18 research outputs found

    Single-cell analysis of cardiogenesis reveals basis for organ-level developmental defects.

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    Organogenesis involves integration of diverse cell types; dysregulation of cell-type-specific gene networks results in birth defects, which affect 5% of live births. Congenital heart defects are the most common malformations, and result from disruption of discrete subsets of cardiac progenitor cells1, but the transcriptional changes in individual progenitors that lead to organ-level defects remain unknown. Here we used single-cell RNA sequencing to interrogate early cardiac progenitor cells as they become specified during normal and abnormal cardiogenesis, revealing how dysregulation of specific cellular subpopulations has catastrophic consequences. A network-based computational method for single-cell RNA-sequencing analysis that predicts lineage-specifying transcription factors2,3 identified Hand2 as a specifier of outflow tract cells but not right ventricular cells, despite the failure of right ventricular formation in Hand2-null mice4. Temporal single-cell-transcriptome analysis of Hand2-null embryos revealed failure of outflow tract myocardium specification, whereas right ventricular myocardium was specified but failed to properly differentiate and migrate. Loss of Hand2 also led to dysregulation of retinoic acid signalling and disruption of anterior-posterior patterning of cardiac progenitors. This work reveals transcriptional determinants that specify fate and differentiation in individual cardiac progenitor cells, and exposes mechanisms of disrupted cardiac development at single-cell resolution, providing a framework for investigating congenital heart defects

    Topical corticosteroid therapy: clobetasol propionate 0.025%

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    Topical corticosteroids have been the cornerstone of treatment over the last six decades for various dermatoses characterized by dry, scaly, crusted, or erythematous skin as well as those associated with inflammation and pruritus. The potency of a topical steroid depends on the specific molecule, the amount of drug reaching the target, absorption through the skin (0.25%–3%), and the formulation. Clobetasol propionate (CP) 0.025% cream formulation is a potent, fifth-generation topical corticosteroid. It is approved by the United States Food and Drug Administration to be applied twice daily for the treatment of moderate-to–severe psoriasis in adults. This case series covers the clinical experience of various dermatologists, including their expert opinion on the safety and efficacy of ImpoyzTM (CP) cream 0.025% in different skin disorders

    Piezo1, a mechanically activated ion channel, is required for vascular development in mice.

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    Mechanosensation is perhaps the last sensory modality not understood at the molecular level. Ion channels that sense mechanical force are postulated to play critical roles in a variety of biological processes including sensing touch/pain (somatosensation), sound (hearing), and shear stress (cardiovascular physiology); however, the identity of these ion channels has remained elusive. We previously identified Piezo1 and Piezo2 as mechanically activated cation channels that are expressed in many mechanosensitive cell types. Here, we show that Piezo1 is expressed in endothelial cells of developing blood vessels in mice. Piezo1-deficient embryos die at midgestation with defects in vascular remodeling, a process critically influenced by blood flow. We demonstrate that Piezo1 is activated by shear stress, the major type of mechanical force experienced by endothelial cells in response to blood flow. Furthermore, loss of Piezo1 in endothelial cells leads to deficits in stress fiber and cellular orientation in response to shear stress, linking Piezo1 mechanotransduction to regulation of cell morphology. These findings highlight an essential role of mammalian Piezo1 in vascular development during embryonic development
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