Defining Lineage-Specific Membrane Fluidity Signatures that Regulate Adhesion Kinetics

Summary: Cellular membrane fluidity is a critical modulator of cell adhesion and migration, prompting us to define the systematic landscape of lineage-specific cellular fluidity throughout differentiation. Here, we have unveiled membrane fluidity landscapes in various lineages ranging from human pluripotency to differentiated progeny: (1) membrane rigidification precedes the exit from pluripotency, (2) membrane composition modulates activin signaling transmission, and (3) signatures are relatively germ layer specific presumably due to unique lipid compositions. By modulating variable lineage-specific fluidity, we developed a label-free “adhesion sorting (AdSort)” method with simple cultural manipulation, effectively eliminating pluripotent stem cells and purifying target population as a result of the over 1,150 of screened conditions combining compounds and matrices. These results underscore the important role of tunable membrane fluidity in influencing stem cell maintenance and differentiation that can be translated into lineage-specific cell purification strategy. : In this article, Takebe and the colleagues unveiled membrane fluidity landscapes in various lineages ranging from human pluripotency to differentiated progeny. By modulating pluripotent fluidity signature, we developed a label-free “adhesion sorting (AdSort)” method with simple cultural manipulation, effectively eliminating pluripotent stem cells as a result of the over 1,150 of screened conditions combining compounds and matrices. Keywords: pluripotency, membrane fluidity, fluidic modulator, cell adhesion, cell sortin

Massive and Reproducible Production of Liver Buds Entirely from Human Pluripotent Stem Cells

Summary: Organoid technology provides a revolutionary paradigm toward therapy but has yet to be applied in humans, mainly because of reproducibility and scalability challenges. Here, we overcome these limitations by evolving a scalable organ bud production platform entirely from human induced pluripotent stem cells (iPSC). By conducting massive “reverse” screen experiments, we identified three progenitor populations that can effectively generate liver buds in a highly reproducible manner: hepatic endoderm, endothelium, and septum mesenchyme. Furthermore, we achieved human scalability by developing an omni-well-array culture platform for mass producing homogeneous and miniaturized liver buds on a clinically relevant large scale (>108). Vascularized and functional liver tissues generated entirely from iPSCs significantly improved subsequent hepatic functionalization potentiated by stage-matched developmental progenitor interactions, enabling functional rescue against acute liver failure via transplantation. Overall, our study provides a stringent manufacturing platform for multicellular organoid supply, thus facilitating clinical and pharmaceutical applications especially for the treatment of liver diseases through multi-industrial collaborations. : With the goal of clinical translation of liver bud transplant therapy, Takebe et al. established a massive organoid production platform from endoderm, endothelial, and mesenchymal progenitor populations specified entirely from human iPSCs, reproducibly demonstrating functionality both in vitro and in vivo. Keywords: iPSC, liver bud, organoid, transplantation, self-organization, endothelial, mesenchymal, liver failure, clinical grad

Brain p3-Alcβ peptide restores neuronal viability impaired by Alzheimer's amyloid β-peptide

We propose a new therapeutic strategy for Alzheimer's disease (AD). Brain peptide p3-Alc beta 37 is generated from the neuronal protein alcadein beta through cleavage of gamma-secretase, similar to the generation of amyloid beta (A beta) derived from A beta-protein precursor/APP. Neurotoxicity by A beta oligomers (A beta o) is the prime cause prior to the loss of brain function in AD. We found that p3-Alc beta 37 and its shorter peptide p3-Alc beta 9-19 enhanced the mitochondrial activity of neurons and protected neurons against A beta o-induced toxicity. This is due to the suppression of the A beta o-mediated excessive Ca2+ influx into neurons by p3-Alc beta. Successful transfer of p3-Alc beta 9-19 into the brain following peripheral administration improved the mitochondrial viability in the brain of AD mice model, in which the mitochondrial activity is attenuated by increasing the neurotoxic human A beta 42 burden, as revealed through brain PET imaging to monitor mitochondrial function. Because mitochondrial dysfunction is common in the brain of AD patients alongside increased A beta and reduced p3-Alc beta 37 levels, the administration of p3-Alc beta 9-19 may be a promising treatment for restoring, protecting, and promoting brain functions in patients with AD