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Novel Biorelevant Intestinal Epithelial In Vitro Models
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Novel Biorelevant Intestinal Epithelial In Vitro Models

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 45108

Special Issue Editors

Dr. Kati Juuti-Uusitalo

E-Mail Website
Guest Editor
Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
Interests: patient derived induced pluripotent stem cells; intestinal epithelial cell differentiation; barrier function; celiac disease; type 1 diabetes
Dr. Keijo Viiri

E-Mail Website
Guest Editor
Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
Interests: intestinal epigenetics; genome-wide analyses; intestinal signalling; intestinal organoids; celiac disease

Special Issue Information

Dear Colleagues,

We are delighted to announce that we are now accepting submissions for the upcoming Special Issue of the International Journal of Molecular Sciences on the topic of Novel Biorelevant Intestinal Epithelial In Vitro Models. The human small intestine is responsible for multiple functions, such as the absorption of nutrients, vitamins or drugs; the transportation of electrolytes; the secretion of biologically active peptide hormones; the formation of an impermeable barrier against viruses and microbes; and even the formation of direct synapses with sensory neurons. Previously, functional assays have been hampered by the low biological resemblance of the in vitro models to actual small intestinal tissue. In recent years, several novel small intestinal in vitro and organotypic ex vivo models, which bear a stronger resemblance to the in vivo tissue than conventional models, have emerged. Many of these novel models are based on patient stem cells, are cultured three-dimensionally, can be co-cultured with several other cell types with which they are known to interact in vivo (e.g., immune and neuronal cells) and thus represent more suitable means of assessing several aspects of intestinal epithelial functionality, such as the gut–brain axis and the effects of the microbiome on intestinal functionality, as well as studying drug absorption and metabolism in several small intestinal diseases.  

We encourage submission of both original research articles and topical reviews on all aspects of novel biorelevant intestinal epithelial in vitro models and their exploitation in endeavours to study the abovementioned aspects. All submitted articles will undergo peer review.

Dr. Kati Juuti-Uusitalo
Dr. Keijo Viiri
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • patient-derived stem cell models
  • microfluidic organ-on-a-chip models of human intestine
  • intestinal organoids
  • gut–brain axis
  • microbiome assays
  • drug delivery assays
  • gastrointestinal hormones
  • intestinal diseases

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Published Papers (7 papers)

