Diabetes through a 3D lens: organoid models

Tsakmaki, Anastasia; Pedro, Patricia Fonseca; Bewick, Gavin

doi:10.1007/s00125-020-05126-3

Cited by 21 publications

(21 citation statements)

References 104 publications

(107 reference statements)

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“…In our study, we evaluated the effect of chronic hyperglycemia on intestinal cell differentiation using small intestinal organoid platforms that analyzed the involvement of metabolic perturbations in EEC physiology, providing a theoretical basis to the study of diabetes physiopathology. Recent studies have shown that organoids represent a platform to explore the differentiation of intestinal cells and to test the capacity of novel molecules to manipulate the density of EECs for treating metabolic disease [18][19][20]. To date, how diabetes or other metabolic diseases could impair intestinal cell differentiation has not been investigated.…”

Section: Discussionmentioning

confidence: 99%

High Glucose Exposure Impairs L-Cell Differentiation in Intestinal Organoids: Molecular Mechanisms and Clinical Implications

Filippello

Mauro

Scamporrino

et al. 2021

IJMS

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Intestinal organoids are used to analyze the differentiation of enteroendocrine cells (EECs) and to manipulate their density for treating type 2 diabetes. EEC differentiation is a continuous process tightly regulated in the gut by a complex regulatory network. However, the effect of chronic hyperglycemia, in the modulation of regulatory networks controlling identity and differentiation of EECs, has not been analyzed. This study aimed to investigate the effect of glucotoxicity on EEC differentiation in small intestinal organoid platforms. Mouse intestinal organoids were cultured in the presence/absence of high glucose concentrations (35 mM) for 48 h to mimic glucotoxicity. Chronic hyperglycemia impaired the expression of markers related to the differentiation of EEC progenitors (Ngn3) and L-cells (NeuroD1), and it also reduced the expression of Gcg and GLP-1 positive cell number. In addition, the expression of intestinal stem cell markers was reduced in organoids exposed to high glucose concentrations. Our data indicate that glucotoxicity impairs L-cell differentiation, which could be associated with decreased intestinal stem cell proliferative capacity. This study provides the identification of new targets involved in new molecular signaling mechanisms impaired by glucotoxicity that could be a useful tool for the treatment of type 2 diabetes.

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Section: Discussionmentioning

confidence: 99%

High Glucose Exposure Impairs L-Cell Differentiation in Intestinal Organoids: Molecular Mechanisms and Clinical Implications

Filippello

Mauro

Scamporrino

et al. 2021

IJMS

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“…Our study provides a snapshot of the chronic hyperlipidemia effect on intestinal cell differentiation by using small intestinal organoid platforms. Organoids allow for the investigation of how biologically active intestinal cells interact in the gut, how TFs regulating gut cell differentiation interact with each other, and how nutritional changes causing metabolic diseases could impair these aspects [ 16 , 28 , 29 ]. In addition, our 3D platform could represent a starting point for the development of on-chip model in order to obtain an enhancement of the understanding of physiopathological alterations that could lead to an improvement in the prevention and treatment of complex chronic diseases such as obesity and diabetes.…”

Section: Discussionmentioning

confidence: 99%

Molecular Effects of Chronic Exposure to Palmitate in Intestinal Organoids: A New Model to Study Obesity and Diabetes

Filippello

Mauro

Scamporrino

et al. 2022

IJMS

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Intestinal cell dysfunctions involved in obesity and associated diabetes could be correlated with impaired intestinal cell development. To date, the molecular mechanisms underlying these dysfunctions have been poorly investigated because of the lack of a good model for studying obesity. The main aim of this study was to investigate the effects of lipotoxicity on intestinal cell differentiation in small intestinal organoid platforms, which are used to analyze the regulation of cell differentiation. Mouse intestinal organoids were grown in the presence/absence of high palmitate concentrations (0.5 mM) for 48 h to simulate lipotoxicity. Palmitate treatment altered the expression of markers involved in the differentiation of enterocytes and goblet cells in the early (Hes1) and late (Muc2) phases of their development, respectively, and it modified enterocytes and goblet cell numbers. Furthermore, the expression of enteroendocrine cell progenitors (Ngn3) and I cells (CCK) markers was also impaired, as well as CCK-positive cell numbers and CCK secretion. Our data indicate, for the first time, that lipotoxicity simultaneously influences the differentiation of specific intestinal cell types in the gut: enterocytes, goblet cells and CCK cells. Through this study, we identified novel targets associated with molecular mechanisms affected by lipotoxicity that could be important for obesity and diabetes therapy.

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“…A human microfluidic organ-chip platform was developed to study the connection among thymic epithelia, hematopoietic stem cells, islet β cells in T1D and pancreatic islet-liver cross-talking in type 2 diabetes (T2D) 140 . Therefore, inter-organ communication in diabetes would be modelled by human microfluidic organ-chip platform 141 , 142 . Moreover, islet organoids with microfluidic systems could also be a simple, advanced method for high-throughput drug screening, which was proven in 2019 143 , 144 .…”

Section: Approach For Producing Human Islet-like Organoidmentioning

confidence: 99%

Making human pancreatic islet organoids: Progresses on the cell origins, biomaterials and three-dimensional technologies

Jiang¹,

Shen²,

Liu³

et al. 2022

Theranostics

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Diabetes is one of the most socially challenging health concerns. Even though islet transplantation has shown promise for insulin-dependent diabetes, there is still no effective method for curing diabetes due to the severe shortage of transplantable donors. In recent years, organoid technology has attracted lots of attention as organoid can mirror the human organ in vivo to the maximum extent in vitro, thus bridging the gap between cellular- and tissue/organ-level biological models. Concurrently, human pancreatic islet organoids are expected to be a considerable source of islet transplantation. To construct human islet-like organoids, the seeding cells, biomaterials and three-dimensional structure are three key elements. Herein, this review summarizes current progresses about the cell origins, biomaterials and advanced technology being applied to make human islet organoids, and discusses the advantages, shortcomings, and future challenges of them as well. We hope this review can offer a cross-disciplinary perspective to build human islet organoids and provide insights for tissue engineering and regenerative medicine.

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Diabetes through a 3D lens: organoid models

Cited by 21 publications

References 104 publications

High Glucose Exposure Impairs L-Cell Differentiation in Intestinal Organoids: Molecular Mechanisms and Clinical Implications

High Glucose Exposure Impairs L-Cell Differentiation in Intestinal Organoids: Molecular Mechanisms and Clinical Implications

Molecular Effects of Chronic Exposure to Palmitate in Intestinal Organoids: A New Model to Study Obesity and Diabetes

Making human pancreatic islet organoids: Progresses on the cell origins, biomaterials and three-dimensional technologies

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