Publications by authors named "Aryeh Warmflash"

BMP signaling is essential for mammalian gastrulation, as it initiates a cascade of signals that control self-organized patterning. As development is highly dynamic, it is crucial to understand how time-dependent combinatorial signaling affects cellular differentiation. Here, we show that BMP signaling duration is a crucial control parameter that determines cell fates upon the exit from pluripotency through its interplay with the induced secondary signal WNT.

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The Wnt pathway is essential for inducing the primitive streak, the precursor of the mesendoderm, as well as setting anterior-posterior coordinates. How Wnt coordinates these diverse activities remains incompletely understood. Here, we show that in Wnt-treated human pluripotent cells, endogenous Nodal signaling is a crucial switch between posteriorizing and primitive streak-including activities.

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Transitioning from pluripotency to differentiated cell fates is fundamental to both embryonic development and adult tissue homeostasis. Improving our understanding of this transition would facilitate our ability to manipulate pluripotent cells into tissues for therapeutic use. Here, we show that membrane voltage (V) regulates the exit from pluripotency and the onset of germ layer differentiation in the embryo, a process that affects both gastrulation and left-right patterning.

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We introduce cytoNet, a cloud-based tool to characterize cell populations from microscopy images. cytoNet quantifies spatial topology and functional relationships in cell communities using principles of network science. Capturing multicellular dynamics through graph features, cytoNet also evaluates the effect of cell-cell interactions on individual cell phenotypes.

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Morphogens are signaling molecules that convey positional information and dictate cell fates during development. Although ectopic expression in model organisms suggests that morphogen gradients form through diffusion, little is known about how morphogen gradients are created and interpreted during mammalian embryogenesis due to the combined difficulties of measuring endogenous morphogen levels and observing development in utero. Here we take advantage of a human gastruloid model to visualize endogenous Nodal protein in living cells, during specification of germ layers.

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In this paper we consider mathematical modeling of the dynamics of self-organized patterning of spatially confined human embryonic stem cells (hESCs) treated with BMP4 (gastruloids) described in recent experimental works (Warmflash in Nat Methods 11:847-854, 2014; Chhabra in PloS Biol 17: 3000498, 2019). In the first part of the paper we use the activator-inhibitor equations of Gierer and Meinhardt to identify 3 reaction-diffusion regimes for each of the three morphogenic proteins, BMP4, Wnt and Nodal, based on the characteristic features of the dynamic patterning. We identify appropriate boundary conditions which correspond to the experimental setup and perform numerical simulations of the reaction-diffusion (RD) systems, using the finite element approximation, to confirm that the RD systems in these regimes produce realistic dynamics of the protein concentrations.

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Understanding human organ formation is a scientific challenge with far-reaching medical implications. Three-dimensional stem-cell cultures have provided insights into human cell differentiation. However, current approaches use scaffold-free stem-cell aggregates, which develop non-reproducible tissue shapes and variable cell-fate patterns.

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Human embryonic stem cells (hESCs) possess an immense potential to generate clinically relevant cell types and unveil mechanisms underlying early human development. However, using hESCs for discovery or translation requires accurately identifying differentiated cell types through comparison with their in vivo counterparts. Here, we set out to determine the identity of much debated BMP-treated hESCs by comparing their transcriptome to recently published single cell transcriptomic data from early human embryos ( Xiang et al.

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Epithelial to mesenchymal transition (EMT) is a highly conserved cellular process in several species, from worms to humans. EMT plays a fundamental role in early embryogenesis, wound healing, and cancer metastasis. For neural crest cell (NCC) development, EMT typically results in forming a migratory and potent cell population that generates a wide variety of cell and tissue, including cartilage, bone, connective tissue, endocrine cells, neurons, and glia amongst many others.

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Self-organized patterning of mammalian embryonic stem cells on micropatterned surfaces has previously been established as an in vitro platform for early mammalian developmental studies, complimentary to in vivo studies. Traditional micropatterning methods, such as micro-contact printing (μCP), involve relatively complicated fabrication procedures, which restricts widespread adoption by biologists. Here, we demonstrate a rapid method of micropatterning by printing hydrogel micro-features onto a glass-bottomed culture vessel.

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Increasing interest has emerged in new mathematical approaches that simplify the study of complex differentiation processes by formalizing Waddington's landscape metaphor. However, a rational method to build these landscape models remains an open problem. Here we study vulval development in C.

