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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 -
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 -
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 -
Frontiers in Endocrinology 2022
Topics: Islets of Langerhans; Pancreas; Pancreas, Exocrine
PubMed: 35966106
DOI: 10.3389/fendo.2022.967066 -
Cell Oct 2017As organisms age, cells accumulate genetic and epigenetic errors that eventually lead to impaired organ function or catastrophic transformation such as cancer. Because...
As organisms age, cells accumulate genetic and epigenetic errors that eventually lead to impaired organ function or catastrophic transformation such as cancer. Because aging reflects a stochastic process of increasing disorder, cells in an organ will be individually affected in different ways, thus rendering bulk analyses of postmitotic adult cells difficult to interpret. Here, we directly measure the effects of aging in human tissue by performing single-cell transcriptome analysis of 2,544 human pancreas cells from eight donors spanning six decades of life. We find that islet endocrine cells from older donors display increased levels of transcriptional noise and potential fate drift. By determining the mutational history of individual cells, we uncover a novel mutational signature in healthy aging endocrine cells. Our results demonstrate the feasibility of using single-cell RNA sequencing (RNA-seq) data from primary cells to derive insights into genetic and transcriptional processes that operate on aging human tissue.
Topics: Adult; Aging; Cellular Senescence; Child; Child, Preschool; Humans; Infant; Middle Aged; Mutation; Pancreas; Polymorphism, Single Nucleotide; Sequence Analysis, RNA; Single-Cell Analysis; Transcription, Genetic
PubMed: 28965763
DOI: 10.1016/j.cell.2017.09.004 -
Journal of Diabetes Investigation Jul 2017Imaging studies of the pancreas provide valuable information on the pathophysiology of diabetes and direction of the clinical management. Comparative studies on the...
Imaging studies of the pancreas provide valuable information on the pathophysiology of diabetes and direction of the clinical management. Comparative studies on the imaging and microscopic pathology will be required to validate the importance of the images.
Topics: Diabetes Mellitus; Humans; Organ Size; Pancreas
PubMed: 27808474
DOI: 10.1111/jdi.12590 -
Diabetes, Obesity & Metabolism Sep 2016A rediscovery of three-dimensional culture has led to the development of organ biogenesis, homeostasis and disease models applicable to human tissues. The so-called... (Review)
Review
A rediscovery of three-dimensional culture has led to the development of organ biogenesis, homeostasis and disease models applicable to human tissues. The so-called organoids that have recently flourished serve as valuable models bridging between cell lines or primary cells grown on the bottom of culture plates and experiments performed in vivo. Though not recapitulating all aspects of organ physiology, the miniature organs generated in a dish are useful models emerging for the pancreas, starting from embryonic progenitors, adult cells, tumour cells and stem cells. This review focusses on the currently available systems and their relevance to the study of the pancreas, of β-cells and of several pancreatic diseases including diabetes. We discuss the expected future developments for studying human pancreas development and function, for developing diabetes models and for producing therapeutic cells.
Topics: Animals; Humans; Insulin-Secreting Cells; Mice; Organ Culture Techniques; Organogenesis; Organoids; Pancreas; Pancreatic Neoplasms
PubMed: 27615129
DOI: 10.1111/dom.12720 -
Developmental Cell Jul 2013Pancreas homeostasis is based on replication of differentiated cells in order to maintain proper organ size and function under changing physiological demand. Recent... (Review)
Review
Pancreas homeostasis is based on replication of differentiated cells in order to maintain proper organ size and function under changing physiological demand. Recent studies suggest that acinar cells, the most abundant cell type in the pancreas, are facultative progenitors capable of reverting to embryonic-like multipotent progenitor cells under injury conditions associated with inflammation. In parallel, it is becoming apparent that within the endocrine pancreas, hormone-producing cells can lose or switch their identity under metabolic stress or in response to single gene mutations. This new view of pancreas dynamics suggests interesting links between pancreas regeneration and pathologies including diabetes and pancreatic cancer.
Topics: Acinar Cells; Carcinoma, Pancreatic Ductal; Cell Death; Cell Dedifferentiation; Cell Differentiation; Cellular Reprogramming; Endocrine Cells; Humans; Pancreas; Pancreatitis; Regeneration; Stem Cells
PubMed: 23867225
DOI: 10.1016/j.devcel.2013.06.013 -
Current Opinion in Endocrinology,... Apr 2014We highlight some of the major recent advances in characterizing human pancreas development and endocrine cell differentiation. (Review)
Review
PURPOSE OF REVIEW
We highlight some of the major recent advances in characterizing human pancreas development and endocrine cell differentiation.
RECENT FINDINGS
Extensive research efforts have helped to define crucial events in the mouse pancreas organogenesis. Information gained from these studies was used to develop human embryonic stem cell (hESC) differentiation protocols with the goal of generating functional glucose-responsive, insulin-producing human β-cells. In spite of remarkable progress in hESC differentiation, current protocols based on mouse developmental biology can produce human β-cells only in vivo. New differentiation markers and recently generated reagents may provide an unprecedented opportunity to develop a high-density expression map of human fetal pancreas and pancreatic islets that could serve as a reference point for in vitro hESC differentiation.
SUMMARY
Integrating an increased knowledge of human pancreas development into hESC differentiation protocols has the potential to greatly advance our ability to generate functional insulin-producing cells for β-cell replacement therapy.
Topics: Animals; Cell Culture Techniques; Cell Differentiation; Cells, Cultured; Embryonic Stem Cells; Endocrine System; Glucose; Humans; Insulin-Secreting Cells; Mice; Organogenesis; Pancreas; Signal Transduction
PubMed: 24569548
DOI: 10.1097/MED.0000000000000047