Novel approaches to studying the role of innervation in the biology of pancreatic islets.
Ontology highlight
ABSTRACT:
SUBMITTER: Rodriguez-Diaz R
PROVIDER: S-EPMC3576136 | biostudies-literature | 2013 Mar
REPOSITORIES: biostudies-literature
Publications
Novel approaches to studying the role of innervation in the biology of pancreatic islets.
Rodriguez-Diaz Rayner R Caicedo Alejandro A
Endocrinology and metabolism clinics of North America 20121220 1
The autonomic nervous system helps regulate glucose homeostasis by acting on pancreatic islets of Langerhans. Despite decades of research on the innervation of the pancreatic islet, the mechanisms used by the autonomic nervous input to influence islet cell biology have not been elucidated. This article discusses how these barriers can be overcome to study the role of the autonomic innervation of the pancreatic islet in glucose metabolism. It describes recent advances in microscopy and novel appr ...[more]
Similar Datasets
Project description:BackgroundPancreatic islets are not fully developed at birth and it is not clear how they are vascularised and innervated. Nerve Growth Factor (NGF) is required to guide sympathetic neurons that innervate peripheral organs and also in cardiovascular system and ovary angiogenesis. Pancreatic beta cells of a transgenic mouse that over-expressed NGF in attracts sympathetic hyper-innervation towards them. Moreover, we have previously demonstrated that adult beta cells synthesize and secrete NGF; however, we do not know how is NGF secreted during development, nor if it might be trophic for sympathetic innervation and survival in the pancreas.We analyzed sympathetic innervation and vasculature development in rat pancreatic islets at different developmental stages; foetal (F19), early postnatal (P1), weaning period (P20) and adults. We temporarily correlated these events to NGF secretion by islet cells.ResultsSympathetic fibres reached pancreatic islets in the early postnatal period, apparently following blood vessels. The maximal number of sympathetic fibres (TH immunopositive) in the periphery of the islets was observed at P20, and then fibres entered the islets and reached the core where beta cells are mainly located. The number of fibres decreased from that stage to adulthood. At all stages studied, islet cells secreted NGF and also expressed the high affinity receptor TrkA. Foetal and neonatal isolated islet cells secreted more NGF than adults. TrkA receptors were expressed at all stages in pancreatic sympathetic fibres and blood vessels. These last structures were NGF-immunoreactive only at early stages (foetal and P0).ConclusionThe results suggest that NGF signalling play an important role in the guidance of blood vessels and sympathetic fibres toward the islets during foetal and neonatal stages and could also preserve innervation at later stages of life.
| S-EPMC2711085 | biostudies-literature
Project description:Stem cells, including both pluripotent stem cells and multipotent somatic stem cells, hold great potential for interrogating the mechanisms of tissue development, homeostasis and pathology, and for treating numerous devastating diseases. Establishment of in vitro platforms to faithfully maintain and precisely manipulate stem cell fates is essential to understand the basic mechanisms of stem cell biology, and to translate stem cells into regenerative medicine. Chemical approaches have recently provided a number of small molecules that can be used to control cell self-renewal, lineage differentiation, reprogramming and regeneration. These chemical modulators have been proven to be versatile tools for probing stem cell biology and manipulating cell fates toward desired outcomes. Ultimately, this strategy is promising to be a new frontier for drug development aimed at endogenous stem cell modulation.
| S-EPMC3541662 | biostudies-other
Project description:Recent progress in genomics and molecular genetics has empowered novel approaches to study gene functions in disease-causing pathogens. In the human malaria parasite Plasmodium falciparum, the application of genome-based analyses, site-directed genome editing, and genetic systems that allow for temporal and quantitative regulation of gene and protein expression have been invaluable in defining the genetic basis of antimalarial resistance and elucidating candidate targets to accelerate drug discovery efforts. Using examples from recent studies, we review applications of some of these approaches in advancing our understanding of Plasmodium biology and illustrate their contributions and limitations in characterizing parasite genomic loci associated with antimalarial drug responses.
