Publications by authors named "Paul De Vos"

389 Publications

vascularization and islet function in a microwell device for pancreatic islet transplantation.

Biomed Mater 2021 Apr 8. Epub 2021 Apr 8.

Faculty of Science and Technology (TNW), University of Twente, Biomaterials Science and Technology, P O Box 217, 7500 AE Enschede, THE NETHERLANDS, Enschede, 7500AE, NETHERLANDS.

Islet encapsulation in membrane-based devices could allow for transplantation of donor islet tissue in the absence of immunosuppression. To achieve long-term survival of islets, the device should allow rapid exchange of essential nutrients and be vascularized to guarantee continued support of islet function. Recently, we have proposed a membrane-based macroencapsulation device consisting of a microwell membrane for islet separation covered by a micropatterned membrane lid. The device can prevent islet aggregation and support functional islet survival in vitro. Here, based on previous modelling studies, we develop an improved device with smaller microwell dimensions, decreased spacing between the microwells and reduced membrane thickness and investigate its performance in vitro and in vivo. This improved device allows for encapsulating higher islet numbers without islet aggregation and by applying an In Vivo Imaging System (IVIS) we demonstrate very good perfusion of the device when implanted intraperitoneally in mice. Besides, when it is implanted subcutaneously in mice, islet viability is maintained and a vascular network in close proximity to the device is developed. All these important findings demonstrate the potential of this device for islet transplantation.
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http://dx.doi.org/10.1088/1748-605X/abf5ecDOI Listing
April 2021

An immune regulatory 3D-printed alginate-pectin construct for immunoisolation of insulin producing β-cells.

Mater Sci Eng C Mater Biol Appl 2021 Apr 5;123:112009. Epub 2021 Mar 5.

Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, EA 11, 9713 GZ Groningen, the Netherlands.

Different bioinks have been used to produce cell-laden alginate-based hydrogel constructs for cell replacement therapy but some of these approaches suffer from issues with print quality, long-term mechanical instability, and bioincompatibility. In this study, new alginate-based bioinks were developed to produce cell-laden grid-shaped hydrogel constructs with stable integrity and immunomodulating capacity. Integrity and printability were improved by including the co-block-polymer Pluronic F127 in alginate solutions. To reduce inflammatory responses, pectin with a low degree of methylation was included and tested for inhibition of Toll-Like Receptor 2/1 (TLR2/1) dimerization and activation and tissue responses under the skin of mice. The viscoelastic properties of alginate-Pluronic constructs were unaffected by pectin incorporation. The tested pectin protected printed insulin-producing MIN6 cells from inflammatory stress as evidenced by higher numbers of surviving cells within the pectin-containing construct following exposure to a cocktail of the pro-inflammatory cytokines namely, IL-1β, IFN-γ, and TNF-α. The results suggested that the cell-laden construct bioprinted with pectin-alginate-Pluronic bioink reduced tissue responses via inhibiting TLR2/1 and support insulin-producing β-cell survival under inflammatory stress. Our study provides a potential novel strategy to improve long-term survival of pancreatic islet grafts for Type 1 Diabetes (T1D) treatment.
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http://dx.doi.org/10.1016/j.msec.2021.112009DOI Listing
April 2021

Impact of electrostatic potential on microcapsule-formation and physicochemical analysis of surface structure: Implications for therapeutic cell-microencapsulation.

J Biomater Appl 2021 Feb 4:885328221988979. Epub 2021 Feb 4.

Oniris Nantes - Site de la Géraudière, Nantes, Pays de la Loire France.

Cell-encapsulation is used for preventing therapeutic cells from being rejected by the host. The technology to encapsulate cells in immunoprotective biomaterials, such as alginate, commonly involves application of an electrostatic droplet generator for reproducible manufacturing droplets of similar size and with similar surface properties. As many factors influencing droplet formation are still unknown, we investigated the impact of several parameters and fitted them to equations to make procedures more reproducible and allow optimal control of capsule size and properties. We demonstrate that droplet size is dependent on an interplay between the critical electric potential (U,), the needle size, and the distance between the needle and the gelation bath, and that it can be predicted with the equations proposed. The droplet formation was meticulously studied and followed by a high-speed camera. The X-ray photoelectron analysis demonstrated optimal gelation and substitution of sodium with calcium on alginate surfaces while the atomic force microscopy analysis demonstrated a low but considerable variation in surface roughness and low surface stiffness. Our study shows the importance of documenting critical parameters to guarantee reproducible manufacturing of beads with constant and adequate size and preventing batch-to-batch variations.
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http://dx.doi.org/10.1177/0885328221988979DOI Listing
February 2021

The Human Milk Oligosaccharides 3-FL, Lacto-N-Neotetraose, and LDFT Attenuate Tumor Necrosis Factor-α Induced Inflammation in Fetal Intestinal Epithelial Cells In Vitro through Shedding or Interacting with Tumor Necrosis Factor Receptor 1.

Mol Nutr Food Res 2021 04 3;65(7):e2000425. Epub 2021 Mar 3.

Immunoendocrinology, Division of Medical Biology, Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, RB, Groningen, 9700, The Netherlands.

Scope: Human milk oligosaccharides (hMOs) can attenuate inflammation by modulating intestinal epithelial cells, but the mechanisms of action are not well-understood. Here, the effects of hMOs on tumor necrosis factor-α (TNF-α) induced inflammatory events in gut epithelial cells are studied.

Methods And Results: The modulatory effects of 2'-fucosyllactose, 3-fucosyllactose (3-FL), 6'-sialyllactose, lacto-N-tetraose, lacto-N-neotetraose (LNnT), lactodifucotetraose (LDFT), and lacto-N-triaose (LNT2) on immature (FHs 74 Int) and adult (T84) intestinal epithelial cells with or without TNF-α are determined. Interleukin-8 (IL-8) secretion in FHs 74 Int and T84 are quantified to determine hMO induced attenuation of inflammatory events by ELISA. 3-FL, LNnT, and LDFT significantly attenuate TNF-α induced inflammation in FHs 74 Int, while LNT2 induces IL-8 secretion in T84. In addition, microscale thermophoresis assays and ELISA are used to study the possible mechanisms of interaction between effective hMOs and tumor necrosis factor receptor 1 (TNFR1). 3-FL, LNnT, and LDFT exert TNFR1 ectodomain shedding while LNnT also shows binding affinity to TNFR1 with a Kd of 900 ± 660 nM.

