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Activation chemistry drives the emergence of functionalised protocells.

ABSTRACT: The complexity of the simplest conceivable cell suggests that the chemistry of prebiotic mixtures needs to be explored to understand the intricate network of prebiotic reactions that led to the emergence of life. Early cells probably relied upon compatible and interconnected chemistries to link RNA, peptides and membranes. Here we show that several types of vesicles, composed of prebiotically plausible mixtures of amphiphiles, spontaneously form and sustain the methyl isocyanide-mediated activation of amino acids, peptides and nucleotides. Activation chemistry also drives the advantageous conversion of reactive monoacylglycerol phosphates into inert cyclophospholipids, thus supporting their potential role as major constituents of protocells. Moreover, activation of prebiotic building blocks within fatty acid-based vesicles yields lipidated species capable of localising to and functionalising primitive membranes. Our findings describe a potentially prebiotic scenario in which the components of primitive cells undergo activation and provide new species that might have enabled an increase in the functionality of protocells.

SUBMITTER: Bonfio C

PROVIDER: S-EPMC8162433 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Wnt signalling pathways play crucial roles in developmental biology, stem cell fate and tissue patterning and have become an attractive therapeutic target in the fields of tissue engineering and regenerative medicine. Wnt signalling has also been shown to play a role in human Mesenchymal Stem Cell (hMSC) fate, which have shown potential as a cell therapy in bone and cartilage tissue engineering. Previous work has shown that biocompatible magnetic nanoparticles (MNP) can be used to stimulate specific mechanosensitive membrane receptors and ion channels in vitro and in vivo. Using this strategy, we determined the effects of mechano-stimulation of the Wnt Frizzled receptor on Wnt pathway activation in hMSC. Frizzled receptors were tagged using anti-Frizzled functionalised MNP (Fz-MNP). A commercially available oscillating magnetic bioreactor (MICA Biosystems) was used to mechanically stimulate Frizzled receptors remotely. Our results demonstrate that Fz-MNP can activate Wnt/β-catenin signalling at key checkpoints in the signalling pathway. Immunocytochemistry indicated nuclear localisation of the Wnt intracellular messenger β-catenin after treatment with Fz-MNP. A Wnt signalling TCF/LEF responsive luciferase reporter transfected into hMSC was used to assess terminal signal activation at the nucleus. We observed an increase in reporter activity after treatment with Fz-MNP and this effect was enhanced after mechano-stimulation using the magnetic array. Western blot analysis was used to probe the mechanism of signalling activation and indicated that Fz-MNP signal through an LRP independent mechanism. Finally, the gene expression profiles of stress response genes were found to be similar when cells were treated with recombinant Wnt-3A or Fz-MNP. This study provides proof of principle that Wnt signalling and Frizzled receptors are mechanosensitive and can be remotely activated in vitro. Using magnetic nanoparticle technology it may be possible to modulate Wnt signalling pathways and thus control stem cell fate for therapeutic purposes.

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Activation chemistry drives the emergence of functionalised protocells.

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