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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 -
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 -
Surgical Pathology Clinics Dec 2016Chronic pancreatitis is a debilitating condition often associated with severe abdominal pain and exocrine and endocrine dysfunction. The underlying cause is... (Review)
Review
Chronic pancreatitis is a debilitating condition often associated with severe abdominal pain and exocrine and endocrine dysfunction. The underlying cause is multifactorial and involves complex interaction of environmental, genetic, and/or other risk factors. The pathology is dependent on the underlying pathogenesis of the disease. This review describes the clinical, gross, and microscopic findings of the main subtypes of chronic pancreatitis: alcoholic chronic pancreatitis, obstructive chronic pancreatitis, paraduodenal ("groove") pancreatitis, pancreatic divisum, autoimmune pancreatitis, and genetic factors associated with chronic pancreatitis. As pancreatic ductal adenocarcinoma may be confused with chronic pancreatitis, the main distinguishing features between these 2 diseases are discussed.
Topics: Alcohol-Induced Disorders; Autoimmune Diseases; Carcinoma, Pancreatic Ductal; Chronic Disease; Diagnosis, Differential; Humans; Pancreas; Pancreatic Ducts; Pancreatic Pseudocyst; Pancreatitis
PubMed: 27926364
DOI: 10.1016/j.path.2016.05.008 -
Clinical and Experimental Immunology Dec 2019In recent years, there have been exciting new insights into pathogenesis of type 1 diabetes in a number of areas of immunology. In this edition, a collection of four...
In recent years, there have been exciting new insights into pathogenesis of type 1 diabetes in a number of areas of immunology. In this edition, a collection of four review articles are presented, which encompass new findings presented at the Immunology of Diabetes Society meeting in London 2018. The articles are focused particularly in 4 related areas of investigation, which include autoantibodies in type 1 diabetes, new autoantigenic targets for CD4 T cells, trafficking of immune cells to the pancreas and islet-immune interactions in the pancreas.
Topics: Autoantibodies; Autoantigens; CD4-Positive T-Lymphocytes; Diabetes Mellitus, Type 1; Humans; Islets of Langerhans; Pancreas
PubMed: 31729755
DOI: 10.1111/cei.13396 -
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 -
Frontiers in Endocrinology 2021At the time of Ivan Pavlov, pancreatic innervation was studied by looking at pancreas secretions in response to electrical stimulation of nerves. Nowadays we have ways... (Review)
Review
At the time of Ivan Pavlov, pancreatic innervation was studied by looking at pancreas secretions in response to electrical stimulation of nerves. Nowadays we have ways to visualize neuronal activity in real time thanks to advances in fluorescent reporters and imaging techniques. We also have very precise optogenetic and pharmacogenetic approaches that allow neuronal manipulations in a very specific manner. These technological advances have been extensively employed for studying the central nervous system and are just beginning to be incorporated for studying visceral innervation. Pancreatic innervation is complex, and the role it plays in physiology and pathophysiology of the organ is still not fully understood. In this review we highlight anatomical aspects of pancreatic innervation, techniques for pancreatic neuronal labeling, and approaches for imaging pancreatic innervation and .
Topics: Animals; Humans; Neurons; Optical Imaging; Pancreas
PubMed: 33986728
DOI: 10.3389/fendo.2021.663022 -
International Journal of Molecular... Dec 2015The Notch signaling pathway plays a significant role in embryonic cell fate determination and adult tissue homeostasis. Various studies have demonstrated the deep... (Review)
Review
The Notch signaling pathway plays a significant role in embryonic cell fate determination and adult tissue homeostasis. Various studies have demonstrated the deep involvement of Notch signaling in the development of the pancreas and the lateral inhibition of Notch signaling in pancreatic progenitor differentiation and maintenance. The targeted inactivation of the Notch pathway components promotes premature differentiation of the endocrine pancreas. However, there is still the contrary opinion that Notch signaling specifies the endocrine lineage. Here, we review the current knowledge of the Notch signaling pathway in pancreatic development and its crosstalk with the Wingless and INT-1 (Wnt) and fibroblast growth factor (FGF) pathways.