Conclusion: The findings indicate that specific hMO types attenuate TNF-α induced inflammation in fetal gut epithelial cells through TNFR1 in a hMO structure-dependent fashion suggest possibilities to apply hMOs in management of TNF-α dependent diseases.
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http://dx.doi.org/10.1002/mnfr.202000425DOI Listing
April 2021

Applying Immunomodulation to Promote Longevity of Immunoisolated Pancreatic Islet Grafts.

Tissue Eng Part B Rev 2021 Feb 24. Epub 2021 Feb 24.

Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Islet transplantation is a promising therapy for insulin-dependent diabetes, but large-scale application is hampered by the lack of a consistent source of insulin-producing cells and need for lifelong administration of immunosuppressive drugs, which are associated with severe side effects. To avoid chronic immunosuppression, islet grafts can be enveloped in immunoisolating polymeric membranes. These immunoisolating polymeric membranes protect islet grafts from cell-mediated rejection while allowing diffusion of oxygen, nutrients, and insulin. Although clinical trials have shown the safety and feasibility of encapsulated islets to control glucose homeostasis, the strategy does up till now not support long-term graft survival. This partly can be explained by a significant loss of insulin-producing cells in the immediate period after implantation. The loss can be prevented by combining immunoisolation with immunomodulation, such as combined administration of immunomodulating cytokines or coencapsulation of immunomodulating cell types such as regulatory T cells, mesenchymal stem cells, or Sertoli cells. Also, administration of specific antibodies or apoptotic donor leucocytes is considered to create a tolerant microenvironment around immunoisolated grafts. In this review, we describe the outcomes and limitations of these approaches, as well as the recent progress in immunoisolating devices. Impact statement Immunoisolation by enveloping islets in semipermeable membranes allows for successful transplantation of islet grafts in the absence of chronic immunosuppression, but the duration of graft survival is still not permanent. The reasons for long-term final graft failure is not fully understood, but combining immunoisolation with immunomodulation of tissues or host immune system has been proposed to enhance the longevity of grafts. This article reviews the recent progress and challenges of immunoisolation, as well as the benefits and feasibility of combining encapsulation approaches with immunomodulation to promote longevity of encapsulated grafts.
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http://dx.doi.org/10.1089/ten.TEB.2020.0326DOI Listing
February 2021

Flexibility of Gut Microbiota in Ageing Individuals during Dietary Fiber Long-Chain Inulin Intake.

Mol Nutr Food Res 2021 02 25;65(4):e2000390. Epub 2021 Jan 25.

Immunoendocrinology, Division of Medical Biology, Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, Groningen, 9700 RB, The Netherlands.

Scope: During ageing, dysbiosis in the intestinal microbiota may occur and impact health. There is a paucity of studies on the effect of fiber on the elderly microbiota and the flexibility of the aged microbiota upon prebiotic intake. It is hypothesized that chicory long-chain inulin consumption can change microbiota composition, microbial fermentation products, and immunity in the elderly.

Methods And Results: A double-blind, placebo-controlled trial is performed in healthy individuals (55-80 years), in which microbiota composition is studied before, during, and after two months of chicory long-chain inulin consumption. Fecal short chain fatty acid concentrations, T cell subsets, and antibody responses against a Hepatitis B (HB) vaccine are measured as well. Inulin consumption modified the microbiota composition, as measured by 16S rRNA sequencing. Participants consuming inulin have higher microbial diversity and a relatively higher abundance of the Bifidobacterium genus, as well as Alistipes shahii, Anaerostipes hadrus, and Parabacteroides distasonis. While the immune responses remain unchanged, the isobutyric acid levels, an undesired fermentation product, tend to be lower in the inulin group.

Conclusions: Overall, it is shown that the gut microbiota composition is still sensitive to chicory long-chain inulin induced changes in an ageing population, although this did not translate into an improved immune response to an HB vaccine.
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http://dx.doi.org/10.1002/mnfr.202000390DOI Listing
February 2021

Dose-dependent effects of necrostatin-1 supplementation to tissue culture media of young porcine islets.

PLoS One 2020 7;15(12):e0243506. Epub 2020 Dec 7.

Department of Surgery, University of California Irvine, Irvine, California, United States of America.

Previous studies have shown that necrostatin-1 (Nec-1) supplementation improved the viability of murine islets following exposure to nitric oxide, increased the survival of human islets during hypoxic culture, and augmented the maturation of pre-weaned porcine islets (PPIs) after 7 days of tissue culture. A limitation of these studies is that only one concentration of Nec-1 was used, and no studies have determined the optimal dose of Nec-1 for PPIs. Thus, the present study examined the effects of Nec-1 on PPIs at four different doses-0, 25, 50, 100, and 200 μM-after 7 days of tissue culture when supplemented on day 3. PPIs were isolated from pancreata of pre-weaned Yorkshire piglets (8-15 days old) and cultured in a specific islet maturation media added with Nec-1 on day 3 of tissue culture at 4 different doses-0, 25, 50, 100, and 200 μM (n = 6 for each dose). After 7 days of tissue culture, islets were assessed for recovery, viability, endocrine cellular content, GLUT2 expression in beta cells, and insulin secretion after glucose challenge. Nec-1 did not affect the viability of both intact islets and dissociated islets cells during tissue culture regardless of doses. Islets cultured in media supplemented with Nec-1 at 100 μM, but not 25, 50, or 200 μM, had a significantly higher recovery, composition of endocrine cells, GLUT2 expression in beta cells, and insulin secretion capacity than control islets cultured in media without Nec-1 supplementation. Moreover, culturing islets in 200 μM Nec-1 supplemented media not only failed to improve the insulin release but resulted in a lower glucose-induced insulin stimulation index compared to islets cultured in media added with 100 μM Nec-1. Xenotransplantation using porcine islets continues to demonstrate scientific advances to justify this area of research. Our findings indicate that Nec-1 supplementation at 100 μM was most effective to enhance the in vitro maturation of PPIs during tissue culture.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243506PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721208PMC
January 2021

Effects of Different Human Milk Oligosaccharides on Growth of in Monoculture and Co-culture With .

Front Microbiol 2020 30;11:569700. Epub 2020 Oct 30.

Immunoendocrinology, Division of Medical Biology, Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.

