-
Diabetologia Oct 2020
Topics: Diabetes Mellitus; Humans; Pancreas
PubMed: 32894305
DOI: 10.1007/s00125-020-05235-z -
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 -
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 -
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 -
Cell Metabolism Sep 2023Type 1 diabetes (T1D) is widely considered to result from the autoimmune destruction of insulin-producing β cells. This concept has been a central tenet for decades of... (Review)
Review
Type 1 diabetes (T1D) is widely considered to result from the autoimmune destruction of insulin-producing β cells. This concept has been a central tenet for decades of attempts seeking to decipher the disorder's pathogenesis and prevent/reverse the disease. Recently, this and many other disease-related notions have come under increasing question, particularly given knowledge gained from analyses of human T1D pancreas. Perhaps most crucial are findings suggesting that a collective of cellular constituents-immune, endocrine, and exocrine in origin-mechanistically coalesce to facilitate T1D. This review considers these emerging concepts, from basic science to clinical research, and identifies several key remaining knowledge voids.
Topics: Humans; Diabetes Mellitus, Type 1; Pancreas, Exocrine; Pancreas; Insulin-Secreting Cells; Immune System; Islets of Langerhans
PubMed: 37478842
DOI: 10.1016/j.cmet.2023.06.018 -
Radiologie (Heidelberg, Germany) Dec 2023
Topics: Humans; Pancreas; Pancreatic Neoplasms; Pancreatic Hormones
PubMed: 38038741
DOI: 10.1007/s00117-023-01232-6 -
Frontiers in Endocrinology 2022
Topics: Islets of Langerhans; Pancreas; Pancreas, Exocrine
PubMed: 35966106
DOI: 10.3389/fendo.2022.967066 -
The British Journal of Surgery Sep 2022
Topics: Humans; Pancreas; Pancreatic Diseases
PubMed: 36084336
DOI: 10.1093/bjs/znac167 -
Nature May 2024Pancreatic intraepithelial neoplasias (PanINs) are the most common precursors of pancreatic cancer, but their small size and inaccessibility in humans make them...
Pancreatic intraepithelial neoplasias (PanINs) are the most common precursors of pancreatic cancer, but their small size and inaccessibility in humans make them challenging to study. Critically, the number, dimensions and connectivity of human PanINs remain largely unknown, precluding important insights into early cancer development. Here, we provide a microanatomical survey of human PanINs by analysing 46 large samples of grossly normal human pancreas with a machine-learning pipeline for quantitative 3D histological reconstruction at single-cell resolution. To elucidate genetic relationships between and within PanINs, we developed a workflow in which 3D modelling guides multi-region microdissection and targeted and whole-exome sequencing. From these samples, we calculated a mean burden of 13 PanINs per cm and extrapolated that the normal intact adult pancreas harbours hundreds of PanINs, almost all with oncogenic KRAS hotspot mutations. We found that most PanINs originate as independent clones with distinct somatic mutation profiles. Some spatially continuous PanINs were found to contain multiple KRAS mutations; computational and in situ analyses demonstrated that different KRAS mutations localize to distinct cell subpopulations within these neoplasms, indicating their polyclonal origins. The extensive multifocality and genetic heterogeneity of PanINs raises important questions about mechanisms that drive precancer initiation and confer differential progression risk in the human pancreas. This detailed 3D genomic mapping of molecular alterations in human PanINs provides an empirical foundation for early detection and rational interception of pancreatic cancer.
Topics: Adult; Female; Humans; Male; Clone Cells; Exome Sequencing; Genetic Heterogeneity; Genomics; Imaging, Three-Dimensional; Machine Learning; Mutation; Pancreas; Pancreatic Neoplasms; Precancerous Conditions; Single-Cell Analysis; Workflow; Disease Progression; Early Detection of Cancer; Oncogenes
PubMed: 38693266
DOI: 10.1038/s41586-024-07359-3 -
Primary Care Sep 2023The pancreas is a vital intra-abdominal organ with dual exocrine and endocrine function. This article provides an overview of several common pancreatic pathologies... (Review)
Review
The pancreas is a vital intra-abdominal organ with dual exocrine and endocrine function. This article provides an overview of several common pancreatic pathologies including pancreatitis, pancreatic cysts, and pancreatic cancer with a focus on clinical presentation as well as initial diagnosis and management.
Topics: Humans; Pancreas; Pancreatitis; Pancreatic Neoplasms
PubMed: 37516510
DOI: 10.1016/j.pop.2023.03.005