Intestine‐on‐chip device increases ECM remodeling inducing faster epithelial cell differentiation

Gregorio, Vincenza De; Corrado, Brunella; Sbrescia, Simone; Sibilio, Sara; Urciuolo, Francesco; Netti, Paolo A.; Imparato, Giorgia

doi:10.1002/bit.27186

Cited by 36 publications

(32 citation statements)

References 35 publications

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“…This study was performed by culturing a monolayer of epithelium above a monolayer of endothelium 46 . Similarly, other studies have demonstrated an effect of ISEMFs on epithelial development and function 14,47 . We were thus curious to determine whether there was an additive effect of ECs and ISEMFs on epithelial biology.…”

Section: Isemf and Ec-derived Vasculature Is Quantitatively Responsivmentioning

confidence: 76%

Patient-derived small intestinal myofibroblasts direct perfused, physiologically responsive capillary development in a microfluidic Gut-on-a-Chip Model

Seiler

Bajinting

Alvarado

et al. 2020

Sci Rep

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The development and physiologic role of small intestine (SI) vasculature is poorly studied. This is partly due to a lack of targetable, organ-specific markers for in vivo studies of two critical tissue components: endothelium and stroma. This challenge is exacerbated by limitations of traditional cell culture techniques, which fail to recapitulate mechanobiologic stimuli known to affect vessel development. Here, we construct and characterize a 3D in vitro microfluidic model that supports the growth of patient-derived intestinal subepithelial myofibroblasts (ISEMFs) and endothelial cells (ECs) into perfused capillary networks. We report how ISEMF and EC-derived vasculature responds to physiologic parameters such as oxygen tension, cell density, growth factors, and pharmacotherapy with an antineoplastic agent (Erlotinib). Finally, we demonstrate effects of ISEMF and EC co-culture on patientderived human intestinal epithelial cells (HIECs), and incorporate perfused vasculature into a gut-ona-chip (GOC) model that includes HIECs. Overall, we demonstrate that ISEMFs possess angiogenic properties as evidenced by their ability to reliably, reproducibly, and quantifiably facilitate development of perfused vasculature in a microfluidic system. We furthermore demonstrate the feasibility of including perfused vasculature, including ISEMFs, as critical components of a novel, patient-derived, GOC system with translational relevance as a platform for precision and personalized medicine research. Blood vessels supply oxygen and nutrients needed to sustain life. As such, their structure and response to physiological stimuli are crucial to nearly all aspects of human biology. This includes normal developmental and pathological conditions affecting the SI such as short gut syndrome, inflammatory bowel disease, and cancer 1-6 .

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Section: Isemf and Ec-derived Vasculature Is Quantitatively Responsivmentioning

confidence: 76%

Patient-derived small intestinal myofibroblasts direct perfused, physiologically responsive capillary development in a microfluidic Gut-on-a-Chip Model

Seiler

Bajinting

Alvarado

et al. 2020

Sci Rep

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“…It is important to clarify that the analysis of single cells falls behind its importance if not associated with spatial information. Moreover, cells have their own identity because of the consistence (rigidity) of their ambient (extracellular matrix) [221][222][223]. The human body, for example, is formed by~100 trillion cells each spatially located in specific tissues with different softness where exerting their functions in a collaborative network with other cells.…”

Section: Discussionmentioning

confidence: 99%

A Single Cell but Many Different Transcripts: A Journey into the World of Long Non-Coding RNAs

