Publications

BackgroundCollective migration is the coordinated movement of a group of cells-a fundamental process in health and disease. Many models have been developed to study the molecular and physical mechanisms of collective migration. However, the aim of this study is to engineer a flexible in vitro framework that allows for mechanobiological quantification of the separate and combined contributions of individual cell mechanics to the directed migration of a collective. We utilised this framework to understand the role of juxtacrine Notch signalling during collective endothelial migration-an essential process during the formation of new blood vessels (known as angiogenesis).ResultsThis framework enables users to perform high spatiotemporal analysis of migrative behaviour, cell-matrix traction forces, and intercellular forces in different microenvironments. With this framework, we show that Notch inhibited collectives adopt a distinct regime of directed collective migration. Whereas the directionality of migration, traction forces and intercellular forces are not affected by Notch inhibition, we observed spatiotemporal differences in migration speed, traction force magnitude and normal and shear stresses within Notch-inhibited collectives.ConclusionsThe in vitro framework is a powerful approach for dissecting the mechanisms of collective migration. With this framework, we show that a potential link exists between the juxtacrine signalling of Notch and an increased mechanical cohesiveness among collective cells.

JTD Keywords: Angiogenesis, Cell-cell dynamics, Cell-matrix dynamics, Collective endothelial migration, Dynamics, Forces, In vitro framework, Juxtacrine notch signalling, Migration kinematics, Morphogenesis, Organization

Human pluripotent stem cell -derived kidney organoids offer unprecedented opportunities for studying polycystic kidney disease (PKD), which still has no effective cure. Here, we developed both in vitro and in vivo organoid models of PKD that manifested tubular injury and aberrant upregulation of renin-angiotensin aldosterone system. Single -cell analysis revealed that a myriad of metabolic changes occurred during cystogenesis, including defective autophagy. Experimental activation of autophagy via ATG5 overexpression or primary cilia ablation significantly inhibited cystogenesis in PKD kidney organoids. Employing the organoid xenograft model of PKD, which spontaneously developed tubular cysts, we demonstrate that minoxidil, a potent autophagy activator and an FDA -approved drug, effectively attenuated cyst formation in vivo. This in vivo organoid model of PKD will enhance our capability to discover novel disease mechanisms and validate candidate drugs for clinical translation.

JTD Keywords: Adenylate kinase, Adult, Animal cell, Animal experiment, Animal model, Animal tissue, Article, Autophagosome, Autophagy, Autophagy (cellular), Autosomal-dominant, Calcium homeostasis, Cilia, Cilium, Cohort analysis, Controlled study, Cyclic amp, Disease, Dominant polycystic kidney, Enzyme linked immunosorbent assay, Epithelium, Exon, Expression, Female, Food and drug administration, Framework, Generation, Growth, Hepatitis a virus cellular receptor 1, Human, Human cell, Humans, Immunohistochemistry, In vitro study, In vivo study, Kidney, Kidney organoid, Kidney polycystic disease, Male, Minoxidil, Mouse, Mutations, Nonhuman, Organoid, Organoids, Platelet derived growth factor beta receptor, Pluripotent stem-cells, Polycystic kidney diseases, Protein kinase lkb1, Renin, Sequestosome 1, Single cell analysis, Single cell rna seq, Small nuclear rna, Tunel assay, Upregulation, Western blotting, Whole exome sequencing

We describe the concepts, methodology, technology, and practice of a user-centric and historical space-oriented approach towards Historical and Cultural Learning (HCL). The Future Memory project pursues the unifying hypothesis that physical space can play a critical role in the authentication and education of this singular historical event, or space as a frame for memory formation and a source of authentication. We illustrate these aspects in the context of concrete Future Memory projects realized over the last ten years in collaboration with several memorial sites, museums, and archives. Based on these experiences, we subsequently analyze the lessons learned and future challenges.

JTD Keywords: Augmented reality, Behavior, Commemoration, Design, Digital heritage, Experience, Framework, Future memory, Mobile, Navigation, Place cells, Post-wtiness era, Space, Virtual reality