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Research

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19 pages, 5532 KiB  
Article
Toward Xeno-Free Differentiation of Human Induced Pluripotent Stem Cell-Derived Small Intestinal Epithelial Cells
by Jaakko Saari, Fatima Siddique, Sanna Korpela, Elina Mäntylä, Teemu O. Ihalainen, Katri Kaukinen, Katriina Aalto-Setälä, Katri Lindfors and Kati Juuti-Uusitalo
Int. J. Mol. Sci. 2022, 23(3), 1312; https://doi.org/10.3390/ijms23031312 - 24 Jan 2022
Cited by 2 | Viewed by 4594
Abstract
The small intestinal epithelium has an important role in nutrition, but also in drug absorption and metabolism. There are a few two-dimensional (2D) patient-derived induced pluripotent stem cell (iPSC)-based intestinal models enabling easy evaluation of transcellular transport. It is known that animal-derived components [...] Read more.
The small intestinal epithelium has an important role in nutrition, but also in drug absorption and metabolism. There are a few two-dimensional (2D) patient-derived induced pluripotent stem cell (iPSC)-based intestinal models enabling easy evaluation of transcellular transport. It is known that animal-derived components induce variation in the experimental outcomes. Therefore, we aimed to refine the differentiation protocol by using animal-free components. More specifically, we compared maturation of 2D-cultured iPCSs toward small intestinal epithelial cells when cultured either with or without serum, and either on Geltrex or on animal-free, recombinant laminin-based substrata. Differentiation status was characterized by qPCR, immunofluorescence imaging, and functionality assays. Our data suggest that differentiation toward definitive endoderm is more efficient without serum. Both collagen- and recombinant laminin-based coating supported differentiation of definitive endoderm, posterior definitive endoderm, and small intestinal epithelial cells from iPS-cells equally well. Small intestinal epithelial cells differentiated on recombinant laminin exhibited slightly more enterocyte specific cellular functionality than cells differentiated on Geltrex. Our data suggest that functional small intestinal epithelial cells can be generated from iPSCs in serum-free method on xeno-free substrata. This method is easily converted to an entirely xeno-free method. Full article
(This article belongs to the Special Issue Novel Biorelevant Intestinal Epithelial In Vitro Models)
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14 pages, 13025 KiB  
Article
Establishment of Intestinal Organoid from Rousettus leschenaultii and the Susceptibility to Bat-Associated Viruses, SARS-CoV-2 and Pteropine Orthoreovirus
by Mohamed Elbadawy, Yuki Kato, Nagisa Saito, Kimika Hayashi, Amira Abugomaa, Mio Kobayashi, Toshinori Yoshida, Makoto Shibutani, Masahiro Kaneda, Hideyuki Yamawaki, Tetsuya Mizutani, Chang-Kweng Lim, Masayuki Saijo, Kazuaki Sasaki, Tatsuya Usui and Tsutomu Omatsu
Int. J. Mol. Sci. 2021, 22(19), 10763; https://doi.org/10.3390/ijms221910763 - 5 Oct 2021
Cited by 18 | Viewed by 6109
Abstract
Various pathogens, such as Ebola virus, Marburg virus, Nipah virus, Hendra virus, Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV), Middle East Respiratory Syndrome Coronavirus (MERS-CoV), and SARS-CoV-2, are threatening human health worldwide. The natural hosts of these pathogens are thought to be bats. The [...] Read more.
Various pathogens, such as Ebola virus, Marburg virus, Nipah virus, Hendra virus, Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV), Middle East Respiratory Syndrome Coronavirus (MERS-CoV), and SARS-CoV-2, are threatening human health worldwide. The natural hosts of these pathogens are thought to be bats. The rousette bat, a megabat, is thought to be a natural reservoir of filoviruses, including Ebola and Marburg viruses. Additionally, the rousette bat showed a transient infection in the experimental inoculation of SARS-CoV-2. In the current study, we established and characterized intestinal organoids from Leschenault’s rousette, Rousettus leschenaultii. The established organoids successfully recapitulated the characteristics of intestinal epithelial structure and morphology, and the appropriate supplements necessary for long-term stable culture were identified. The organoid showed susceptibility to Pteropine orthoreovirus (PRV) but not to SARS-CoV-2 in experimental inoculation. This is the first report of the establishment of an expandable organoid culture system of the rousette bat intestinal organoid and its sensitivity to bat-associated viruses, PRV and SARS-CoV-2. This organoid is a useful tool for the elucidation of tolerance mechanisms of the emerging rousette bat-associated viruses such as Ebola and Marburg virus. Full article
(This article belongs to the Special Issue Novel Biorelevant Intestinal Epithelial In Vitro Models)
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12 pages, 1906 KiB  
Article
Interleukin-4 Promotes Tuft Cell Differentiation and Acetylcholine Production in Intestinal Organoids of Non-Human Primate
by Akihiko Inaba, Ayane Arinaga, Keisuke Tanaka, Takaho Endo, Norihito Hayatsu, Yasushi Okazaki, Takumi Yamane, Yuichi Oishi, Hiroo Imai and Ken Iwatsuki
Int. J. Mol. Sci. 2021, 22(15), 7921; https://doi.org/10.3390/ijms22157921 - 24 Jul 2021
Cited by 12 | Viewed by 4906
Abstract
In the intestine, the innate immune system excludes harmful substances and invading microorganisms. Tuft cells are taste-like chemosensory cells found in the intestinal epithelium involved in the activation of group 2 innate lymphoid cells (ILC2). Although tuft cells in other tissues secrete the [...] Read more.