Human milk oligosaccharides (hMOs) are important bioactive components in mother's milk contributing to infant health by supporting colonization and growth of gut microbes. In particular, genus is considered to be supported by hMOs. Approximately 200 different hMOs have been discovered and characterized, but only a few abundant hMOs can be produced in sufficient amounts to be applied in infant formula. These hMOs are usually supplied in infant formula as single molecule, and it is unknown which and how individual hMOs support growth of individual gut bacteria. To investigate how individual hMOs influence growth of several relevant intestinal bacteria species, we studied the effects of three hMOs (2'-fucosyllactose, 3-fucosyllactose, and 6'-sialyllactose) and an hMO acid hydrolysate (lacto-N-triose) on three and one and introduced a co-culture system of two bacterial strains to study possible cross-feeding in presence and absence of hMOs. We observed that in monoculture, subsp. could grow well on all hMOs but in a structure-dependent way. reached a lower cell density on the hMOs in stationary phase compared to glucose, while subsp. and were not able to grow on the tested hMOs. In a co-culture of subsp. with , different effects were observed with the different hMOs; 6'-sialyllactose, rather than 2'-fucosyllactose, 3-fucosyllactose, and lacto-N-triose, was able to promote the growth of subsp. . Our observations demonstrate that effects of hMOs on the tested gut microbiota are hMO-specific and provide new means to support growth of these specific beneficial microorganisms in the intestine.
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http://dx.doi.org/10.3389/fmicb.2020.569700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662573PMC
October 2020

Impact of dietary fibers in infant formulas on gut microbiota and the intestinal immune barrier.

Food Funct 2020 Nov;11(11):9445-9467

Immunoendocrinology, Division of Medical Biology, Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, The Netherlands.

Human milk (HM) is the gold standard for the nutrition of infants. An important component of HM is human milk oligosaccharides (hMOs), which play an important role in gut microbiota colonization and gut immune barrier establishment, and thereby contribute to the maturation of the immune system in early life. Guiding these processes is important as disturbances have life-long health effects and can lead to the development of allergic diseases. Unfortunately, not all infants can be exclusively fed with HM. These infants are routinely fed with infant formulas that contain hMO analogs and other non-digestible carbohydrates (NDCs) to mimic the effects of hMOs. Currently, the hMO analogs 2'-fucosyllactose (2'-FL), galacto-oligosaccharides (GOS), fructo-oligosaccharides (FOS), and pectins are added to infant formulas; however, these NDCs cannot mimic all hMO functions and therefore new NDCs and NDC mixtures need to become available for specific groups of neonates like preterm and disease-prone neonates. In this review, we discuss human data on the beneficial effects of infant formula supplements such as the specific hMO analog 2'-FL and NDCs as well as their mechanism of effects like stimulation of microbiota development, maturation of different parts of the gut immune barrier and anti-pathogenic effects. Insights into the structure-specific mechanisms by which hMOs and NDCs exert their beneficial functions might contribute to the development of new tailored NDCs and NDC mixtures. We also describe the needs for new in vitro systems that can be used for research on hMOs and NDCs. The current data suggest that "tailored infant formulas" for infants of different ages and healthy statuses are needed to ensure a healthy development of the microbiota and the gut immune system of infants.
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http://dx.doi.org/10.1039/d0fo01700kDOI Listing
November 2020

Toll-like receptor 2-modulating pectin-polymers in alginate-based microcapsules attenuate immune responses and support islet-xenograft survival.

Biomaterials 2021 Jan 19;266:120460. Epub 2020 Oct 19.

Immunoendocrinology, Division of Medical Biology, Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, EA 11, 9713 GZ, Groningen, the Netherlands.

Encapsulation of pancreatic islets in alginate-microcapsules is used to reduce or avoid the application of life-long immunosuppression in preventing rejection. Long-term graft function, however, is limited due to varying degrees of host tissue responses against the capsules. Major graft-longevity limiting responses include inflammatory responses provoked by biomaterials and islet-derived danger-associated molecular patterns (DAMPs). This paper reports on a novel strategy for engineering alginate microcapsules presenting immunomodulatory polymer pectin with varying degrees of methyl-esterification (DM) to reduce these host tissue responses. DM18-pectin/alginate microcapsules show a significant decrease of DAMP-induced Toll-Like Receptor-2 mediated immune activation in vitro, and reduce peri-capsular fibrosis in vivo in mice compared to higher DM-pectin/alginate microcapsules and conventional alginate microcapsules. By testing efficacy of DM18-pectin/alginate microcapsules in vivo, we demonstrate that low-DM pectin support long-term survival of xenotransplanted rat islets in diabetic mice. This study provides a novel strategy to attenuate host responses by creating immunomodulatory capsule surfaces that attenuate activation of specific pro-inflammatory immune receptors locally at the transplantation site.
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http://dx.doi.org/10.1016/j.biomaterials.2020.120460DOI Listing
January 2021

Design and characterization of Squalene-Gusperimus nanoparticles for modulation of innate immunity.

Int J Pharm 2020 Nov 19;590:119893. Epub 2020 Sep 19.

Grupo de Investigación Ciencia de los Materiales, Instituto de Química, Facultad de Ciencias Exactas y Naturales, Universidad de Antioquia, Calle 70 No. 52-21, Medellín, Antioquia, Colombia.

Immunosuppressive drugs are widely used for the treatment of autoimmune diseases and to prevent rejection in organ transplantation. Gusperimus is a relatively safe immunosuppressive drug with low cytotoxicity and reversible side effects. It is highly hydrophilic and unstable. Therefore, it requires administration in high doses which increases its side effects. To overcome this, here we encapsulated gusperimus as squalene-gusperimus nanoparticles (Sq-GusNPs). These nanoparticles (NPs) were obtained from nanoassembly of the squalene gusperimus (Sq-Gus) bioconjugate in water, which was synthesized starting from squalene. The size, charge, and dispersity of the Sq-GusNPs were optimized using the response surface methodology (RSM). The colloidal stability of the Sq-GusNPs was tested using an experimental block design at different storage temperatures after preparing them at different pH conditions. Sq-GusNPs showed to be colloidally stable, non-cytotoxic, readily taken up by cells, and with an anti-inflammatory effect sustained over time. We demonstrate that gusperimus was stabilized through its conjugation with squalene and subsequent formation of NPs allowing its controlled release. Overall, the Sq-GusNPs have the potential to be used as an alternative in approaches for the treatment of different pathologies where a controlled release of gusperimus could be required.
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http://dx.doi.org/10.1016/j.ijpharm.2020.119893DOI Listing
November 2020

Low methyl-esterified pectin protects pancreatic β-cells against diabetes-induced oxidative and inflammatory stress via galectin-3.