| S-EPMC8162148 | biostudies-literature
Project description:Pancreatic islets adapt to the increase in insulin demand during pregnancy by upregulating ?-cell number, insulin synthesis, and secretion. These changes require prolactin receptor (PrlR) signaling, as mice with PrlR deletion are glucose intolerant with a lower ?-cell mass. Prolactin also prevents ?-cell apoptosis. Many genes participate in these adaptive changes in the islet, and Lrrc55 is one of the most upregulated genes with unknown function in islets. Because Lrrc55 expression increases in parallel to the increase in ?-cell number and insulin production during pregnancy, we hypothesize that Lrrc55 might regulate ?-cell proliferation/apoptosis (thus ?-cell number) and insulin synthesis. Here, we found that Lrrc55 expression was upregulated by >60-fold during pregnancy in a PrlR-dependent manner, and this increase was restricted only to the islets. Overexpression of Lrrc55 in ?-cells had minimal effect on ?-cell proliferation and glucose-stimulated insulin secretion but protected ?-cells from glucolipotoxicity-induced reduction in insulin gene expression. Moreover, Lrrc55 protects ?-cells from glucolipotoxicity-induced apoptosis, with upregulation of prosurvival signals and downregulation of proapoptotic signals of the endoplasmic reticulum (ER) stress pathway. Furthermore, Lrrc55 attenuated calcium depletion induced by glucolipotoxicity, which may contribute to its antiapoptotic effect. Hence our findings suggest that Lrrc55 is a novel prosurvival factor that is upregulated specifically in islets during pregnancy, and it prevents conversion of adaptive unfolded protein response to unresolved ER stress and apoptosis in ?-cells. Lrrc55 could be a potential therapeutic target in diabetes by reducing ER stress and promoting ?-cell survival.
| S-EPMC6879869 | biostudies-literature
Project description:Innervation plays a key role in the development and homeostasis of organs and tissues of the orofacial complex. Among these structures, teeth are peculiar organs as they are not innervated until later stages of development. Furthermore, the implication of neurons in tooth initiation, morphogenesis and differentiation is still controversial. Co-cultures constitute a valuable method to investigate and manipulate the interactions of nerve fibers with their target organs in a controlled and isolated environment. Conventional co-cultures between neurons and their target tissues have already been performed, but these cultures do not offer optimal conditions that are closely mimicking the in vivo situation. Indeed, specific cell populations require different culture media in order to preserve their physiological properties. In this study we evaluate the usefulness of a microfluidics system for co-culturing mouse trigeminal ganglia and developing teeth. This device allows the application of specific media for the appropriate development of both neuronal and dental tissues. The results show that mouse trigeminal ganglia and teeth survive for long culture periods in this microfluidics system, and that teeth maintain the attractive or repulsive effect on trigeminal neurites that has been observed in vivo. Neurites are repealed when co-cultured with embryonic tooth germs, while postnatal teeth exert an attractive effect to trigeminal ganglia-derived neurons. In conclusion, microfluidics system devices provide a valuable tool for studying the behavior of neurons during the development of orofacial tissues and organs, faithfully imitating the in vivo situation.
| S-EPMC4142415 | biostudies-literature
Project description:Islet perifusion systems can be used to monitor the highly dynamic insulin release of pancreatic islets in glucose-stimulated insulin secretion (GSIS) assays. Here, we present a new generation of the microfluidic hanging-drop-based islet perifusion platform that was developed to study the alterations in insulin secretion dynamics from single pancreatic islet microtissues at high temporal resolution. The platform was completely redesigned to increase experimental throughput and to reduce operational complexity. The experimental throughput was increased fourfold by implementing a network of interconnected hanging drops, which allows for performing GSIS assays with four individual islet microtissues in parallel with a sampling interval of 30 s. We introduced a self-regulating drop-height mechanism that enables continuous flow and maintains a constant liquid volume in the chip, which enables simple and robust operation. Upon glucose stimulation, reproducible biphasic insulin release was simultaneously observed from all islets in the system. The measured insulin concentrations showed low sample-to-sample variation as a consequence of precise liquid handling with stable drop volumes, equal flow rates in the channels, and accurately controlled sampling volumes in all four drops. The presented device will be a valuable tool in islet and diabetes research for studying dynamic insulin secretion from individual pancreatic islets.
| S-EPMC8149801 | biostudies-literature
Project description:OBJECTIVE:Translation of basic research from bench-to-bedside relies on a better understanding of similarities and differences between mouse and human cell biology, tissue formation, and organogenesis. Thus, establishing ex vivo modeling systems of mouse and human pancreas development will help not only to understand evolutionary conserved mechanisms of differentiation and morphogenesis but also to understand pathomechanisms of disease and design strategies for tissue engineering. METHODS:Here, we established a simple and reproducible Matrigel-based three-dimensional (3D) cyst culture model system of mouse and human pancreatic progenitors (PPs) to study pancreatic epithelialization and endocrinogenesis ex vivo. In addition, we reanalyzed previously reported single-cell RNA sequencing (scRNA-seq) of mouse and human pancreatic lineages to obtain a comprehensive picture of differential expression of key transcription factors (TFs), cell-cell adhesion molecules and cell polarity components in PPs during endocrinogenesis. RESULTS:We generated mouse and human polarized pancreatic epithelial cysts derived from PPs. This system allowed to monitor establishment of pancreatic epithelial polarity and lumen formation in cellular and sub-cellular resolution in a dynamic time-resolved fashion. Furthermore, both mouse and human pancreatic cysts were able to differentiate towards the endocrine fate. This differentiation system together with scRNA-seq analysis revealed how apical-basal polarity and tight and adherens junctions change during endocrine differentiation. CONCLUSIONS:We have established a simple 3D pancreatic cyst culture system that allows to tempo-spatial resolve cellular and subcellular processes on the mechanistical level, which is otherwise not possible in vivo.
