The intestinal tissue homeostasis – the role of extracellular matrix remodeling in inflammatory bowel disease

Mortensen, Joachim Høg; Lindholm, Majken; Langholm, Lasse; Kjeldsen, Jens; Bay‐Jensen, Anne‐Christine; Karsdal, Morten A.; Manon‐Jensen, Tina

doi:10.1080/17474124.2019.1673729

Cited by 55 publications

(67 citation statements)

References 133 publications

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“…ECM is a physiologically functional tissue element, responsible for cell adhesion, cell-cell communication, and cell proliferation [15]. Basically, the ECM is composed of glycosaminoglycans (GAGs), most often covalently linked to several proteins forming the proteoglycans, and fibrous proteins as collagen, elastin, fibronectin, and laminin [16]. These components are secreted locally by the cells and assembled into the organized meshwork that is the ECM microenvironment.…”

Section: Introductionmentioning

confidence: 99%

Recellularized Colorectal Cancer Patient-Derived Scaffolds as In Vitro Pre-Clinical 3D Model for Drug Screening

Sensi

D’Angelo

Piccoli

et al. 2020

Cancers

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Colorectal cancer (CRC) shows highly ineffective therapeutic management. An urgent unmet need is the random assignment to adjuvant chemotherapy of high-risk stage II and stage III CRC patients without any predictive factor of efficacy. In the field of drug discovery, a critical step is the preclinical evaluation of drug cytotoxicity, efficacy, and efficiency. We proposed a patient-derived 3D preclinical model for drug evaluation that could mimic in vitro the patient’s disease. Surgically resected CRC tissue and adjacent healthy colon mucosa were decellularized by a detergent-enzymatic treatment. Scaffolds were recellularized with HT29 and HCT116 cells. Qualitative and quantitative characterization of matched recellularized samples were evaluated through histology, immunofluorescences, scanning electron microscopy, and DNA amount quantification. A chemosensitivity test was performed using an increasing concentration of 5-fluorouracil (5FU). In vivo studies were carried out using zebrafish (Danio rerio) animal model. Permeability test and drug absorption were also determined. The decellularization protocol allowed the preservation of the original structure and ultrastructure. Five days after recellularization with HT29 and HCT116 cell lines, the 3D CRC model exhibited reduced sensitivity to 5FU treatments compared with conventional 2D cultures. Calculated the half maximal inhibitory concentration (IC50) for HT29 treated with 5FU resulted in 11.5 µM in 3D and 1.3 µM in 2D, and for HCT116, 9.87 µM in 3D and 1.7 µM in 2D. In xenograft experiments, HT29 extravasation was detected after 4 days post-injection, and we obtained a 5FU IC50 fully comparable to that observed in the 3D CRC model. Using confocal microscopy, we demonstrated that the drug diffused through the repopulated 3D CRC scaffolds and co-localized with the cell nuclei. The bioengineered CRC 3D model could be a reliable preclinical patient-specific platform to bridge the gap between in vitro and in vivo drug testing assays and provide effective cancer treatment.

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Section: Introductionmentioning

confidence: 99%

Recellularized Colorectal Cancer Patient-Derived Scaffolds as In Vitro Pre-Clinical 3D Model for Drug Screening

Sensi

D’Angelo

Piccoli

et al. 2020

Cancers

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“…7 Therefore, proteins related to the intestinal epithelium for assessing intestinal permeability/epithelial integrity and intestinal tissue homeostasis may be used to evaluate the disease burden. 1,11,[13][14][15][25][26][27] The antibody in the PRO-C23 ELISA only recognised the C-terminus sequence of the ectodomain of type 23 collagen and had no cross-reaction with the C-terminus of type XIII and XXV collagen, which have similar sequences. This data confirmed the specificity of the antibody.…”

Section: Discussionmentioning

confidence: 99%

“…Adapted from Karsdal et al 27 inflamed intestinal tissue, [7][8][9][10] and increased ECM remodeling was highly affected in both UC and CD, including remodelling of the basement membrane which was also related to epithelial cells driven by increased protease activity. [11][12][13][14][15][16][17][18][19][20][21] Based on this background it was likely that type 23 collagen was also affected by the ECM remodelling in UC and CD. Type 23 collagen was found to be related to cell adhesion and metastasis in vitro.…”

