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Gastroenterology May 2019Since the discovery of the first trypsinogen mutation in families with hereditary pancreatitis, pancreatic genetics has made rapid progress. The identification of... (Review)
Review
Since the discovery of the first trypsinogen mutation in families with hereditary pancreatitis, pancreatic genetics has made rapid progress. The identification of mutations in genes involved in the digestive protease-antiprotease pathway has lent additional support to the notion that pancreatitis is a disease of autodigestion. Clinical and experimental observations have provided compelling evidence that premature intrapancreatic activation of digestive proteases is critical in pancreatitis onset. However, disease course and severity are mostly governed by inflammatory cells that drive local and systemic immune responses. In this article, we review the genetics, cell biology, and immunology of pancreatitis with a focus on protease activation pathways and other early events.
Topics: Animals; Apoptosis; Enzyme Activation; Genetic Predisposition to Disease; Humans; Inflammation Mediators; Mutation; Necrosis; Pancreas; Pancreatitis; Peptide Hydrolases; Phenotype; Prognosis; Protein Folding; Risk Factors; Signal Transduction
PubMed: 30660731
DOI: 10.1053/j.gastro.2018.11.081 -
Nature May 2018The pancreas is made from two distinct components: the exocrine pancreas, a reservoir of digestive enzymes, and the endocrine islets, the source of the vital metabolic... (Review)
Review
The pancreas is made from two distinct components: the exocrine pancreas, a reservoir of digestive enzymes, and the endocrine islets, the source of the vital metabolic hormone insulin. Human islets possess limited regenerative ability; loss of islet β-cells in diseases such as type 1 diabetes requires therapeutic intervention. The leading strategy for restoration of β-cell mass is through the generation and transplantation of new β-cells derived from human pluripotent stem cells. Other approaches include stimulating endogenous β-cell proliferation, reprogramming non-β-cells to β-like cells, and harvesting islets from genetically engineered animals. Together these approaches form a rich pipeline of therapeutic development for pancreatic regeneration.
Topics: Adult Stem Cells; Animals; Cell Proliferation; Cellular Reprogramming; Humans; Islets of Langerhans; Pancreas; Pluripotent Stem Cells; Regeneration; Regenerative Medicine
PubMed: 29769672
DOI: 10.1038/s41586-018-0088-0 -
Experimental & Molecular Medicine Mar 2016In order to ensure normal body function, the human body is dependent on a tight control of its blood glucose levels. This is accomplished by a highly sophisticated... (Review)
Review
In order to ensure normal body function, the human body is dependent on a tight control of its blood glucose levels. This is accomplished by a highly sophisticated network of various hormones and neuropeptides released mainly from the brain, pancreas, liver, intestine as well as adipose and muscle tissue. Within this network, the pancreas represents a key player by secreting the blood sugar-lowering hormone insulin and its opponent glucagon. However, disturbances in the interplay of the hormones and peptides involved may lead to metabolic disorders such as type 2 diabetes mellitus (T2DM) whose prevalence, comorbidities and medical costs take on a dramatic scale. Therefore, it is of utmost importance to uncover and understand the mechanisms underlying the various interactions to improve existing anti-diabetic therapies and drugs on the one hand and to develop new therapeutic approaches on the other. This review summarizes the interplay of the pancreas with various other organs and tissues that maintain glucose homeostasis. Furthermore, anti-diabetic drugs and their impact on signaling pathways underlying the network will be discussed.
