Nurturing protectors: Macrophages in the human pancreatic islet.

Two recent publications in Cell Stem Cell, Yang et al. and Migliorini et al., utilized pluripotent stem cell-derived co-culture systems to explore the role of macrophages within the pancreatic islet during development and disease states.

Heterozygous missense variant in GLI2 impairs human endocrine pancreas development.

Missense variants are the most common type of coding genetic variants. Their functional assessment is fundamental for defining any implication in human diseases and may also uncover genes that are essential for human organ development. Here, we apply CRISPR-Cas9 gene editing on human iPSCs to study a heterozygous missense variant in GLI2 identified in two siblings with early-onset and insulin-dependent diabetes of unknown cause.

Acinar-ductal cell rearrangement drives branching morphogenesis of the murine pancreas in an IGF/PI3K-dependent manner.

During organ formation, progenitor cells need to acquire different cell identities and organize themselves into distinct structural units. How these processes are coordinated and how tissue architecture(s) is preserved despite the dramatic cell rearrangements occurring in developing organs remain unclear. Here, we identified cellular rearrangements between acinar and ductal progenitors as a mechanism to drive branching morphogenesis in the pancreas while preserving the integrity of the acinar-ductal functional unit.

In-Depth Analysis of the Pancreatic Extracellular Matrix during Development for Next-Generation Tissue Engineering.

The pancreas is a complex organ consisting of differentiated cells and extracellular matrix (ECM) organized adequately to enable its endocrine and exocrine functions. Although much is known about the intrinsic factors that control pancreas development, very few studies have focused on the microenvironment surrounding pancreatic cells. This environment is composed of various cells and ECM components, which play a critical role in maintaining tissue organization and homeostasis.

Understanding cell fate acquisition in stem-cell-derived pancreatic islets using single-cell multiome-inferred regulomes.

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.

3D multicellular systems in disease modelling: From organoids to organ-on-chip.

Cell-cell interactions underlay organ formation and function during homeostasis. Changes in communication between cells and their surrounding microenvironment are a feature of numerous human diseases, including metabolic disease and neurological disorders. In the past decade, cross-disciplinary research has been conducted to engineer novel synthetic multicellular organ systems in 3D, including organoids, assembloids, and organ-on-chip models.

Identification and implication of tissue-enriched ligands in epithelial-endothelial crosstalk during pancreas development.

Development of the pancreas is driven by an intrinsic program coordinated with signals from other cell types in the epithelial environment. These intercellular communications have been so far challenging to study because of the low concentration, localized production and diversity of the signals released. Here, we combined scRNAseq data with a computational interactomic approach to identify signals involved in the reciprocal interactions between the various cell types of the developing pancreas.

Functional genomics and the future of iPSCs in disease modeling.

Induced pluripotent stem cells (iPSCs) are valuable in disease modeling because of their potential to expand and differentiate into virtually any cell type and recapitulate key aspects of human biology. Functional genomics are genome-wide studies that aim to discover genotype-phenotype relationships, thereby revealing the impact of human genetic diversity on normal and pathophysiology. In this review, we make the case that human iPSCs (hiPSCs) are a powerful tool for functional genomics, since they provide an in vitro platform for the study of population genetics.

Development of a 3D atlas of the embryonic pancreas for topological and quantitative analysis of heterologous cell interactions.

Generating comprehensive image maps, while preserving spatial three-dimensional (3D) context, is essential in order to locate and assess quantitatively specific cellular features and cell-cell interactions during organ development. Despite recent advances in 3D imaging approaches, our current knowledge of the spatial organization of distinct cell types in the embryonic pancreatic tissue is still largely based on two-dimensional histological sections. Here, we present a light-sheet fluorescence microscopy approach to image the pancreas in three dimensions and map tissue interactions at key time points in the mouse embryo.

The postnatal pancreatic microenvironment guides β cell maturation through BMP4 production.

Glucose homeostasis depends on regulated insulin secretion from pancreatic β cells, which acquire their mature phenotype postnatally. The functional maturation of β cells is regulated by a combination of cell-autonomous and exogenous factors; the identity of the latter is mostly unknown. Here, we identify BMP4 as a critical component through which the pancreatic microenvironment regulates β cell function.

Quantitative lineage analysis identifies a hepato-pancreato-biliary progenitor niche.

Studies based on single cells have revealed vast cellular heterogeneity in stem cell and progenitor compartments, suggesting continuous differentiation trajectories with intermixing of cells at various states of lineage commitment and notable degrees of plasticity during organogenesis. The hepato-pancreato-biliary organ system relies on a small endoderm progenitor compartment that gives rise to a variety of different adult tissues, including the liver, pancreas, gall bladder and extra-hepatic bile ducts. Experimental manipulation of various developmental signals in the mouse embryo has underscored important cellular plasticity in this embryonic territory.

Engineering life in synthetic systems.

The second EMBO-EMBL Symposium 'Synthetic Morphogenesis: From Gene Circuits to Tissue Architecture' was held virtually in March 2021, with participants from all over the world joining from the comfort of their sofas to discuss synthetic morphogenesis at large. Leading scientists from a range of disciplines, including developmental biology, physics, chemistry and computer science, covered a gamut of topics from the principles of cell and tissue organization, patterning and gene regulatory networks, to synthetic approaches for exploring evolutionary and developmental biology principles. Here, we describe some of the high points.