Carbohydr Polym 2020 Dec 6;249:116863. Epub 2020 Aug 6.

Immunoendocrinology, Division of Medical Biology, Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, EA 11, 9713 GZ, Groningen, The Netherlands.

Insufficient intake of dietary fibers in Western societies is considered a major contributing factor in the high incidence rates of diabetes. The dietary fiber pectin has been suggested to be beneficial for management of both Diabetes Type 1 and Type 2, but mechanisms and effects of pectin on insulin producing pancreatic β-cells are unknown. Our study aimed to determine the effects of lemon pectins with different degree of methyl-esterification (DM) on β-cells under oxidative (streptozotocin) and inflammatory (cytokine) stress and to elucidate the underlying rescuing mechanisms, including effects on galectin-3. We found that specific pectins had rescuing effects on toxin and cytokine induced stress on β-cells but effects depended on the pectin concentration and DM-value. Protection was more pronounced with low DM5 pectin and was enhanced with higher pectin-concentrations. Our findings show that specific pectins might prevent diabetes by making insulin producing β-cells less susceptible for stress.
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http://dx.doi.org/10.1016/j.carbpol.2020.116863DOI Listing
December 2020

The effects of different dietary fiber pectin structures on the gastrointestinal immune barrier: impact via gut microbiota and direct effects on immune cells.

Exp Mol Med 2020 09 10;52(9):1364-1376. Epub 2020 Sep 10.

Immunoendocrinology, Division of Medical Biology, Department of Pathology and Medical Biology, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.

Pectins are dietary fibers with different structural characteristics. Specific pectin structures can influence the gastrointestinal immune barrier by directly interacting with immune cells or by impacting the intestinal microbiota. The impact of pectin strongly depends on the specific structural characteristics of pectin; for example, the degree of methyl-esterification, acetylation and rhamnogalacturonan I or rhamnogalacturonan II neutral side chains. Here, we review the interactions of specific pectin structures with the gastrointestinal immune barrier. The effects of pectin include strengthening the mucus layer, enhancing epithelial integrity, and activating or inhibiting dendritic cell and macrophage responses. The direct interaction of pectins with the gastrointestinal immune barrier may be governed through pattern recognition receptors, such as Toll-like receptors 2 and 4 or Galectin-3. In addition, specific pectins can stimulate the diversity and abundance of beneficial microbial communities. Furthermore, the gastrointestinal immune barrier may be enhanced by short-chain fatty acids. Moreover, pectins can enhance the intestinal immune barrier by favoring the adhesion of commensal bacteria and inhibiting the adhesion of pathogens to epithelial cells. Current data illustrate that pectin may be a powerful dietary fiber to manage and prevent several inflammatory conditions, but additional human studies with pectin molecules with well-defined structures are urgently needed.
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http://dx.doi.org/10.1038/s12276-020-0449-2DOI Listing
September 2020

In vitro degradation profiles and in vivo biomaterial-tissue interactions of microwell array delivery devices.

J Biomed Mater Res B Appl Biomater 2021 Jan 16;109(1):117-127. Epub 2020 Jul 16.

Department of Cell Biology - Inspired Tissue Engineering (cBITE), MERLN Institute for Technology Inspired Regenerative Medicine, Maastricht University, Maastricht, The Netherlands.

To effectively apply microwell array cell delivery devices their biodegradation rate must be tailored towards their intended use and implantation location. Two microwell array devices with distinct degradation profiles, either suitable for the fabrication of retrievable systems in the case of slow degradation, or cell delivery systems capable of extensive remodeling using a fast degrading polymer, were compared in this study. Thin films of a poly(ethylene glycol)-poly(butylene terephthalate) (PEOT-PBT) and a poly(ester urethane) were evaluated for their in vitro degradation profiles over 34 weeks incubation in PBS at different pH values. The PEOT-PBT films showed minimal in vitro degradation over time, while the poly(ester urethane) films showed extensive degradation and fragmentation over time. Subsequently, microwell array cell delivery devices were fabricated from these polymers and intraperitoneally implanted in Albino Oxford rats to study their biocompatibility over a 12-week period. The PEOT-PBT implants shown to be capable to maintain the microwell structure over time. Implants provoked a foreign body response resulting in multilayer fibrosis that integrated into the surrounding tissue. The poly(ester urethane) implants showed a loss of the microwell structures over time, as well as a fibrotic response until the onset of fragmentation, at least 4 weeks post implantation. It was concluded that the PEOT-PBT implants could be used as retrievable cell delivery devices while the poly(ester urethane) implants could be used for cell delivery devices that require remodeling within a 4-12 week period.
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http://dx.doi.org/10.1002/jbm.b.34686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754331PMC
January 2021

A High Cell-Bearing Capacity Multibore Hollow Fiber Device for Macroencapsulation of Islets of Langerhans.

Macromol Biosci 2020 08 22;20(8):e2000021. Epub 2020 Jun 22.

Bioartificial Organs, Biomaterials Science and Technology Department, Faculty of Science and Technology, TechMed Centre, University of Twente, Enschede, 7500AE, The Netherlands.

Macroencapsulation of islets of Langerhans is a promising strategy for transplantation of insulin-producing cells in the absence of immunosuppression to treat type 1 diabetes. Hollow fiber membranes are of interest there because they offer a large surface-to-volume ratio and can potentially be retrieved or refilled. However, current available fibers have limitations in exchange of nutrients, oxygen, and delivery of insulin potentially impacting graft survival. Here, multibore hollow fibers for islets encapsulation are designed and tested. They consist of seven bores and are prepared using nondegradable polymers with high mechanical stability and low cell adhesion properties. Human islets encapsulated there have a glucose induced insulin response (GIIS) similar to nonencapsulated islets. During 7 d of cell culture in vitro, the GIIS increases with graded doses of islets demonstrating the suitability of the microenvironment for islet survival. Moreover, first implantation studies in mice demonstrate device material biocompatibility with minimal tissue responses. Besides, formation of new blood vessels close to the implanted device is observed, an important requirement for maintaining islet viability and fast exchange of glucose and insulin. The results indicate that the developed fibers have high islet bearing capacity and can potentially be applied for a clinically applicable bioartificial pancreas.
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http://dx.doi.org/10.1002/mabi.202000021DOI Listing
August 2020

Touching the High Complexity of Prebiotic Vivinal Galacto-oligosaccharides Using Porous Graphitic Carbon Ultra-High-Performance Liquid Chromatography Coupled to Mass Spectrometry.

