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Bioinspired Molecular Factories with Architecture and In Vivo Functionalities as Cell Mimics.

ABSTRACT: Despite huge need in the medical domain and significant development efforts, artificial cells to date have limited composition and functionality. Although some artificial cells have proven successful for producing therapeutics or performing in vitro specific reactions, they have not been investigated in vivo to determine whether they preserve their architecture and functionality while avoiding toxicity. Here, these limitations are overcome and customizable cell mimic is achieved-molecular factories (MFs)-by supplementing giant plasma membrane vesicles derived from donor cells with nanometer-sized artificial organelles (AOs). MFs inherit the donor cell's natural cytoplasm and membrane, while the AOs house reactive components and provide cell-like architecture and functionality. It is demonstrated that reactions inside AOs take place in a close-to-nature environment due to the unprecedented level of complexity in the composition of the MFs. It is further demonstrated that in a zebrafish vertebrate animal model, these cell mimics show no apparent toxicity and retain their integrity and function. The unique advantages of highly varied composition, multicompartmentalized architecture, and preserved functionality in vivo open new biological avenues ranging from the study of biorelevant processes in robust cell-like environments to the production of specific bioactive compounds.

SUBMITTER: Einfalt T

PROVIDER: S-EPMC7029636 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Bioinspired Molecular Factories with Architecture and In Vivo Functionalities as Cell Mimics.

Einfalt Tomaž T Garni Martina M Witzigmann Dominik D Sieber Sandro S Baltisberger Niklaus N Huwyler Jörg J Meier Wolfgang W Palivan Cornelia G CG

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20200109 4

Despite huge need in the medical domain and significant development efforts, artificial cells to date have limited composition and functionality. Although some artificial cells have proven successful for producing therapeutics or performing in vitro specific reactions, they have not been investigated in vivo to determine whether they preserve their architecture and functionality while avoiding toxicity. Here, these limitations are overcome and customizable cell mimic is achieved-molecular factor ...[more]

PMID: 32099756

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Project description:Heart failure is associated with hypertrophying of cardiomyocytes and changes in transcriptional activity. Studies from rapidly dividing cells in culture have suggested that transcription may be compartmentalized into factories within the nucleus, but this phenomenon has not been tested in vivo and the role of nuclear architecture in cardiac gene regulation is unknown. While alterations to transcription have been linked to disease, little is known about the regulation of the spatial organization of transcription and its properties in the pathological setting. In the present study, we investigate the structural features of endogenous transcription factories in the heart and determine the principles connecting chromatin structure to transcriptional regulation in vivo. Super-resolution imaging of endogenous RNA polymerase II clusters in neonatal and adult cardiomyocytes revealed distinct properties of transcription factories in response to pathological stress: neonatal nuclei demonstrated changes in number of clusters, with parallel increases in nuclear area, while the adult nuclei underwent changes in size and intensity of RNA polymerase II foci. Fluorescence in situ hybridization-based labeling of genes revealed locus-specific relationships between expression change and anatomical localization-with respect to nuclear periphery and heterochromatin regions, both sites associated with gene silencing-in the nuclei of cardiomyocytes in hearts (but not liver hepatocytes) of mice subjected to pathologic stimuli that induce heart failure. These findings demonstrate a role for chromatin organization and rearrangement of nuclear architecture for cell type-specific transcription in vivo during disease. RNA polymerase II ChIP and chromatin conformation capture studies in the same model system demonstrate formation and reorganization of distinct nuclear compartments regulating gene expression. These findings reveal locus-specific compartmentalization of stress-activated, housekeeping and silenced genes in the anatomical context of the endogenous nucleus, revealing basic principles of global chromatin structure and nuclear architecture in the regulation of gene expression in healthy and diseased conditions.

Dataset Information

Bioinspired Molecular Factories with Architecture and In Vivo Functionalities as Cell Mimics.

Publications

Bioinspired Molecular Factories with Architecture and In Vivo Functionalities as Cell Mimics.

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