Dupilumab Use in Patients With Hypereosinophilic Syndromes: A Multicenter Case Series and Review of the Literature.

Background: Hypereosinophilic syndromes (HES) are defined as hypereosinophilia with eosinophil-related clinical manifestations, some of which overlap in presentation with asthma, atopic dermatitis, eosinophilic esophagitis, and/or chronic rhinosinusitis with nasal polyps. Dupilumab is approved to treat these conditions but can induce a transient rise in the absolute eosinophil count and rare eosinophil-related complications.

Objective: To determine whether eosinophil-related complications of dupilumab are increased in HES.

Mesenchymal Vangl1 and Vangl2 facilitate airway elongation and widening independently of the planar cell polarity complex.

Adult mammalian lungs exhibit a fractal pattern, as each successive generation of airways is a fraction of the size of the parental branch. Achieving this structure likely requires precise control of airway length and diameter, as the embryonic airways initially lack the fractal scaling observed in the adult. In monolayers and tubes, directional growth can be regulated by the planar cell polarity (PCP) complex.

Bioprinting Cell-Laden Hydrogels for Studies of Epithelial Tissue Morphogenesis.

The extracellular matrix (ECM) provides dynamic structural and molecular signals that affect the form and function of developing tissues. In order to parse how the individual features of the ECM impact cell- and tissue-level behavior during development, engineered culture models should reproduce key structural and molecular features of native ECM. Here, we describe a protocol for bioprinting epithelial cell aggregates embedded within a collagen-Matrigel ink in order to study the dynamic interplay between epithelial tissues and aligned networks of type I collagen fibers.

Biophysics of morphogenesis in the vertebrate lung.

Morphogenesis is a physical process that sculpts the final functional forms of tissues and organs. Remarkably, the lungs of terrestrial vertebrates vary dramatically in form across species, despite providing the same function of transporting oxygen and carbon dioxide. These divergent forms arise from distinct physical processes through which the epithelium of the embryonic lung responds to the mechanical properties of its surrounding mesenchymal microenvironment.

Vangl-dependent mesenchymal thinning shapes the distal lung during murine sacculation.

The planar cell polarity (PCP) complex is speculated to function in murine lung development, where branching morphogenesis generates an epithelial tree whose distal tips expand dramatically during sacculation. Here, we show that PCP is dispensable in the airway epithelium for sacculation. Rather, we find a Celsr1-independent role for the PCP component Vangl in the pulmonary mesenchyme: loss of Vangl1/2 inhibits mesenchymal thinning and expansion of the saccular epithelium.

Interplay between hormonal and mechanical signals in mammary morphodynamics.

Mammographic density is a well-established risk factor for breast cancer. In a recent study, Northey et al. reveal that the associated increase in tissue stiffness elevates extracellular signal-regulated kinase (ERK) activity, promoting progesterone receptor-dependent receptor activator of nuclear factor κβ (RANK) signaling.

Relatively Rare Populations of Invasive Cells Drive Progression of Heterogeneous Tumors.

Introduction: Breast tumors often display an astonishing degree of spatial and temporal heterogeneity, which are associated with cancer progression, drug resistance, and relapse. Triple-negative breast cancer (TNBC) is a particularly aggressive and heterogeneous subtype for which targeted therapies are scarce. Consequently, patients with TNBC have a poorer overall prognosis compared to other breast cancer patients.

Mechanical properties pattern the skin.

Morphogens induce variations in tissue mechanics to promote feather budding.

Spatial patterning of energy metabolism during tissue morphogenesis.

Biophysical signaling organizes forces to drive tissue morphogenesis, a process co-opted during disease progression. The systematic buildup of forces at the tissue scale is energetically demanding. Just as mechanical forces, gene expression, and concentrations of morphogens vary spatially across a developing tissue, there might similarly be spatial variations in energy consumption.

Mesenchymal facilitates airway elongation and widening independently of the planar cell polarity complex.

A hallmark of mammalian lungs is the fractal nature of the bronchial tree. In the adult, each successive generation of airways is a fraction of the size of the parental branch. This fractal structure is physiologically beneficial, as it minimizes the energy needed for breathing.

pYtags enable spatiotemporal measurements of receptor tyrosine kinase signaling in living cells.

Receptor tyrosine kinases (RTKs) are major signaling hubs in metazoans, playing crucial roles in cell proliferation, migration, and differentiation. However, few tools are available to measure the activity of a specific RTK in individual living cells. Here, we present pYtags, a modular approach for monitoring the activity of a user-defined RTK by live-cell microscopy.

