profibrotic genes and demonstrated differential responses to this cytokine in each of the 4 lines. Increases in profibrotic gene expression (Col1a1, FN, TIMP1) along with genes associated with epithelial-mesenchymal transition (vimentin and N-cadherin) were observed in TGFβ -treated epithelial cells. Conclusions We demonstrate the feasibility of utilizing iPSC-HIO technology to model intestinal fibrotic responses in vitro. This now permits the generation of near unlimited quantities of patient-specific cells that could be used to reveal cell- and environmental-specific mechanisms underpinning intestinal fibrosis.

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Section: Resultsmentioning

confidence: 86%

Development of a Personalized Intestinal Fibrosis Model Using Human Intestinal Organoids Derived From Induced Pluripotent Stem Cells

Estrada

Patel

Rabizadeh

et al. 2021

Inflammatory Bowel Diseases

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“…RhoGTPases (RhoA, Rac1, and Cdc42) are key modulators of intestinal mucosa and GI diseases [ 39 ]. The RhoA signaling pathway is involved in the mechanism of IBD [ 25 ].…”

Section: Resultsmentioning

confidence: 99%

Bamboo Shoot and Artemisia capillaris Extract Mixture Ameliorates Dextran Sodium Sulfate-Induced Colitis

Kim

Lee

et al. 2022

CIMB

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Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract and is characterized by recurrent chronic inflammation and mucosal damage of the gastrointestinal tract. Recent studies have demonstrated that bamboo shoot (BS) and Artemisia capillaris (AC) extracts enhance anti-inflammatory effects in various disease models. However, it is uncertain whether there is a synergistic protective effect of BS and AC in dextran sodium sulfate (DSS)-induced colitis. In the current study, we tested the combined effects of BS and AC extracts (BA) on colitis using in vivo and in vitro models. Compared with control mice, oral administration of DSS exacerbated colon length and increased the disease activity index (DAI) and histological damage. In DSS-induced colitis, treatment with BA significantly alleviated DSS-induced symptoms such as colon shortening, DAI, histological damage, and colonic pro-inflammatory marker expression compared to single extracts (BS or AC) treatment. Furthermore, we found BA treatment attenuated the ROS generation, F-actin formation, and RhoA activity compared with the single extract (BS or AC) treatment in DSS-treated cell lines. Collectively, these findings suggest that BA treatment has a positive synergistic protective effect on colonic inflammation compared with single extracts, it may be a highly effective complementary natural extract mixture for the prevention or treatment of IBD.

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“…Rho GTPase signaling has been linked to cell polarity and other cellular processes (e.g., cell cycle, cell migration, cytoskeletal structure) in a variety of biological situations [ 36 , 37 ]. CDC42, a key member of the Rho GTPase family, has been linked to various aspects of cellular biology, including the establishment of polarity in epithelial cells [ 38 ]. CDC42 interacts with and activates multiple effector proteins when activated in GTP-bound form.…”

Section: Discussionmentioning

confidence: 99%

Whole Exome Sequencing and In Silico Analysis of Human Sertoli in Patients with Non-Obstructive Azoospermia

Azizi

Karoii

Skutella

2022

IJMS

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Non-obstructive azoospermia (NOA) is a serious cause of male infertility. The Sertoli cell responds to androgens and takes on roles supporting spermatogenesis, which may cause infertility. This work aims to enhance the genetic diagnosis of NOA via the discovery of new and hub genes implicated in human NOA and to better assess the odds of successful sperm extraction according to the individual’s genotype. Whole exome sequencing (WES) was done on three NOA patients to find key genes involved in NOA. We evaluated genome-wide transcripts (about 50,000 transcripts) by microarray between the Sertoli of non-obstructive azoospermia and normal cells. The microarray analysis of three human cases with different non-obstructive azoospermia revealed that 32 genes were upregulated, and the expressions of 113 genes were downregulated versus the normal case. For this purpose, Enrich Shiny GO, STRING, and Cytoscape online evaluations were applied to predict the functional and molecular interactions of proteins and then recognize the master pathways. The functional enrichment analysis demonstrated that the biological process (BP) terms “inositol lipid-mediated signaling”, “positive regulation of transcription by RNA polymerase II”, and “positive regulation of DNA-templated transcription” significantly changed in upregulated differentially expressed genes (DEGs). The BP investigation of downregulated DEGs highlighted “mitotic cytokinesis”, “regulation of protein-containing complex assembly”, “cytoskeleton-dependent cytokinesis”, and the “peptide metabolic process”. Overrepresented molecular function (MF) terms in upregulated DEGs included “ubiquitin-specific protease binding”, “protease binding”, “phosphatidylinositol trisphosphate phosphatase activity”, and “clathrin light chain binding”. Interestingly, the MF analysis of the downregulated DEGs revealed overexpression in “ATPase inhibitor activity”, “glutathione transferase activity”, and “ATPase regulator activity”. Our findings suggest that these genes and their interacting hub proteins could help determine the pathophysiologies of germ cell abnormalities and infertility.

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Rho GTPases as Key Molecular Players within Intestinal Mucosa and GI Diseases

Cited by 18 publications

References 189 publications

Development of a Personalized Intestinal Fibrosis Model Using Human Intestinal Organoids Derived From Induced Pluripotent Stem Cells

Development of a Personalized Intestinal Fibrosis Model Using Human Intestinal Organoids Derived From Induced Pluripotent Stem Cells

Bamboo Shoot and Artemisia capillaris Extract Mixture Ameliorates Dextran Sodium Sulfate-Induced Colitis

Whole Exome Sequencing and In Silico Analysis of Human Sertoli in Patients with Non-Obstructive Azoospermia

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