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Mammalian embryonic development is a complex process driven by self-organization. Understanding how a fertilized egg develops into an embryo composed of more than 200 cell types in precise spatial patterns remains one of the fundamental challenges in biology. Pluripotent stem cells have been used as in vitro models for investigating mammalian development, and represent promising building blocks for regenerative therapies.

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Stem cell-based models of embryos are known by various names, with different naming conventions, leading to confusion regarding their composition and potential. We propose the need for a general term for the field to promote public engagement and the development of a systematic nomenclature system to differentiate between specific models.

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In the developing mammalian embryo, intercellular signaling allows cells to self-organize to create spatial patterns of different cell fates. This process is challenging to study because of the difficulty of observing or manipulating embryos on the spatial and temporal scales required. In vitro models can provide a complement to in vivo systems for addressing these issues.

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Article Synopsis
  • Recent advancements in various scientific fields have reignited interest in how mechanical and biochemical interactions contribute to the organization of cells and tissues.
  • New technologies in microscopy and computational analysis allow for better observation and understanding of patterns related to signaling and force generation in living systems.
  • This roadmap presents diverse case studies exploring the dynamic relationship between mechanics and biochemistry, emphasizing its role in shaping organismal development through various processes across different scales and organisms.
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Despite its importance, understanding the early phases of human development has been limited by availability of human samples. The recent emergence of stem-cell-derived embryo models, a new field aiming to use stem cells to construct in vitro models to recapitulate snapshots of the development of the mammalian conceptus, opens up exciting opportunities to promote fundamental understanding of human development and advance reproductive and regenerative medicine. This Review provides a summary of the current knowledge of early mammalian development, using mouse and human conceptuses as models, and emphasizes their similarities and critical differences.

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Morphogens play an essential role in cell fate specification and patterning including in laying out the mammalian body plan during gastrulation. In vivo studies have shed light on the signaling pathways involved in this process and the phenotypes associated with their disruption, however, several important open questions remain regarding how morphogens function in space and time. Self-organized patterning systems based on embryonic stem cells have emerged as a powerful platform for beginning to address these questions that is complementary to in vivo approaches.

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The pluripotent epiblast gives rise to all tissues and organs in the adult body. Its differentiation starts at gastrulation, when the epiblast generates mesoderm and endoderm germ layers through epithelial-mesenchymal transition (EMT). Although gastrulation EMT coincides with loss of epiblast pluripotency, pluripotent cells in development and can adopt either mesenchymal or epithelial morphology.

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During gastrulation, the pluripotent epiblast self-organizes into the 3 germ layers-endoderm, mesoderm and ectoderm, which eventually form the entire embryo. Decades of research in the mouse embryo have revealed that a signaling cascade involving the Bone Morphogenic Protein (BMP), WNT, and NODAL pathways is necessary for gastrulation. In vivo, WNT and NODAL ligands are expressed near the site of gastrulation in the posterior of the embryo, and knockout of these ligands leads to a failure to gastrulate.

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During development, the ectoderm is patterned by a combination of BMP and WNT signaling. Research in model organisms has provided substantial insight into this process; however, there are currently no systems in which to study ectodermal patterning in humans. Further, the complexity of neural plate border specification has made it difficult to transition from discovering the genes involved to deeper mechanistic understanding.

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Unlabelled: During embryonic development, diffusible signaling molecules called morphogens are thought to determine cell fates in a concentration-dependent way. Yet, in mammalian embryos, concentrations change rapidly compared to the time for making cell fate decisions. Here, we use human embryonic stem cells (hESCs) to address how changing morphogen levels influence differentiation, focusing on how BMP4 and Nodal signaling govern the cell-fate decisions associated with gastrulation.

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Article Synopsis
  • - WNT/β-catenin signaling is essential throughout life, impacting embryo development, adult stem cell maintenance, and being linked to various cancers, yet its signal transduction dynamics remain poorly understood.
  • - This study used live cell imaging to show that β-catenin signaling in pluripotent stem cells adapts to constant WNT signals, with dynamics becoming more stable when cells differentiate.
  • - Additionally, the research found that external factors, such as differentiation stage and interactions with other signaling pathways (like TGFβ ligands), significantly influence the dynamics of WNT/β-catenin signaling.
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Nondestructive measurements of cell persistence and gene expression are crucial for longitudinal research studies and for prognostic assessment of cell therapies. Here we describe S-MiRAGE, a platform that utilizes small secreted RNA molecules as sensitive and quantitatively accurate reporters of cellular processes. S-MiRAGE allows cellular numbers or gene expression to be measured from culture media or from biofluids.

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