Human stem cell models: lessons for pancreatic development and disease

A comprehensive understanding of mechanisms that underlie the development and function of human cells requires human cell models. For the pancreatic lineage, protocols have been developed to differentiate human pluripotent stem cells (hPSCs) into pancreatic endocrine and exocrine cells through intermediates resembling in vivo development. In recent years, this differentiation system has been employed to decipher mechanisms of pancreatic development, congenital defects of the pancreas, as well as genetic forms of diabetes and exocrine diseases. In this review, we summarize recent insights gained from studies of pancreatic hPSC models. We discuss how genome-scale analyses of the differentiation system have helped elucidate roles of chromatin state, transcription factors, and noncoding RNAs in pancreatic development and how the analysis of cells with disease-relevant mutations has provided insight into the molecular underpinnings of genetically determined diseases of the pancreas

Interrogating islets in health and disease with single-cell technologies

BACKGROUND: Blood glucose levels are tightly controlled by the coordinated actions of hormone-producing endocrine cells that reside in pancreatic islets. Islet cell malfunction underlies diabetes development and progression. Due to the cellular heterogeneity within islets, it has been challenging to uncover how specific islet cells contribute to glucose homeostasis and diabetes pathogenesis. Recent advances in single-cell technologies and computational methods have opened up new avenues to resolve islet heterogeneity and study islet cell states in health and disease. SCOPE OF REVIEW: In the past year, a multitude of studies have been published that used single-cell approaches to interrogate the transcriptome and proteome of the different islet cell types. Here, we summarize the conclusions of these studies, as well as discuss the technologies used and the challenges faced with computational analysis of single-cell data from islet studies. MAJOR CONCLUSIONS: By analyzing single islet cells from rodents and humans at different ages and disease states, the studies reviewed here have provided new insight into endocrine cell function and facilitated a high resolution molecular characterization of poorly understood processes, including regeneration, maturation, and diabetes pathogenesis. Gene expression programs and pathways identified in these studies pave the way for the discovery of new targets and approaches to prevent, monitor, and treat diabetes

NEOTROPICAL XENARTHRANS: a data set of occurrence of xenarthran species in the Neotropics

Xenarthrans – anteaters, sloths, and armadillos – have essential functions for ecosystem maintenance, such as insect control and nutrient cycling, playing key roles as ecosystem engineers. Because of habitat loss and fragmentation, hunting pressure, and conflicts with 24 domestic dogs, these species have been threatened locally, regionally, or even across their full distribution ranges. The Neotropics harbor 21 species of armadillos, ten anteaters, and six sloths. Our dataset includes the families Chlamyphoridae (13), Dasypodidae (7), Myrmecophagidae (3), Bradypodidae (4), and Megalonychidae (2). We have no occurrence data on Dasypus pilosus (Dasypodidae). Regarding Cyclopedidae, until recently, only one species was recognized, but new genetic studies have revealed that the group is represented by seven species. In this data-paper, we compiled a total of 42,528 records of 31 species, represented by occurrence and quantitative data, totaling 24,847 unique georeferenced records. The geographic range is from the south of the USA, Mexico, and Caribbean countries at the northern portion of the Neotropics, to its austral distribution in Argentina, Paraguay, Chile, and Uruguay. Regarding anteaters, Myrmecophaga tridactyla has the most records (n=5,941), and Cyclopes sp. has the fewest (n=240). The armadillo species with the most data is Dasypus novemcinctus (n=11,588), and the least recorded for Calyptophractus retusus (n=33). With regards to sloth species, Bradypus variegatus has the most records (n=962), and Bradypus pygmaeus has the fewest (n=12). Our main objective with Neotropical Xenarthrans is to make occurrence and quantitative data available to facilitate more ecological research, particularly if we integrate the xenarthran data with other datasets of Neotropical Series which will become available very soon (i.e. Neotropical Carnivores, Neotropical Invasive Mammals, and Neotropical Hunters and Dogs). Therefore, studies on trophic cascades, hunting pressure, habitat loss, fragmentation effects, species invasion, and climate change effects will be possible with the Neotropical Xenarthrans dataset

A systems view of epigenetic networks regulating pancreas development and β-cell function

The development of the pancreas and determination of endocrine cell fate are controlled by a highly complex interplay of signaling events and transcriptional networks. It is now known that an interconnected epigenetic program is also required to drive these processes. Recent studies using genome-wide approaches have implicated epigenetic regulators, such as DNA and histone-modifying enzymes and noncoding RNAs, to play critical roles in pancreas development and the maintenance of cell identity and function. Furthermore, genome-wide analyses have implicated epigenetic changes as a casual factor in the pathogenesis of diabetes. In the future, genomic approaches to further our understanding of the role of epigenetics in endocrine cell development and function will be useful for devising strategies to produce or manipulate β-cells for therapies of diabetes

Advances in β cell replacement and regeneration strategies for treating diabetes

In the past decade, new approaches have been explored that are aimed at restoring functional β cell mass as a treatment strategy for diabetes. The two most intensely pursued strategies are β cell replacement through conversion of other cell types and β cell regeneration by enhancement of β cell replication. The approach closest to clinical implementation is the replacement of β cells with human pluripotent stem cell-derived (hPSC-derived) cells, which are currently under investigation in a clinical trial to assess their safety in humans. In addition, there has been success in reprogramming developmentally related cell types into β cells. Reprogramming approaches could find therapeutic applications by inducing β cell conversion in vivo or by reprogramming cells ex vivo followed by implantation. Finally, recent studies have revealed novel pharmacologic targets for stimulating β cell replication. Manipulating these targets or the pathways they regulate could be a strategy for promoting the expansion of residual β cells in diabetic patients. Here, we provide an overview of progress made toward β cell replacement and regeneration and discuss promises and challenges for clinical implementation of these strategies

Pseudotemporal ordering of single cells reveals metabolic control of postnatal ß cell proliferation

Pancreatic β cell mass for appropriate blood glucose control is established during early postnatal life. β cell proliferative capacity declines postnatally, but the extrinsic cues and intracellular signals that cause this decline remain unknown. To obtain a high-resolution map of β cell transcriptome dynamics after birth, we generated single-cell RNA-seq data of β cells from multiple postnatal time points and ordered cells based on transcriptional similarity using a new analytical tool. This analysis captured signatures of immature, proliferative β cells and established high expression of amino acid metabolic, mitochondrial, and Srf/Jun/Fos transcription factor genes as their hallmark feature. Experimental validation revealed high metabolic activity in immature β cells and a role for reactive oxygen species and Srf/Jun/Fos transcription factors in driving postnatal β cell proliferation and mass expansion. Our work provides the first high-resolution molecular characterization of state changes in postnatal β cells and paves the way for the identification of novel therapeutic targets to stimulate β cell regeneration