J Agric Food Chem 2020 Jul 7;68(29):7800-7808. Epub 2020 Jul 7.

Laboratory of Food Chemistry, Wageningen University & Research, Bornse Weilanden 9, 6708 WG Wageningen, Netherlands.

Galacto-oligosaccharides (GOS) are used in infant formula to replace the health effects of human milk oligosaccharides, which appear to be dependent upon the structure of the individual oligosaccharides present. However, a comprehensive overview of the structure-specific effects is still limited as a result of the high structural complexity of GOS. In this study, porous graphitic carbon (PGC) was used as the stationary phase during ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS). This approach resulted in the recognition of more than 100 different GOS structures in one single run, including reducing and non-reducing GOS isomers. Using nuclear magnetic resonance-validated structures of GOS trisaccharides, we discovered MS fragmentation rules to distinguish reducing isomers with a mono- and disubstituted terminal glucose by UHPLC-PGC-MS. UHPLC-PGC-MS enabled effective recognition of structural features of individual GOS components in complex GOS preparations and during, e.g., biological conversion reactions. Hence, this study lays the groundwork for future research into structure-specific health effects of GOS.
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http://dx.doi.org/10.1021/acs.jafc.0c02684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378999PMC
July 2020

Human Milk Oligosaccharides Mediate the Crosstalk Between Intestinal Epithelial Caco-2 Cells and Lactobacillus PlantarumWCFS1in an In Vitro Model with Intestinal Peristaltic Shear Force.

J Nutr 2020 08;150(8):2077-2088

Immunoendocrinology, Division of Medical Biology, Department of Pathology and Medical Biology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.

Background: The intestinal epithelial cells, food molecules, and gut microbiota are continuously exposed to intestinal peristaltic shear force. Shear force may impact the crosstalk of human milk oligosaccharides (hMOs) with commensal bacteria and intestinal epithelial cells.

Objectives: We investigated how hMOs combined with intestinal peristaltic shear force impact intestinal epithelial cells and crosstalk with a commensal bacterium.

Methods: We applied the Ibidi system to mimic intestinal peristaltic shear force. Caco-2 cells were exposed to a shear force (5 dynes/cm2) for 3 d, and then stimulated with the hMOs, 2'-fucosyllactose (2'-FL), 3-FL, and lacto-N-triose II (LNT2). In separate experiments, Lactobacillus plantarumWCFS1 adhesion to Caco-2 cells was studied with the same hMOs and shear force. Effects were tested on gene expression of glycocalyx-related molecules (glypican 1 [GPC1], hyaluronan synthase 1 [HAS1], HAS2, HAS3, exostosin glycosyltransferase 1 [EXT1], EXT2), defensin β-1 (DEFB1), and tight junction (tight junction protein 1 [TJP1], claudin 3 [CLDN3]) in Caco-2 cells. Protein expression of tight junctions was also quantified.

Results: Shear force dramatically decreased gene expression of the main enzymes for making glycosaminoglycan side chains (HAS3 by 43.3% and EXT1 by 68.7%) (P <0.01), but did not affect GPC1 which is the gene responsible for the synthesis of glypican 1 which is a major protein backbone of glycocalyx. Expression of DEFB1, TJP1, and CLDN3 genes was decreased 60.0-94.9% by shear force (P <0.001). The presence of L. plantarumWCFS1 increased GPC1, HAS2, HAS3, and ZO-1 expression by 1.78- to 3.34-fold (P <0.05). Under shear force, all hMOs significantly stimulated DEFB1 and ZO-1, whereas only 3-FL and LNT2 enhanced L. plantarumWCFS1 adhesion by 1.85- to 1.90-fold (P <0.01).

Conclusions: 3-FL and LNT2 support the crosstalk between the commensal bacterium L. plantarumWCFS1 and Caco-2 intestinal epithelial cells, and shear force can increase the modulating effects of hMOs.
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http://dx.doi.org/10.1093/jn/nxaa162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7398781PMC
August 2020

Cell-laden alginate hydrogels for the treatment of diabetes.

Expert Opin Drug Deliv 2020 08;17(8):1113-1118

NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country UPV/EHU , Vitoria-Gasteiz, Spain.

Introduction: Diabetes mellitus is an ever-increasing medical condition that currently suffers 1 of 11 adults who may have lifelong commitment with insulin injections. Cell-laden hydrogels releasing insulin may provide the ultimate means of correcting diabetes. Here, we provide insights of this cell-based approach including latest preclinical and clinical progress both from academia and industry.

Area Covered: The present article focuses on reviewing latest advances in cell-laden hydrogels both from the technological and biological perspective. The most relevant clinical results including clinical trials are also discussed.

Expert Opinion: Current progress in technological issues (stem cells, devices, biomaterials) have contributed cell encapsulation science to have a very relevant progress in the field of diabetes treatment.
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http://dx.doi.org/10.1080/17425247.2020.1778667DOI Listing
August 2020

Endo-1,3(4)-β-Glucanase-Treatment of Oat β-Glucan Enhances Fermentability by Infant Fecal Microbiota, Stimulates Dectin-1 Activation and Attenuates Inflammatory Responses in Immature Dendritic Cells.

Nutrients 2020 Jun 3;12(6). Epub 2020 Jun 3.

Laboratory of Food Chemistry, Wageningen University & Research, Bornse Weilanden 9, 6708 WG Wageningen, The Netherlands.