Topics: Animals; Cell Communication; Diabetes Mellitus, Type 2; Glucose; Homeostasis; Humans; Insulin; Islets of Langerhans; Pancreas; Pancreas, Exocrine; Signal Transduction
PubMed: 26964835
DOI: 10.1038/emm.2016.6 -
Diabetologia Oct 2020For much of the last century, our knowledge regarding the pancreas in type 1 and type 2 diabetes was largely derived from autopsy studies of individuals with these... (Review)
Review
For much of the last century, our knowledge regarding the pancreas in type 1 and type 2 diabetes was largely derived from autopsy studies of individuals with these disorders or investigations utilising rodent models of either disease. While many important insights emanated from these efforts, the mode for investigation has increasingly seen change due to the availability of transplant-quality organ-donor tissues, improvements in pancreatic imaging, advances in metabolic assessments of living patients, genetic analyses, technological advances for laboratory investigation and more. As a result, many long-standing notions regarding the role for and the changes that occur in the pancreas in individuals with these disorders have come under question, while, at the same time, new issues (e.g., beta cell persistence, disease heterogeneity, exocrine contributions) have arisen. In this article, we will consider the vital role of the pancreas in human health and physiology, including discussion of its anatomical features and dual (exocrine and endocrine) functions. Specifically, we convey changes that occur in the pancreas of those with either type 1 or type 2 diabetes, with careful attention to the facets that may contribute to the pathogenesis of either disorder. Finally, we discuss the emerging unknowns with the belief that understanding the role of the pancreas in type 1 and type 2 diabetes will lead to improvements in disease diagnosis, understanding of disease heterogeneity and optimisation of treatments at a personalised level. Graphical abstract.
Topics: Adipose Tissue; Amyloidosis; Autoimmunity; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glucagon-Secreting Cells; Humans; Insulin-Secreting Cells; Islet Amyloid Polypeptide; Islets of Langerhans; Pancreas; Pancreas, Exocrine; Somatostatin-Secreting Cells
PubMed: 32894306
DOI: 10.1007/s00125-020-05203-7 -
Expert Review of Gastroenterology &... Nov 2019: Pancreas divisum is the most common congenital malformation of the pancreas with the majority asymptomatic. The etiological role, pathogenesis, clinical significance... (Review)
Review
: Pancreas divisum is the most common congenital malformation of the pancreas with the majority asymptomatic. The etiological role, pathogenesis, clinical significance and management of pancreas divisum in pancreatic disease has not been clearly defined and our understanding is yet to be fully elucidated.: This review describes the role of pancreas divisum in the development of pancreatic disease and the ambiguity related to it. In our attempt to offer clarity, a comprehensive search on PubMed, Ovid, Embase and Cochrane Library from inception to May 2019 was undertaken using key words "pancreas divisum", "idiopathic recurrent acute pancreatitis" and "chronic pancreatitis".: Current research fails to define a clear association between pancreas divisum and pancreatic disease. Though debatable, several studies do suggest a pathological role of pancreas divisum in pancreatic disease and a benefit of minor papilla therapy in the setting of acute recurrent pancreatitis. Surgical and endoscopic therapeutic modalities have not been directly compared. With the current data available, it would be imprudent to advise a definitive line of management for pancreatic disease associated with pancreas divisum and should involve a comprehensive discussion with the individual patient to define expectations before embarking on any medical and/or interventional therapy.
Topics: Digestive System Abnormalities; Humans; Pancreas; Pancreatitis; Pancreatitis, Chronic; Predictive Value of Tests; Prognosis; Recurrence; Risk Assessment; Risk Factors
PubMed: 31663403
DOI: 10.1080/17474124.2019.1685871 -
Cell Metabolism Jan 2023Current differentiation protocols have not been successful in reproducibly generating fully functional human beta cells in vitro, partly due to incomplete understanding...
Current differentiation protocols have not been successful in reproducibly generating fully functional human beta cells in vitro, partly due to incomplete understanding of human pancreas development. Here, we present detailed transcriptomic analysis of the various cell types of the developing human pancreas, including their spatial gene patterns. We integrated single-cell RNA sequencing with spatial transcriptomics at multiple developmental time points and revealed distinct temporal-spatial gene cascades. Cell trajectory inference identified endocrine progenitor populations and branch-specific genes as the progenitors differentiate toward alpha or beta cells. Spatial differentiation trajectories indicated that Schwann cells are spatially co-located with endocrine progenitors, and cell-cell connectivity analysis predicted that they may interact via L1CAM-EPHB2 signaling. Our integrated approach enabled us to identify heterogeneity and multiple lineage dynamics within the mesenchyme, showing that it contributed to the exocrine acinar cell state. Finally, we have generated an interactive web resource for investigating human pancreas development for the research community.