Plasticity in airway smooth muscle differentiation during mouse lung development.

It has been proposed that smooth muscle differentiation may physically sculpt airway epithelial branches in mammalian lungs. Serum response factor (SRF) acts with its co-factor myocardin to activate the expression of contractile smooth muscle markers. In the adult, however, smooth muscle exhibits a variety of phenotypes beyond contractile, and these are independent of SRF/myocardin-induced transcription.

Analysis of Cre lines for targeting embryonic airway smooth muscle.

During development of the embryonic mouse lung, the pulmonary mesenchyme differentiates into smooth muscle that wraps around the airway epithelium. Inhibiting smooth muscle differentiation leads to cystic airways, while enhancing it stunts epithelial branching. These findings support a conceptual model wherein the differentiation of smooth muscle sculpts the growing epithelium into branches at precise positions and with stereotyped morphologies.

How to build an epithelial tree.

Nature has evolved a variety of mechanisms to build epithelial trees of diverse architectures within different organs and across species. Epithelial trees are elaborated through branch initiation and extension, and their morphogenesis ends with branch termination. Each of these steps of the branching process can be driven by the actions of epithelial cells themselves (epithelial-intrinsic mechanisms) or by the cells of their surrounding tissues (epithelial-extrinsic mechanisms).

Genetically defined individual reference ranges for tryptase limit unnecessary procedures and unmask myeloid neoplasms.

Serum tryptase is a biomarker used to aid in the identification of certain myeloid neoplasms, most notably systemic mastocytosis, where basal serum tryptase (BST) levels >20 ng/mL are a minor criterion for diagnosis. Although clonal myeloid neoplasms are rare, the common cause for elevated BST levels is the genetic trait hereditary α-tryptasemia (HαT) caused by increased germline TPSAB1 copy number. To date, the precise structural variation and mechanism(s) underlying elevated BST in HαT and the general clinical utility of tryptase genotyping, remain undefined.

Mechanical Control of Cell Differentiation: Insights from the Early Embryo.

Differentiation is the process by which a cell activates the expression of tissue-specific genes, downregulates the expression of potency markers, and acquires the phenotypic characteristics of its mature fate. The signals that regulate differentiation include biochemical and mechanical factors within the surrounding microenvironment. We describe recent breakthroughs in our understanding of the mechanical control mechanisms that regulate differentiation, with a specific emphasis on the differentiation events that build the early mouse embryo.

Patterning the embryonic pulmonary mesenchyme.

Smooth muscle guides the morphogenesis of several epithelia during organogenesis, including the mammalian airways. However, it remains unclear how airway smooth muscle differentiation is spatiotemporally patterned and whether it originates from transcriptionally distinct mesenchymal progenitors. Using single-cell RNA-sequencing of embryonic mouse lungs, we show that the pulmonary mesenchyme contains a continuum of cell identities, but no transcriptionally distinct progenitors.

Transmural pressure signals through retinoic acid to regulate lung branching.

During development, the mammalian lung undergoes several rounds of branching, the rate of which is tuned by the relative pressure of the fluid within the lumen of the lung. We carried out bioinformatics analysis of RNA-sequencing of embryonic mouse lungs cultured under physiologic or sub-physiologic transmural pressure and identified transcription factor-binding motifs near genes whose expression changes in response to pressure. Surprisingly, we found retinoic acid (RA) receptor binding sites significantly overrepresented in the promoters and enhancers of pressure-responsive genes.

Substratum stiffness regulates Erk signaling dynamics through receptor-level control.

The EGFR/Erk pathway is triggered by extracellular ligand stimulation, leading to stimulus-dependent dynamics of pathway activity. Although mechanical properties of the microenvironment also affect Erk activity, their effects on Erk signaling dynamics are poorly understood. Here, we characterize how the stiffness of the underlying substratum affects Erk signaling dynamics in mammary epithelial cells.

Stress ball morphogenesis: How the lizard builds its lung.

The function of the lung is closely coupled to its structural anatomy, which varies greatly across vertebrates. Although architecturally simple, a complex pattern of airflow is thought to be achieved in the lizard lung due to its cavernous central lumen and honeycomb-shaped wall. We find that the wall of the lizard lung is generated from an initially smooth epithelial sheet, which is pushed through holes in a hexagonal smooth muscle meshwork by forces from fluid pressure, similar to a stress ball.