Anisotropic expansion of hepatocyte lumina enforced by apical bulkheads

Lumen morphogenesis results from the interplay between molecular pathways and mechanical forces. In several organs, epithelial cells share their apical surfaces to form a tubular lumen. In the liver, however, hepatocytes share the apical surface only between adjacent cells and form narrow lumina that grow anisotropically, generating a 3D network of bile canaliculi (BC). Here, by studying lumenogenesis in differentiating mouse hepatoblasts in vitro, we discovered that adjacent hepatocytes assemble a pattern of specific extensions of the apical membrane traversing the lumen and ensuring its anisotropic expansion. These previously unrecognized structures form a pattern, reminiscent of the bulkheads of boats, also present in the developing and adult liver. Silencing of Rab35 resulted in loss of apical bulkheads and lumen anisotropy, leading to cyst formation. Strikingly, we could reengineer hepatocyte polarity in embryonic liver tissue, converting BC into epithelial tubes. Our results suggest that apical bulkheads are cell-intrinsic anisotropic mechanical elements that determine the elongation of BC during liver tissue morphogenesis

Lipid nanoparticles for targeted siRNA delivery – going from bench to bedside

Timofei S Zatsepin,1–3 Yuri V Kotelevtsev,1 Victor Koteliansky1,2 1Center of Functional Genomics, Skolkovo Institute of Science and Technology, 2Department of Chemistry, Lomonosov Moscow State University, 3Production Department, Central Research Institute of Epidemiology, Moscow, Russia Abstract: This review covers the basic aspects of small interfering RNA delivery by lipid nanoparticles (LNPs) and elaborates on the current status of clinical trials for these systems. We briefly describe the roles of all LNP components and possible strategies for their improvement. We also focus on the current clinical trials using LNP-formulated RNA and the possible outcomes for therapy in the near future. Also, we present a critical analysis of selected clinical trials that reveals the common logic behind target selection. We address this review to a wide audience, especially to medical doctors who are interested in the application of RNA interference–based treatment platforms. We anticipate that this review may spark interest in this particular audience and generate new ideas in target selection for the disorders they are dealing with. Keywords: RNA therapeutics, siRNA, mRNA, lipid nanoparticle, targeted delivery, clinical tria