: Non-digestible carbohydrates are added to infant formula to mimic the effects of human milk oligosaccharide by acting as prebiotics and stimulating the immune system. Although not yet used in infant formulas, β-glucans are known to have beneficial health effects, and are therefore of potential interest for supplementation. : We investigated the fermentation of native and endo-1,3(4)-β-glucanase-treated oat β-glucan using pooled fecal inocula of 2- and 8-week-old infants. While native oat β-glucan was not utilized, both inocula specifically utilized oat β-glucan oligomers containing β(1→4)-linkages formed upon enzyme treatment. The fermentation rate was highest in the fecal microbiota of 2-week-old infants, and correlated with a high lactate production. Fermentation of media supplemented with native and enzyme-treated oat β-glucans increased the relative abundance of and attenuated pro-inflammatory cytokine production (IL-1β, IL-6, TNFα) in immature dendritic cells. This attenuating effect was more pronounced after enzyme treatment. This attenuation might result from the enhanced ability of fermented oat β-glucan to stimulate Dectin-1 receptors. : Our findings demonstrate that endo-1,3(4)-β-glucanase treatment enhances the fermentability of oat β-glucan and attenuates pro-inflammatory responses. Hence, this study shows that especially enzyme-treated oat β-glucans have a high potential for supplementation of infant formula.
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http://dx.doi.org/10.3390/nu12061660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352905PMC
June 2020

Inhibitory Effects of Dietary -Glycans From Bovine Lactoferrin on Toll-Like Receptor 8; Comparing Efficacy With Chloroquine.

Front Immunol 2020 12;11:790. Epub 2020 May 12.

Immunoendocrinology, Division of Medical Biology, Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.

Toll-like receptor 8 (TLR-8) plays a role in the pathogenesis of autoimmune disorders and associated gastrointestinal symptoms that reduce quality of life of patients. Dietary interventions are becoming more accepted as mean to manage onset, progression, and treatment of a broad spectrum of inflammatory conditions. In this study, we assessed the impact of -glycans derived from bovine lactoferrin (bLF) on the inhibition of TLR-8 activation. We investigated the effects of -glycans in their native form, as well as in its partially demannosylated and partially desialylated form, on HEK293 cells expressing TLR-8, and in human monocyte-derived dendritic cells (MoDCs). We found that in HEK293 cells, -glycans strongly inhibited the ssRNA40 induced TLR-8 activation but to a lesser extent the R848 induced TLR-8 activation. The impact was compared with a pharmaceutical agent, i.e., chloroquine (CQN), that is clinically applied to antagonize endosomal TLR- activation. Inhibitory effects of the -glycans were not influenced by the partially demannosylated or partially desialylated -glycans. As the difference in charge of the -glycans did not influence the inhibition capacity of TLR-8, it is possible that the inhibition mediated by the -glycans is a result of a direct interaction with the receptor rather than a result of pH changes in the endosome. The inhibition of TLR-8 in MoDCs resulted in a significant decrease of IL-6 when cells were treated with the unmodified (0.5-fold, < 0.0001), partially demannosylated (0.3-fold, < 0.0001) and partially desialylated (0.4-fold, < 0.0001) -glycans. Furthermore, the partially demannosylated and partially desialylated -glycans showed stronger inhibition of IL-6 production compared with the native -glycans. This provides evidence that glycan composition plays a role in the immunomodulatory activity of the isolated -glycans from bLF on MoDCs. Compared to CQN, the -glycans are specific inhibitors of TLR-8 activation and of IL-6 production in MoDCs. Our findings demonstrate that isolated -glycans from bLF have attenuating effects on TLR-8 induced immune activation in HEK293 cells and human MoDCs. The inhibitory capacity of -glycans isolated from bLF onTLR-8 activation may become a food-based strategy to manage autoimmune, infections or other inflammatory disorders.
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http://dx.doi.org/10.3389/fimmu.2020.00790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235371PMC
March 2021

Fermentation of Chicory Fructo-Oligosaccharides and Native Inulin by Infant Fecal Microbiota Attenuates Pro-Inflammatory Responses in Immature Dendritic Cells in an Infant-Age-Dependent and Fructan-Specific Way.

Mol Nutr Food Res 2020 07 2;64(13):e2000068. Epub 2020 Jun 2.

Immunoendocrinology, Division of Medical Biology, Department of Pathology and Medical Biology, University of Groningen and University Medical Centre Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands.

Scope: Inulin-type fructans are commonly applied in infant formula to support development of gut microbiota and immunity. These inulin-type fructans are considered to be fermented by gut microbiota, but it is unknown how fermentation impacts immune modulating capacity and whether the process of fermentation is dependent on the infant's age.

Methods And Results: The in vitro fermentation of chicory fructo-oligosaccharides (FOS) and native inulin are investigated using pooled fecal inocula of two- and eight-week-old infants. Both inocula primarily utilize the trisaccharides in FOS, while they almost completely utilize native inulin with degree of polymerization (DP) 3-8. Fecal microbiota of eight-week-old infants degrades longer chains of native inulin up to DP 16. This correlates with a higher abundance of Bifidobacterium and higher production of acetate and lactate after 26 h of fermentation. Fermented FOS and native inulin attenuate pro-inflammatory cytokines produced by immature dendritic cells (DCs), but profiles and magnitude of attenuation are stronger with native inulin than with FOS.

Conclusion: The findings demonstrate that fermentation of FOS and native inulin is dependent on the infant's age and fructan structure. Fermentation enhances attenuating effects of pro-inflammatory responses in DCs, which depend mainly on microbial metabolites formed during fermentation.
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http://dx.doi.org/10.1002/mnfr.202000068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378940PMC
July 2020

Controlled Release of Stem Cell Secretome Attenuates Inflammatory Response against Implanted Biomaterials.

Adv Healthc Mater 2020 06 18;9(12):e1901874. Epub 2020 May 18.

Sue and Bill Stem Cell Center, University of California Irvine, Irvine, CA, 92617, USA.

Inflammatory response against implanted biomaterials impairs their functional integration and induces medical complications in the host's body. To suppress such immune responses, one approach is the administration of multiple drugs to halt inflammatory pathways. This challenges patient's adherence and can cause additional complications such as infection. Alternatively, biologics that regulate multiple inflammatory pathways are attractive agents in addressing the implants immune complications. Secretome of mesenchymal stromal cells (MSCs) is a multipotent biologic, regulating the homeostasis of lymphocytes and leukocytes. Here, it is reported that alginate microcapsules loaded with processed conditioned media (pCM-Alg) reduces the infiltration and/or expression of CD68+ macrophages likely through the controlled release of pCM. In vitro cultures revealed that alginate can dose dependently induce macrophages to secrete TNFα, IL-6, IL-1β, and GM-CSF. Addition of pCM to the cultures attenuates the secretion of TNFα (p = 0.023) and IL-6 (p < 0.0001) by alginate or lipopolysaccharide (LPS) stimulations. Mechanistically, pCM suppressed the NfκB pathway activation of macrophages in response to LPS (p < 0.0001) in vitro and cathepsin activity (p = 0.005) in response to alginate in vivo. These observations suggest the efficacy of using MSC-derived secretome to prevent or delay the host rejection of implants.
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http://dx.doi.org/10.1002/adhm.201901874DOI Listing
June 2020

The Effect of a Fast-Releasing Hydrogen Sulfide Donor on Vascularization of Subcutaneous Scaffolds in Immunocompetent and Immunocompromised Mice.