In the intestine, the innate immune system excludes harmful substances and invading microorganisms. Tuft cells are taste-like chemosensory cells found in the intestinal epithelium involved in the activation of group 2 innate lymphoid cells (ILC2). Although tuft cells in other tissues secrete the neurotransmitter acetylcholine (ACh), their function in the gut remains poorly understood. In this study, we investigated changes in the expression of genes and cell differentiation of the intestinal epithelium by stimulation with interleukin-4 (IL-4) or IL-13 in macaque intestinal organoids. Transcriptome analysis showed that tuft cell marker genes were highly expressed in the IL-4- and IL-13-treated groups compared with the control, and the gene expression of choline acetyltransferase (ChAT), a synthesis enzyme of ACh, was upregulated in IL-4- and IL-13-treated groups. ACh accumulation was observed in IL-4-induced organoids using high-performance liquid chromatography-mass spectrometry (HPLC/MS), and ACh strongly released granules from Paneth cells. This study is the first to demonstrate ACh upregulation by IL-4 induction in primates, suggesting that IL-4 plays a role in Paneth cell granule secretion via paracrine stimulation. Full article
(This article belongs to the Special Issue Novel Biorelevant Intestinal Epithelial In Vitro Models)
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12 pages, 14286 KiB  
Article
The Role of Processed Aloe vera Gel in Intestinal Tight Junction: An In Vivo and In Vitro Study
by Thu Han Le Phan, Se Yong Park, Hyun Jin Jung, Min Woo Kim, Eunae Cho, Kyu-Suk Shim, Eunju Shin, Jin-Ha Yoon, Han-Joo Maeng, Ju-Hee Kang and Seung Hyun Oh
Int. J. Mol. Sci. 2021, 22(12), 6515; https://doi.org/10.3390/ijms22126515 - 17 Jun 2021
Cited by 5 | Viewed by 5275
Abstract
Leaky gut is a condition of increased paracellular permeability of the intestine due to compromised tight junction barriers. In recent years, this affliction has drawn the attention of scientists from different fields, as a myriad of studies prosecuted it to be the silent [...] Read more.
Leaky gut is a condition of increased paracellular permeability of the intestine due to compromised tight junction barriers. In recent years, this affliction has drawn the attention of scientists from different fields, as a myriad of studies prosecuted it to be the silent culprit of various immune diseases. Due to various controversies surrounding its culpability in the clinic, approaches to leaky gut are restricted in maintaining a healthy lifestyle, avoiding irritating factors, and practicing alternative medicine, including the consumption of supplements. In the current study, we investigate the tight junction-modulating effects of processed Aloe vera gel (PAG), comprising 5–400-kD polysaccharides as the main components. Our results show that oral treatment of 143 mg/kg PAG daily for 10 days improves the age-related leaky gut condition in old mice, by reducing their individual urinal lactulose/mannitol (L/M) ratio. In concordance with in vivo experiments, PAG treatment at dose 400 μg/mL accelerated the polarization process of Caco-2 monolayers. The underlying mechanism was attributed to enhancement in the expression of intestinal tight junction-associated scaffold protein zonula occludens (ZO)-1 at the translation level. This was induced by activation of the MAPK/ERK signaling pathway, which inhibits the translation repressor 4E-BP1. In conclusion, we propose that consuming PAG as a complementary food has the potential to benefit high-risk patients. Full article
(This article belongs to the Special Issue Novel Biorelevant Intestinal Epithelial In Vitro Models)
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19 pages, 7219 KiB  
Article
A 3D Renal Proximal Tubule on Chip Model Phenocopies Lowe Syndrome and Dent II Disease Tubulopathy
by Sindhu Naik, Andrew R. Wood, Maté Ongenaert, Paniz Saidiyan, Edo D. Elstak, Henriëtte L. Lanz, Jan Stallen, Richard Janssen, Elizabeth Smythe and Kai S. Erdmann
Int. J. Mol. Sci. 2021, 22(10), 5361; https://doi.org/10.3390/ijms22105361 - 19 May 2021
Cited by 10 | Viewed by 5053
Abstract
Lowe syndrome and Dent II disease are X-linked monogenetic diseases characterised by a renal reabsorption defect in the proximal tubules and caused by mutations in the OCRL gene, which codes for an inositol-5-phosphatase. The life expectancy of patients suffering from Lowe syndrome is [...] Read more.
Lowe syndrome and Dent II disease are X-linked monogenetic diseases characterised by a renal reabsorption defect in the proximal tubules and caused by mutations in the OCRL gene, which codes for an inositol-5-phosphatase. The life expectancy of patients suffering from Lowe syndrome is largely reduced because of the development of chronic kidney disease and related complications. There is a need for physiological human in vitro models for Lowe syndrome/Dent II disease to study the underpinning disease mechanisms and to identify and characterise potential drugs and drug targets. Here, we describe a proximal tubule organ on chip model combining a 3D tubule architecture with fluid flow shear stress that phenocopies hallmarks of Lowe syndrome/Dent II disease. We demonstrate the high suitability of our in vitro model for drug target validation. Furthermore, using this model, we demonstrate that proximal tubule cells lacking OCRL expression upregulate markers typical for epithelial–mesenchymal transition (EMT), including the transcription factor SNAI2/Slug, and show increased collagen expression and deposition, which potentially contributes to interstitial fibrosis and disease progression as observed in Lowe syndrome and Dent II disease. Full article
(This article belongs to the Special Issue Novel Biorelevant Intestinal Epithelial In Vitro Models)
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Review