| S-EPMC6812400 | biostudies-literature
Project description:The prevalence of diabetes is increasing rapidly worldwide. A cardinal feature of most forms of diabetes is the lack of insulin-producing capability, due to the loss of insulin-producing ?-cells, impaired glucose-sensitive insulin secretion from the ?-cell, or a combination thereof, the reasons for which largely remain elusive. Reversible phosphorylation is an important and versatile mechanism for regulating the biological activity of many intracellular proteins, which, in turn, controls a variety of cellular functions. For instance, significant changes in protein kinase activities and in protein phosphorylation patterns occur subsequent to the stimulation of insulin release by glucose. Therefore, the molecular mechanisms regulating the phosphorylation of proteins involved in the insulin secretory process by the ?-cell have been extensively investigated. However, far less is known about the role and regulation of protein dephosphorylation by various protein phosphatases. Herein, we review extant data implicating serine/threonine and tyrosine phosphatases in various aspects of healthy and diabetic islet biology, ranging from control of hormonal stimulus-secretion coupling to mitogenesis and apoptosis.
| S-EPMC4038671 | biostudies-literature
Project description:The fine-tuning of glucose uptake mechanisms is rendered by various glucose transporters with distinct transport characteristics. In the pancreatic islet, facilitative diffusion glucose transporters (GLUTs), and sodium-glucose cotransporters (SGLTs) contribute to glucose uptake and represent important components in the glucose-stimulated hormone release from endocrine cells, therefore playing a crucial role in blood glucose homeostasis. This review summarizes the current knowledge about cell type-specific expression profiles as well as proven and putative functions of distinct GLUT and SGLT family members in the human and rodent pancreatic islet and further discusses their possible involvement in onset and progression of diabetes mellitus. In context of GLUTs, we focus on GLUT2, characterizing the main glucose transporter in insulin-secreting β-cells in rodents. In addition, we discuss recent data proposing that other GLUT family members, namely GLUT1 and GLUT3, render this task in humans. Finally, we summarize latest information about SGLT1 and SGLT2 as representatives of the SGLT family that have been reported to be expressed predominantly in the α-cell population with a suggested functional role in the regulation of glucagon release.
| S-EPMC7462922 | biostudies-literature
Project description:The pancreas became one of the first objects of regenerative medicine, since other possibilities of dealing with the pancreatic endocrine insufficiency were clearly exhausted. The number of people living with diabetes mellitus is currently approaching half a billion, hence the crucial relevance of new methods to stimulate regeneration of the insulin-secreting β-cells of the islets of Langerhans. Natural restrictions on the islet regeneration are very tight; nevertheless, the islets are capable of physiological regeneration via β-cell self-replication, direct differentiation of multipotent progenitor cells and spontaneous α- to β- or δ- to β-cell conversion (trans-differentiation). The existing preclinical models of β-cell dysfunction or ablation (induced surgically, chemically or genetically) have significantly expanded our understanding of reparative regeneration of the islets and possible ways of its stimulation. The ultimate goal, sufficient level of functional activity of β-cells or their substitutes can be achieved by two prospective broad strategies: β-cell replacement and β-cell regeneration. The "regeneration" strategy aims to maintain a preserved population of β-cells through in situ exposure to biologically active substances that improve β-cell survival, replication and insulin secretion, or to evoke the intrinsic adaptive mechanisms triggering the spontaneous non-β- to β-cell conversion. The "replacement" strategy implies transplantation of β-cells (as non-disintegrated pancreatic material or isolated donor islets) or β-like cells obtained ex vivo from progenitors or mature somatic cells (for example, hepatocytes or α-cells) under the action of small-molecule inducers or by genetic modification. We believe that the huge volume of experimental and clinical studies will finally allow a safe and effective solution to a seemingly simple goal-restoration of the functionally active β-cells, the innermost hope of millions of people globally.
| S-EPMC7304103 | biostudies-literature