Biomolecules 2020 05 6;10(5). Epub 2020 May 6.

Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands.

Islet transplantation into subcutaneous polymer scaffolds has shown to successfully induce normoglycemia in type 1 diabetes models. Vascularization of these scaffolds is imperative for optimal control of glucose levels. We studied the effect of the vascular stimulator hydrogen sulfide (HS) on the degree of vascularization of a scaffold and the role of the immune system in this process. Scaffolds were subcutaneously implanted in immunocompetent C57BL/6 and immunocompromised nude mice. Mice received twice-daily intraperitoneal injections of the fast-releasing HS donor sodium hydrosulfide (NaHS, 25 or 50 μmol/kg) or saline for 28 days. After 63 days the vascular network was analyzed by histology and gene expression. Here we showed that the vascularization of a subcutaneous scaffold in nude mice was significantly impaired by HS treatment. Both the CD31 gene and protein expression were reduced in these scaffolds compared to the saline-treated controls. In C57BL/6 mice, the opposite was found, the vascularization of the scaffold was significantly increased by HS. The mRNA expression of the angiogenesis marker CD105 was significantly increased compared to the controls as well as the number of CD31 positive blood vessels. In conclusion, the immune system plays an important role in the HS mediated effect on vascularization of subcutaneous scaffolds.
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http://dx.doi.org/10.3390/biom10050722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7277536PMC
May 2020

Disease managing capacities and mechanisms of host effects of lactic acid bacteria.

Crit Rev Food Sci Nutr 2021 5;61(8):1365-1393. Epub 2020 May 5.

Immunoendocrinology, Division of Medical Biology, Department of Pathology and Medical Biology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.

Consumption of lactic acid bacteria (LAB) has been suggested to confer health-promoting effects on the host. However, effects of LABs have been reported to be species- and strain-specific and the mechanisms involved are subjects of discussion. Here, the possible mechanisms by which LABs induce antipathogenic, gut barrier enhancing and immune modulating effects in consumers are reviewed. Specific strains for which it has been proven that health is improved by these mechanisms are discussed. However, most strains probably act via several or combinations of mechanisms depending on which effector molecules they express. Current insight is that these effector molecules are either present on the cell wall of LAB or are excreted. These molecules are reviewed as well as the ligand binding receptors in the host. Also postbiotics are discussed. Finally, we provide an overview of the efficacy of LABs in combating infections caused by , , , , and virus, in controlling gut inflammatory diseases, in managing allergic disorders, and in alleviating cancer.
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http://dx.doi.org/10.1080/10408398.2020.1758625DOI Listing
March 2021

More than sugar in the milk: human milk oligosaccharides as essential bioactive molecules in breast milk and current insight in beneficial effects.

Crit Rev Food Sci Nutr 2021 24;61(7):1184-1200. Epub 2020 Apr 24.

Immunoendocrinology, Division of Medical Biology, Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Human milk is the gold standard for newborn infants. Breast milk not only provides nutrients, it also contains bioactive components that guide the development of the infant's intestinal immune system, which can have a lifelong effect. The bioactive molecules in breast milk regulate microbiota development, immune maturation and gut barrier function. Human milk oligosaccharides (hMOs) are the most abundant bioactive molecules in human milk and have multiple beneficial functions such as support of growth of beneficial bacteria, anti-pathogenic effects, immune modulating effects, and stimulation of intestine barrier functions. Here we critically review the current insight into the benefits of bioactive molecules in mother milk that contribute to neonatal development and focus on current knowledge of hMO-functions on microbiota and the gastrointestinal immune barrier. hMOs produced via genetically engineered microorganisms are now applied in infant formulas to mimic the nutritional composition of breast milk as closely as possible, and their prospects and scientific challenges are discussed in depth.
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http://dx.doi.org/10.1080/10408398.2020.1754756DOI Listing
March 2021

Selective Modification of Streptozotocin at the C3 Position to Improve Its Bioactivity as Antibiotic and Reduce Its Cytotoxicity towards Insulin-Producing β Cells.

Antibiotics (Basel) 2020 Apr 15;9(4). Epub 2020 Apr 15.

Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 7, 9747 AG Groningen, The Netherlands.

With the increasing resistance of bacteria to current antibiotics, novel compounds are urgently needed to treat bacterial infections. Streptozotocin (STZ) is a natural product that has broad-spectrum antibiotic activity, albeit with limited use because of its toxicity to pancreatic β cells. In an attempt to derivatize STZ through structural modification at the C3 position, we performed the synthesis of three novel STZ analogues by making use of our recently developed regioselective oxidation protocol. Keto-STZ () shows the highest inhibition of bacterial growth (minimum inhibitory concentration (MIC) and viability assays), but is also the most cytotoxic compound. Pre-sensitizing the bacteria with GlcNAc increased the antimicrobial effect, but did not result in complete killing. Interestingly, -STZ () revealed moderate concentration-dependent antimicrobial activity and no cytotoxicity towards β cells, and deoxy-STZ () showed no activity at all.
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http://dx.doi.org/10.3390/antibiotics9040182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235802PMC
April 2020

Phenotypic and functional translation of IL1RL1 locus polymorphisms in lung tissue and asthmatic airway epithelium.

JCI Insight 2020 04 23;5(8). Epub 2020 Apr 23.

Division of Respiratory Medicine, NIHR, Nottingham Biomedical Research Centre, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom.