Topics: Humans; Transcriptome; Pancreas; Gene Expression Profiling; Cell Differentiation; Pancreas, Exocrine; Single-Cell Analysis; Gene Expression Regulation, Developmental
PubMed: 36513063
DOI: 10.1016/j.cmet.2022.11.009 -
Islets 2015Mice remain the most studied animal model in pancreas research. Since the findings of this research are typically extrapolated to humans, it is important to understand... (Review)
Review
Mice remain the most studied animal model in pancreas research. Since the findings of this research are typically extrapolated to humans, it is important to understand both similarities and differences between the 2 species. Beside the apparent difference in size and macroscopic organization of the organ in the 2 species, there are a number of less evident and only recently described differences in organization of the acinar and ductal exocrine tissue, as well as in the distribution, composition, and architecture of the endocrine islets of Langerhans. Furthermore, the differences in arterial, venous, and lymphatic vessels, as well as innervation are potentially important. In this article, the structure of the human and the mouse pancreas, together with the similarities and differences between them are reviewed in detail in the light of conceivable repercussions for basic research and clinical application.
Topics: Animals; Disease Models, Animal; Humans; Insulin-Secreting Cells; Islets of Langerhans; Mice; Pancreas
PubMed: 26030186
DOI: 10.1080/19382014.2015.1024405 -
Cell Systems Oct 2016Although the function of the mammalian pancreas hinges on complex interactions of distinct cell types, gene expression profiles have primarily been described with bulk...
Although the function of the mammalian pancreas hinges on complex interactions of distinct cell types, gene expression profiles have primarily been described with bulk mixtures. Here we implemented a droplet-based, single-cell RNA-seq method to determine the transcriptomes of over 12,000 individual pancreatic cells from four human donors and two mouse strains. Cells could be divided into 15 clusters that matched previously characterized cell types: all endocrine cell types, including rare epsilon-cells; exocrine cell types; vascular cells; Schwann cells; quiescent and activated stellate cells; and four types of immune cells. We detected subpopulations of ductal cells with distinct expression profiles and validated their existence with immuno-histochemistry stains. Moreover, among human beta- cells, we detected heterogeneity in the regulation of genes relating to functional maturation and levels of ER stress. Finally, we deconvolved bulk gene expression samples using the single-cell data to detect disease-associated differential expression. Our dataset provides a resource for the discovery of novel cell type-specific transcription factors, signaling receptors, and medically relevant genes.
Topics: Animals; Cell Differentiation; Gene Expression Profiling; Gene Expression Regulation, Developmental; Humans; Islets of Langerhans; Mice; Pancreas; Pancreas, Exocrine; Single-Cell Analysis; Transcription Factors; Transcriptome
PubMed: 27667365
DOI: 10.1016/j.cels.2016.08.011 -
Developmental Cell May 2023Pancreatic islet cells derived from human pluripotent stem cells hold great promise for modeling and treating diabetes. Differences between stem-cell-derived and primary...
Pancreatic islet cells derived from human pluripotent stem cells hold great promise for modeling and treating diabetes. Differences between stem-cell-derived and primary islets remain, but molecular insights to inform improvements are limited. Here, we acquire single-cell transcriptomes and accessible chromatin profiles during in vitro islet differentiation and pancreas from childhood and adult donors for comparison. We delineate major cell types, define their regulomes, and describe spatiotemporal gene regulatory relationships between transcription factors. CDX2 emerged as a regulator of enterochromaffin-like cells, which we show resemble a transient, previously unrecognized, serotonin-producing pre-β cell population in fetal pancreas, arguing against a proposed non-pancreatic origin. Furthermore, we observe insufficient activation of signal-dependent transcriptional programs during in vitro β cell maturation and identify sex hormones as drivers of β cell proliferation in childhood. Altogether, our analysis provides a comprehensive understanding of cell fate acquisition in stem-cell-derived islets and a framework for manipulating cell identities and maturity.
Topics: Adult; Humans; Islets of Langerhans; Pancreas; Cell Differentiation; Insulin-Secreting Cells; Pluripotent Stem Cells
PubMed: 37040771
DOI: 10.1016/j.devcel.2023.03.011 -
Frontiers in Endocrinology 2022
Topics: Islets of Langerhans; Pancreas; Pancreas, Exocrine
PubMed: 35966106
DOI: 10.3389/fendo.2022.967066