Alessio

Bonadio

Buson

et al. 2020

IJMS

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In late 2012 it was evidenced that most of the human genome is transcribed but only a small percentage of the transcripts are translated. This observation supported the importance of non-coding RNAs and it was confirmed in several organisms. The most abundant non-translated transcripts are long non-coding RNAs (lncRNAs). In contrast to protein-coding RNAs, they show a more cell-specific expression. To understand the function of lncRNAs, it is fundamental to investigate in which cells they are preferentially expressed and to detect their subcellular localization. Recent improvements of techniques that localize single RNA molecules in tissues like single-cell RNA sequencing and fluorescence amplification methods have given a considerable boost in the knowledge of the lncRNA functions. In recent years, single-cell transcription variability was associated with non-coding RNA expression, revealing this class of RNAs as important transcripts in the cell lineage specification. The purpose of this review is to collect updated information about lncRNA classification and new findings on their function derived from single-cell analysis. We also retained useful for all researchers to describe the methods available for single-cell analysis and the databases collecting single-cell and lncRNA data. Tables are included to schematize, describe, and compare exposed concepts.Int. J. Mol. Sci. 2020, 21, 302 2 of 32 not achieved by transcription factors (TFs) alone because of their low number (approximately 1500 in mammals [4]) compared to genes to regulate (90% of the genome is transcribed in human [5]). A single TF is estimated to regulate only ten thousand genes according to Chromatin immunoprecipitation and DNA sequencing experiments (ChIp-seq) [6]. Moreover, the involvement of non-coding RNAs in gene expression regulation was evident [7,8]. The evidence that the non-protein coding component of the human genome is actively transcribed and carries out crucial functions limits the importance of coding genes in genome regulation. Non-coding transcripts become one of the stars of modern biology, especially because of their involvement in a wide range of regulatory processes and changed the association of non-coding regions to junk DNA [3].The genome of multicellular eukaryotes is mostly comprised of non-coding DNA (less than 2% of the human genome codes for proteins [9] while 90% of the human genome is transcribed). Non-coding DNA is transcribed into different classes of non-coding RNAs (ncRNAs) that include structural RNAs (rRNAs and tRNAs) and regulatory RNAs [10]. rRNAs and tRNAs are involved in mRNA translation and can be long or short in size. Regulatory RNAs are further divided into three classes: Small, medium, and long non-coding RNAs. Small non-coding RNAs are between 20 and 50 nucleotides long and include microRNAs (miRNAs) that participate in post-transcriptional regulation [11], small interfering RNAs (siRNAs) that are double-stranded RNAs involved in gene silencing through RNA interfering pathway [12], piwi interacting R...

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“…Specifically, the CF-CAT was achieved in vitro by using a bottom up approach ( Figure 1 ) and it featured the presence of fibroblasts embedded in their own native ECM. By using the same approach, our group already demonstrated the possibility of recapitulating in vitro the physio-pathological environment of different tissues in terms of composition and features of the organ-specific ECM, as well as interaction between the epithelial and stromal compartments [ 9 , 52 , 53 ]. CF arises from CFTR mutation in epithelial cells, but the severe complications of this pathology involve the entire pulmonary tissue and dramatically compromise lung functions.…”

Section: Discussionmentioning

confidence: 99%

Intrinsic Abnormalities of Cystic Fibrosis Airway Connective Tissue Revealed by an In Vitro 3D Stromal Model

Mazio

Scognamiglio

Cegli

et al. 2020

Cells

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Cystic fibrosis is characterized by lung dysfunction involving mucus hypersecretion, bacterial infections, and inflammatory response. Inflammation triggers pro-fibrotic signals that compromise lung structure and function. At present, several in vitro cystic fibrosis models have been developed to study epithelial dysfunction but none of these focuses on stromal alterations. Here we show a new cystic fibrosis 3D stromal lung model made up of primary fibroblasts embedded in their own extracellular matrix and investigate its morphological and transcriptomic features. Cystic fibrosis fibroblasts showed a high proliferation rate and produced an abundant and chaotic matrix with increased protein content and elastic modulus. More interesting, they had enhanced pro-fibrotic markers and genes involved in epithelial function and inflammatory response. In conclusion, our study reveals that cystic fibrosis fibroblasts maintain in vitro an activated pro-fibrotic state. This abnormality may play in vivo a role in the modulation of epithelial and inflammatory cell behavior and lung remodeling. We argue that the proposed bioengineered model may provide new insights on epithelial/stromal/inflammatory cells crosstalk in cystic fibrosis, paving the way for novel therapeutic strategies.

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Intestine‐on‐chip device increases ECM remodeling inducing faster epithelial cell differentiation

Cited by 36 publications

References 35 publications

Patient-derived small intestinal myofibroblasts direct perfused, physiologically responsive capillary development in a microfluidic Gut-on-a-Chip Model

Patient-derived small intestinal myofibroblasts direct perfused, physiologically responsive capillary development in a microfluidic Gut-on-a-Chip Model

A Single Cell but Many Different Transcripts: A Journey into the World of Long Non-Coding RNAs

Intrinsic Abnormalities of Cystic Fibrosis Airway Connective Tissue Revealed by an In Vitro 3D Stromal Model

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