Topics: Animals; Fibroblast Growth Factors; Humans; Pancreas; Receptors, Notch; Signal Transduction
PubMed: 26729103
DOI: 10.3390/ijms17010048 -
Diabetes Oct 2021β-Cells in the islet of Langerhans have a central role in maintaining energy homeostasis. Understanding the physiology of β-cells and other islet cells requires a deep... (Review)
Review
β-Cells in the islet of Langerhans have a central role in maintaining energy homeostasis. Understanding the physiology of β-cells and other islet cells requires a deep understanding of their structural and functional organization, their interaction with vessels and nerves, the layout of paracrine interactions, and the relationship between subcellular compartments and protein complexes inside each cell. These elements are not static; they are dynamic and exert their biological actions at different scales of time. Therefore, scientists must be able to investigate (and visualize) short- and long-lived events within the pancreas and β-cells. Current technological advances in microscopy are able to bridge multiple spatiotemporal scales in biology to reveal the complexity and heterogeneity of β-cell biology. Here, I briefly discuss the historical discoveries that leveraged microscopes to establish the basis of β-cell anatomy and structure, the current imaging platforms that allow the study of islet and β-cell biology at multiple scales of resolution, and their challenges and implications. Lastly, I outline how the remarkable longevity of structural elements at different scales in biology, from molecules to cells to multicellular structures, could represent a previously unrecognized organizational pattern in developing and adult β-cells and pancreas biology.
Topics: Animals; Cell Self Renewal; Cell Survival; Homeostasis; Humans; Insulin-Secreting Cells; Islets of Langerhans; Pancreas; Time Factors
PubMed: 34593534
DOI: 10.2337/dbi21-0008 -
Diabetologia Oct 2020Improving our understanding of mammalian pancreas development is crucial for the development of more effective cellular therapies for diabetes. Most of what we know... (Review)
Review
Improving our understanding of mammalian pancreas development is crucial for the development of more effective cellular therapies for diabetes. Most of what we know about mammalian pancreas development stems from mouse genetics. We have learnt that a unique set of transcription factors controls endocrine and exocrine cell differentiation. Transgenic mouse models have been instrumental in studying the function of these transcription factors. Mouse and human pancreas development are very similar in many respects, but the devil is in the detail. To unravel human pancreas development in greater detail, in vitro cellular models (including directed differentiation of stem cells, human beta cell lines and human pancreatic organoids) are used; however, in vivo validation of these results is still needed. The current best 'model' for studying human pancreas development are individuals with monogenic forms of diabetes. In this review, we discuss mammalian pancreas development, highlight some discrepancies between mouse and human, and discuss selected transcription factors that, when mutated, cause permanent neonatal diabetes. Graphical abstract.
Topics: Animals; Cell Line; Diabetes Mellitus; Gene Expression Regulation, Developmental; Humans; In Vitro Techniques; Insulin-Secreting Cells; Mice; Organoids; Pancreas; Pluripotent Stem Cells; Transcription Factors
PubMed: 32894307
DOI: 10.1007/s00125-020-05161-0 -
Cells Nov 2020Pancreatic ductal adenocarcinoma (PDA) is characterized by an extensive fibroinflammatory microenvironment that accumulates from the onset of disease progression.... (Review)
Review
Pancreatic ductal adenocarcinoma (PDA) is characterized by an extensive fibroinflammatory microenvironment that accumulates from the onset of disease progression. Cancer-associated fibroblasts (CAFs) are a prominent cellular component of the stroma, but their role during carcinogenesis remains controversial, with both tumor-supporting and tumor-restraining functions reported in different studies. One explanation for these contradictory findings is the heterogeneous nature of the fibroblast populations, and the different roles each subset might play in carcinogenesis. Here, we review the current literature on the origin and function of pancreatic fibroblasts, from the developing organ to the healthy adult pancreas, and throughout the initiation and progression of PDA. We also discuss clinical approaches to targeting fibroblasts in PDA.
Topics: Animals; Cancer-Associated Fibroblasts; Embryonic Development; Fibroblasts; Humans; Mesoderm; Pancreas; Pancreatic Neoplasms
PubMed: 33198201
DOI: 10.3390/cells9112464