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18 pages, 1611 KiB  
Review
The Progress of Intestinal Epithelial Models from Cell Lines to Gut-On-Chip
by Shafaque Rahman, Mohammed Ghiboub, Joanne M. Donkers, Evita van de Steeg, Eric A. F. van Tol, Theodorus B. M. Hakvoort and Wouter J. de Jonge
Int. J. Mol. Sci. 2021, 22(24), 13472; https://doi.org/10.3390/ijms222413472 - 15 Dec 2021
Cited by 43 | Viewed by 8529
Abstract
Over the past years, several preclinical in vitro and ex vivo models have been developed that helped to understand some of the critical aspects of intestinal functions in health and disease such as inflammatory bowel disease (IBD). However, the translation to the human [...] Read more.
Over the past years, several preclinical in vitro and ex vivo models have been developed that helped to understand some of the critical aspects of intestinal functions in health and disease such as inflammatory bowel disease (IBD). However, the translation to the human in vivo situation remains problematic. The main reason for this is that these approaches fail to fully reflect the multifactorial and complex in vivo environment (e.g., including microbiota, nutrition, and immune response) in the gut system. Although conventional models such as cell lines, Ussing chamber, and the everted sac are still used, increasingly more sophisticated intestinal models have been developed over the past years including organoids, InTESTine™ and microfluidic gut-on-chip. In this review, we gathered the most recent insights on the setup, advantages, limitations, and future perspectives of most frequently used in vitro and ex vivo models to study intestinal physiology and functions in health and disease. Full article
(This article belongs to the Special Issue Novel Biorelevant Intestinal Epithelial In Vitro Models)
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14 pages, 1996 KiB  
Review
Modeling Intestinal Stem Cell Function with Organoids
by Toshio Takahashi, Kazuto Fujishima and Mineko Kengaku
Int. J. Mol. Sci. 2021, 22(20), 10912; https://doi.org/10.3390/ijms222010912 - 9 Oct 2021
Cited by 22 | Viewed by 9333
Abstract
Intestinal epithelial cells (IECs) are crucial for the digestive process and nutrient absorption. The intestinal epithelium is composed of the different cell types of the small intestine (mainly, enterocytes, goblet cells, Paneth cells, enteroendocrine cells, and tuft cells). The small intestine is characterized [...] Read more.
Intestinal epithelial cells (IECs) are crucial for the digestive process and nutrient absorption. The intestinal epithelium is composed of the different cell types of the small intestine (mainly, enterocytes, goblet cells, Paneth cells, enteroendocrine cells, and tuft cells). The small intestine is characterized by the presence of crypt-villus units that are in a state of homeostatic cell turnover. Organoid technology enables an efficient expansion of intestinal epithelial tissue in vitro. Thus, organoids hold great promise for use in medical research and in the development of new treatments. At present, the cholinergic system involved in IECs and intestinal stem cells (ISCs) are attracting a great deal of attention. Thus, understanding the biological processes triggered by epithelial cholinergic activation by acetylcholine (ACh), which is produced and released from neuronal and/or non-neuronal tissue, is of key importance. Cholinergic signaling via ACh receptors plays a pivotal role in IEC growth and differentiation. Here, we discuss current views on neuronal innervation and non-neuronal control of the small intestinal crypts and their impact on ISC proliferation, differentiation, and maintenance. Since technology using intestinal organoid culture systems is advancing, we also outline an organoid-based organ replacement approach for intestinal diseases. Full article
(This article belongs to the Special Issue Novel Biorelevant Intestinal Epithelial In Vitro Models)
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