The IL1RL1 (ST2) gene locus is robustly associated with asthma; however, the contribution of single nucleotide polymorphisms (SNPs) in this locus to specific asthma subtypes and the functional mechanisms underlying these associations remain to be defined. We tested for association between IL1RL1 region SNPs and characteristics of asthma as defined by clinical and immunological measures and addressed functional effects of these genetic variants in lung tissue and airway epithelium. Utilizing 4 independent cohorts (Lifelines, Dutch Asthma GWAS [DAG], Genetics of Asthma Severity and Phenotypes [GASP], and Manchester Asthma and Allergy Study [MAAS]) and resequencing data, we identified 3 key signals associated with asthma features. Investigations in lung tissue and primary bronchial epithelial cells identified context-dependent relationships between the signals and IL1RL1 mRNA and soluble protein expression. This was also observed for asthma-associated IL1RL1 nonsynonymous coding TIR domain SNPs. Bronchial epithelial cell cultures from asthma patients, exposed to exacerbation-relevant stimulations, revealed modulatory effects for all 4 signals on IL1RL1 mRNA and/or protein expression, suggesting SNP-environment interactions. The IL1RL1 TIR signaling domain haplotype affected IL-33-driven NF-κB signaling, while not interfering with TLR signaling. In summary, we identify that IL1RL1 genetic signals potentially contribute to severe and eosinophilic phenotypes in asthma, as well as provide initial mechanistic insight, including genetic regulation of IL1RL1 isoform expression and receptor signaling.
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http://dx.doi.org/10.1172/jci.insight.132446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205441PMC
April 2020

Functionalization of Alginate with Extracellular Matrix Peptides Enhances Viability and Function of Encapsulated Porcine Islets.

Adv Healthc Mater 2020 05 7;9(9):e2000102. Epub 2020 Apr 7.

Mechanical Engineering, Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, 315 Ferst Drive, Atlanta, GA, 30332, USA.

Translation of transplanted alginate-encapsulated pancreatic islets to treat type 1 diabetes has been hindered by inconsistent long-term efficacy. This loss of graft function can be partially attributed to islet dysfunction associated with the destruction of extracellular matrix (ECM) interactions during the islet isolation process as well as immunosuppression-associated side effects. This study aims at recapitulating islet-ECM interactions by the direct functionalization of alginate with the ECM-derived peptides RGD, LRE, YIGSR, PDGEA, and PDSGR. Peptide functionalization is controlled in a concentration-dependent manner and its presentation is found to be homogeneous across the microcapsule environment. Preweaned porcine islets are encapsulated in peptide-functionalized alginate microcapsules, and those encapsulated in RGD-functionalized alginate displays enhanced viability and glucose-stimulated insulin release. Effects are RGD-specific and not observed with its scrambled control RDG nor with LRE, YIGSR, PDGEA, and PDSGR. This study supports the sustained presentation of ECM-derived peptides in helping to maintain health of encapsulated pancreatic islets and may aid in prolonging longevity of encapsulated islet grafts.
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http://dx.doi.org/10.1002/adhm.202000102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598935PMC
May 2020

The impact of oligosaccharide content, glycosidic linkages and lactose content of galacto-oligosaccharides (GOS) on the expression of mucus-related genes in goblet cells.

Food Funct 2020 Apr;11(4):3506-3515

Immunoendocrinology, Division of Medical Biology, Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen (RUG-UMCG), Hanzeplein 1, 9700 RB Groningen, The Netherlands.

Galacto-oligosaccharides (GOS) have been reported to modulate the function of intestinal goblet cells and to improve mucus barrier function. However, GOS is available in many structurally different compositions and it is unknown how GOS structural diversity impacts this modulation of goblet cells. This study aims to investigate the effects of oligosaccharide content and glycosidic linkages of GOS on expression of genes associated with the secretory function of goblet cells. To investigate the effect of oligosaccharide content, LS174T cells were incubated with (β1 → 4)GOS of variable transgalactosylated oligosaccharides and lactose (Lac) composition. To investigate the effect of glycosidic linkages, we compared the effects of (β1 → 4)GOS with (β1 → 3)GOS, and with a mixture of α-linked oligosaccharides (lactose-derived oligosaccharides-LDO). The changes in mRNA expression of mucus-related genes were assessed by RT-PCR. GOS containing Lac significantly enhanced the expression of MUC2, TFF3 and RETNLB but not of Golgi sulfotransferases genes. In contrast, GOS without Lac did not impact these genes. Lac alone significantly enhanced MUC2, TFF3, RETNLB, CHST5, and GAL3ST2 genes suggesting that Lac might be responsible for goblet cell modulation in (β1 → 4)GOS preparations. (β1 → 3)GOS induced the expression of MUC2 and TFF3, and downregulated the RETNLB gene. Compared with the (β1 → 3) and GOS (β1 → 4)GOS, the α-linked LDO significantly upregulated the expression MUC2, TFF3, RETNLB and the Golgi sulfotransferases genes. We identify structural features of GOS that contribute to enhanced mucus integrity. Our study might lead to better GOS formulations for foods to prevent or treat different types of intestinal disorders.
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http://dx.doi.org/10.1039/d0fo00064gDOI Listing
April 2020

Acetate and Butyrate Improve β-cell Metabolism and Mitochondrial Respiration under Oxidative Stress.

Int J Mol Sci 2020 Feb 24;21(4). Epub 2020 Feb 24.

Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, EA11, 9713 GZ Groningen, The Netherlands.

Islet dysfunction mediated by oxidative and mitochondrial stress contributes to the development of type 1 and 2 diabetes. Acetate and butyrate, produced by gut microbiota via fermentation, have been shown to protect against oxidative and mitochondrial stress in many cell types, but their effect on pancreatic β-cell metabolism has not been studied. Here, human islets and the mouse insulinoma cell line MIN6 were pre-incubated with 1, 2, and 4 mM of acetate or butyrate with and without exposure to the apoptosis inducer and metabolic stressor streptozotocin (STZ). Both short-chain fatty acids (SCFAs) enhanced the viability of islets and β-cells, but the beneficial effects were more pronounced in the presence of STZ. Both SCFAs prevented STZ-induced cell apoptosis, viability reduction, mitochondrial dysfunction, and the overproduction of reactive oxygen species (ROS) and nitric oxide (NO) at a concentration of 1 mM but not at higher concentrations. These rescue effects of SCFAs were accompanied by preventing reduction of the mitochondrial fusion genes , , and . In addition, elevation of the fission genes and during STZ exposure was prevented. Acetate showed more efficiency in enhancing metabolism and inhibiting ROS, while butyrate had less effect but was stronger in inhibiting the SCFA receptor GPR41 and NO generation. Our data suggest that SCFAs play an essential role in supporting β-cell metabolism and promoting survival under stressful conditions. It therewith provides a novel mechanism by which enhanced dietary fiber intake contributes to the reduction of Western diseases such as diabetes.
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http://dx.doi.org/10.3390/ijms21041542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073211PMC
February 2020