Cargo proteins in extracellular vesicles: potential for novel therapeutics in non-alcoholic steatohepatitis

Background Extracellular vesicles (EVs) are recognized as novel cell-free therapeutics. Non-alcoholic steatohepatitis (NASH) remains a critical health problem. Herein, we show that EVs from pan peroxisome proliferator-activated receptor agonist-primed induced mesenchymal stem cell (pan PPAR-iMSC-EVs) has unique cargo protein signatures, and demonstrate its therapeutic function in NASH. Results A unique protein signatures were identified in pan PPAR-iMSC-EVs against those from non-stimulated iMSC-EVs. NASH mice receiving pan PPAR-iMSC-EVs showed reduced steatotic changes and ameliorated ER stress and mitochondiral oxidative stress induced by inflammation. Moreover, pan PPAR-iMSC-EVs promoted liver regeneration via inhibiting apoptosis and enhancing proliferation. Conclusions We conclude that our strategy for enriching unique cargo proteins in EVs may facilitate the development of novel therapeutic option for NASH. Graphical Abstract

Logic-Based Modeling and Virtual Drug Screening for the Prediction of Novel Therapeutic Targets and Combination Regimens Against E2F1-driven Melanoma Progression

Skin melanoma presents increasing prevalence and poor outcomes. Progression to aggressive stages is characterized by overexpression of the transcription factor E2F1 and activation of downstream pro-metastatic gene regulatory networks (GRNs). Appropriate therapeutic manipulation of the E2F1-governed GRNs holds potential to prevent metastasis, however these networks entail complex feedback and feedforward regulatory motifs among various regulatory layers, which challenge the characterization of drug targetablemake it difficult to identify druggable components. To this end, computational approaches such as mathematical modeling and virtual screening are important tools to unveil the dynamics of these signaling networks and comprehensively identify critical components that could be further explored as therapeutic targets. Herein, we integrated a well-established E2F1-mediated epithelial-mesenchymal transition (EMT) map with transcriptomics data from E2F1-expressing melanoma cells to reconstruct a core regulatory network underlying aggressive melanoma. Using logic-based in silico perturbation experiments of a core regulatory network, we identifiedy that simultaneous perturbation of AKT1 and MDM2 drastically reduces EMT in metastatic melanoma. Using the structures of the two protein signatures along with virtual screening of lead-like compound library available in ZINC12 database, we identified a number of lead compounds that efficiently inhibit AKT1 and MDM2 without eliciting toxicities. We propose that these compounds could be taken into account in the design of novel therapeutic strategies for the management of aggressive melanoma. were identified using virtual screening of lead-like compound library available in ZINC12 database. Subsequent high-throughput virtual screening of drug library using the structures of the two protein signatures predicted a number of lead compounds that efficiently inhibit AKT1 and MDM2 without eliciting toxicities. These can be experimentally evaluated and further considered as new anti-melanoma metastatic agents, in monotherapies or combination regimens.

Immunosuppressive Protein Signatures Carried by Syncytiotrophoblast-Derived Exosomes and Their Role in Human Pregnancy

The syncytiotrophoblast (STB) of human placenta constitutively and throughout pregnancy produces and secretes exosomes - nanometer-sized membrane-bound extracellular vesicles from the endosomal compartment that convey cell-cell contact ‘by proxy’ transporting information between donor and recipient cells locally and at a distance. Released in the maternal blood, STB-derived exosomes build an exosomal gradient around the feto-placental unit acting as a shield that protects the fetus from maternal immune attack. They carry signal molecules and ligands that comprise distinct immunosuppressive protein signatures which interfere with maternal immune mechanisms, potentially dangerous for the ongoing pregnancy. We discuss three immunosuppressive signatures carried by STB exosomes and their role in three important immune mechanisms 1) NKG2D receptor–mediated cytotoxicity, 2) apoptosis of activated immune cells and 3) PD-1-mediated immunosuppression and priming of T regulatory cells. A schematic presentation is given on how these immunosuppressive protein signatures, delivered by STB exosomes, modulate the maternal immune system and contribute to the development of maternal-fetal tolerance.