Pancreatic cell fate specification: insights into developmental mechanisms and their application for lineage reprogramming.

Diabetes is a group of metabolic disorders, which results from insufficient functional pancreatic β-cell mass either due to the autoimmune destruction of insulin producing β-cells, or their death or de-differentiation as compensation for insulin resistance. The ability to reprogram cell types within close developmental proximity to β-cells offers a strategy to replenish β-cell mass and a future possible treatment of diabetes. Here, we review recent advances in the fields of pancreas development and lineage reprogramming.

Employing core regulatory circuits to define cell identity.

The interplay between extrinsic signaling and downstream gene networks controls the establishment of cell identity during development and its maintenance in adult life. Advances in next-generation sequencing and single-cell technologies have revealed additional layers of complexity in cell identity. Here, we review our current understanding of transcription factor (TF) networks as key determinants of cell identity.

A Specialized Niche in the Pancreatic Microenvironment Promotes Endocrine Differentiation.

The interplay between pancreatic epithelium and the surrounding microenvironment is pivotal for pancreas formation and differentiation as well as adult organ homeostasis. The mesenchyme is the main component of the embryonic pancreatic microenvironment, yet its cellular identity is broadly defined, and whether it comprises functionally distinct cell subsets is not known. Using genetic lineage tracing, transcriptome, and functional studies, we identified mesenchymal populations with different roles during pancreatic development.

Direct Lineage Reprogramming: Harnessing Cell Plasticity between Liver and Pancreas.

Direct lineage reprogramming of abundant and accessible cells into therapeutically useful cell types holds tremendous potential in regenerative medicine. To date, a number of different cell types have been generated by lineage reprogramming methods, including cells from the neural, cardiac, hepatic, and pancreatic lineages. The success of this strategy relies on developmental biology and the knowledge of cell-fate-defining transcriptional networks.

A whole organism small molecule screen identifies novel regulators of pancreatic endocrine development.

An early step in pancreas development is marked by the expression of the transcription factor Pdx1 within the pancreatic endoderm, where it is required for the specification of all endocrine cell types. Subsequently, Pdx1 expression becomes restricted to the β-cell lineage, where it plays a central role in β-cell function. This pivotal role of Pdx1 at various stages of pancreas development makes it an attractive target to enhance pancreatic β-cell differentiation and increase β-cell function.

Pancreas organogenesis: The interplay between surrounding microenvironment(s) and epithelium-intrinsic factors.

During embryonic development, pancreatic epithelial cells engage in concomitant morphogenetic and fate specification events that will give rise to the final organ architecture and functions. Cues from the surrounding microenvironment are known to influence the behavior of epithelial progenitors and orchestrate these concomitant events throughout pancreas development. Nevertheless, the composition of the pancreatic microenvironment remains elusive; also, the interplay between components of the surrounding microenvironment and the epithelium is poorly characterized.

Robo signalling controls pancreatic progenitor identity by regulating Tead transcription factors.

A complex interplay of intrinsic factors and extrinsic signalling pathways controls both cell lineage commitment and maintenance of cell identity. Loss of defined cellular states is the cause of many different cancers, including pancreatic cancer. Recent findings suggest a clinical role for the conserved SLIT/ROBO signalling pathway in pancreatic cancer.

The RhoGAP Stard13 controls insulin secretion through F-actin remodeling.

Objective: Actin cytoskeleton remodeling is necessary for glucose-stimulated insulin secretion in pancreatic β-cells. A mechanistic understanding of actin dynamics in the islet is paramount to a better comprehension of β-cell dysfunction in diabetes. Here, we investigate the Rho GTPase regulator Stard13 and its role in F-actin cytoskeleton organization and islet function in adult mice.

Stepwise reprogramming of liver cells to a pancreas progenitor state by the transcriptional regulator Tgif2.

The development of a successful lineage reprogramming strategy of liver to pancreas holds promises for the treatment and potential cure of diabetes. The liver is an ideal tissue source for generating pancreatic cells, because of its close developmental origin with the pancreas and its regenerative ability. Yet, the molecular bases of hepatic and pancreatic cellular plasticity are still poorly understood.

The histone methyltransferase Setd7 promotes pancreatic progenitor identity.

Cell fate specification depends on transcriptional activation driven by lineage-specific transcription factors as well as changes in chromatin organization. To date, the interplay between transcription factors and chromatin modifiers during development is not well understood. We focus here on the initiation of the pancreatic program from multipotent endodermal progenitors.

Xenopus as a model system for studying pancreatic development and diabetes.

Diabetes is a chronic disease caused by the loss or dysfunction of the insulin-producing β-cells in the pancreas. To date, much of our knowledge about β-cells in humans comes from studying rare monogenic forms of diabetes. Importantly, the majority of mutations so far associated to monogenic diabetes are in genes that exert a regulatory role in pancreatic development and/or β-cell function.

Simply the right time to turn on insulin.

Recent research has made important progress in the directed differentiation of human pluripotent stem cells into insulin-producing beta-like cells . A new study published in this issue of reports that timely induction of NEUROG3 expression in pancreatic progenitors is a crucial checkpoint for generation of functional human beta cells.