Section: Introductionmentioning

confidence: 99%

Elevated ectodomain of type 23 collagen is a novel biomarker of the intestinal epithelium to monitor disease activity in ulcerative colitis and Crohn's disease

et al. 2021

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Background Impaired intestinal epithelial barrier is highly affected in inflammatory bowel disease. Transmembrane collagens connecting the epithelial cells to the extracellular matrix have an important role in epithelial cell homeostasis. Thus, we sought to determine whether the transmembrane type 23 collagen could serve as a surrogate marker for disease activity in patients with Crohn’s disease and ulcerative colitis. Methods We developed an enzyme-linked immunosorbent assay to detect the ectodomain of type 23 collagen (PRO-C23) in serum, followed by evaluation of its levels in both acute and chronic dextran sulfate sodium colitis models in rats and human inflammatory bowel disease cohorts. Serum from 44 Crohn’s disease and 29 ulcerative colitis patients with active and inactive disease was included. Results In the acute and chronic dextran sulfate sodium-induced rat colitis model, the PRO-C23 serum levels were significantly increased after colitis and returned to normal levels after disease remission. Serum levels of PRO-C23 were elevated in Crohn’s disease ( p < 0.05) and ulcerative colitis ( p < 0.001) patients with active disease compared to healthy donors. PRO-C23 differentiated healthy donors from ulcerative colitis (area under the curve: 0.81, p = 0.0009) and Crohn’s disease (area under the curve: 0.70, p = 0.0124). PRO-C23 differentiated ulcerative colitis patients with active disease from those in remission (Area under the curve: 0.75, p = 0.0219) and Crohn’s disease patients with active disease from those in remission (area under the curve: 0.68, p = 0.05). Conclusion PRO-C23 was elevated in rats with active colitis, and inflammatory bowel disease patients with active disease. Therefore, PRO-C23 may be used as a surrogate marker for monitoring disease activity in ulcerative colitis and Crohn’s disease.

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“…The impact of this remodeling, including ECM biochemical and mechanical property alterations, on the disease process is a concept that is now well-accepted [45,46]. During colorectal pathologies, especially during IBD and CRC, an intense remodeling of the ECM is observed [47][48][49]. IBD is a term regrouping two types of GI disorders: Crohn's disease (CD) and ulcerative colitis (UC).…”

Section: Proteinsmentioning

confidence: 99%

Extracellular Matrix Mechanical Properties and Regulation of the Intestinal Stem Cells: When Mechanics Control Fate

Onfroy-Roy

Hamel

Foncy

et al. 2020

Cells

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Intestinal stem cells (ISC) are crucial players in colon epithelium physiology. The accurate control of their auto-renewal, proliferation and differentiation capacities provides a constant flow of regeneration, maintaining the epithelial intestinal barrier integrity. Under stress conditions, colon epithelium homeostasis in disrupted, evolving towards pathologies such as inflammatory bowel diseases or colorectal cancer. A specific environment, namely the ISC niche constituted by the surrounding mesenchymal stem cells, the factors they secrete and the extracellular matrix (ECM), tightly controls ISC homeostasis. Colon ECM exerts physical constraint on the enclosed stem cells through peculiar topography, stiffness and deformability. However, little is known on the molecular and cellular events involved in ECM regulation of the ISC phenotype and fate. To address this question, combining accurately reproduced colon ECM mechanical parameters to primary ISC cultures such as organoids is an appropriated approach. Here, we review colon ECM physical properties at physiological and pathological states and their bioengineered in vitro reproduction applications to ISC studies.

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The intestinal tissue homeostasis – the role of extracellular matrix remodeling in inflammatory bowel disease

Cited by 55 publications

References 133 publications

Recellularized Colorectal Cancer Patient-Derived Scaffolds as In Vitro Pre-Clinical 3D Model for Drug Screening

Recellularized Colorectal Cancer Patient-Derived Scaffolds as In Vitro Pre-Clinical 3D Model for Drug Screening

Elevated ectodomain of type 23 collagen is a novel biomarker of the intestinal epithelium to monitor disease activity in ulcerative colitis and Crohn's disease

Extracellular Matrix Mechanical Properties and Regulation of the Intestinal Stem Cells: When Mechanics Control Fate

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