Dataset Information

Evaluating the Endocytosis and Lineage-Specification Properties of Mesenchymal Stem Cell Derived Extracellular Vesicles for Targeted Therapeutic Applications.

ABSTRACT: Mesenchymal stem cells (MSCs) are multipotent cells with regenerative and immunomodulatory properties. Several aspects of MSC function have been attributed to the paracrine effects of MSC derived extracellular vesicles (EVs). Although MSC EVs show great promise for regenerative medicine applications, insights into their uptake mechanisms by different target cells and the ability to control MSC EV properties for defined function in vivo have remained elusive knowledge gaps. The primary goal of this study is to elucidate how the basic properties of MSC derived EVs can be exploited for function-specific activity in regenerative medicine. Our first important observation is that, MSC EVs possess a common mechanism of endocytosis across multiple cell types. Second, altering the MSC state by inducing differentiation into multiple lineages did not affect the exosomal properties or endocytosis but triggered the expression of lineage-specific genes and proteins in vitro and in vivo respectively. Overall, the results presented in this study show a common mechanism of endocytosis for MSC EVs across different cell types and the feasibility to generate functionally enhanced EVs by modifications to parental MSCs.

SUBMITTER: Huang CC

PROVIDER: S-EPMC7063066 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Publications

Evaluating the Endocytosis and Lineage-Specification Properties of Mesenchymal Stem Cell Derived Extracellular Vesicles for Targeted Therapeutic Applications.

Huang Chun-Chieh CC Kang Miya M Narayanan Raghuvaran R DiPietro Luisa A LA Cooper Lyndon F LF Gajendrareddy Praveen P Ravindran Sriram S

Frontiers in pharmacology 20200303

Mesenchymal stem cells (MSCs) are multipotent cells with regenerative and immunomodulatory properties. Several aspects of MSC function have been attributed to the paracrine effects of MSC derived extracellular vesicles (EVs). Although MSC EVs show great promise for regenerative medicine applications, insights into their uptake mechanisms by different target cells and the ability to control MSC EV properties for defined function <i>in vivo</i> have remained elusive knowledge gaps. The primary goa ...[more]

PMID: 32194405

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Project description:Endometrial-derived Mesenchymal Stem Cells (endMSCs) are involved in the regeneration and remodeling of human endometrium, being considered one of the most promising candidates for stem cell-based therapies. Their therapeutic effects have been found to be mediated by extracellular vesicles (EV-endMSCs) with pro-angiogenic, anti-apoptotic, and immunomodulatory effects. Based on that, the main goal of this study was to characterize the proteome and microRNAome of these EV-endMSCs by proteomics and transcriptomics approaches. Additionally, we hypothesized that inflammatory priming of endMSCs may contribute to modify the therapeutic potential of these vesicles. High-throughput proteomics revealed that 617 proteins were functionally annotated as Extracellular exosome (GO:0070062), corresponding to the 70% of the EV-endMSC proteome. Bioinformatics analyses allowed us to identify that these proteins were involved in adaptive/innate immune response, complement activation, antigen processing/presentation, negative regulation of apoptosis, and different signaling pathways, among others. Of note, multiplexed quantitative proteomics and Systems Biology analyses showed that IFNγ priming significantly modulated the protein profile of these vesicles. As expected, proteins involved in antigen processing and presentation were significantly increased. Interestingly, immunomodulatory proteins, such as CSF1, ERAP1, or PYCARD were modified. Regarding miRNAs expression profile in EV-endMSCs, Next-Generation Sequencing (NGS) showed that the preferred site of microRNAome targeting was the nucleus (n = 371 microTargets), significantly affecting signal transduction (GO:0007165), cell proliferation (GO:0008283), and apoptotic processes (GO:0006915), among others. Interestingly, NGS analyses highlighted that several miRNAs, such as hsa-miR-150-5p or hsa-miR-196b-5p, were differentially expressed in IFNγ-primed EV-endMSCs. These miRNAs have a functional involvement in glucocorticoid receptor signaling, IL-6/8/12 signaling, and in the role of macrophages. In summary, these results allowed us to understand the complexity of the molecular networks in EV-endMSCs and their potential effects on target cells. To our knowledge, this is the first comprehensive study based on proteomic and genomic approaches to unravel the therapeutic potential of these extracellular vesicles, that may be used as immunomodulatory effectors in the treatment of inflammatory conditions.

Dataset Information

Evaluating the Endocytosis and Lineage-Specification Properties of Mesenchymal Stem Cell Derived Extracellular Vesicles for Targeted Therapeutic Applications.

Publications

Evaluating the Endocytosis and Lineage-Specification Properties of Mesenchymal Stem Cell Derived Extracellular Vesicles for Targeted Therapeutic Applications.

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