Mesenchymal stromal cell exosome-enhanced regulatory T-cell production through an antigen-presenting cell-mediated pathway.

Background Aims: The immunomodulatory property of mesenchymal stromal cell (MSC) exosomes is well documented. On the basis of our previous report that MSC exosomes increased regulatory T-cell (Treg) production in mice with allogenic skin graft but not in ungrafted mice, we hypothesize that an activated immune system is key to exosome-mediated Treg production.

Methods: To test our hypothesis, MSC exosomes were incubated with mouse spleen CD4 T cells that were activated with either anti-CD3/CD28 mAbs or allogenic antigen-presenting cell (APC)-enriched spleen CD11c cells to determine whether production of mouse CD4CD25 T cells or CD4CD25Foxp3 Tregs could be induced.

Isolation and Characterization of Exosome from Human Embryonic Stem Cell-Derived C-Myc-Immortalized Mesenchymal Stem Cells.

Mesenchymal stem cells (MSC) are currently the cell type of choice in many cell therapy trials. The number of therapeutic applications for MSCs registered as product IND submissions with the FDA and initiation of registered clinical trials has increased substantially in recent years, in particular between 2006 and 2012. However, defined mechanisms of action underpinning the therapeutic efficacy of MSCs are lacking, but they are increasingly attributed to MSC trophic secretion rather than their differentiation potential.

MSC secretes at least 3 EV types each with a unique permutation of membrane lipid, protein and RNA.

Mesenchymal stem cell (MSC), a widely used adult stem cell candidate for regenerative medicine, has been shown to exert some of its therapeutic effects through the secretion of extracellular vesicles (EVs). These homogenously sized EVs of 100-150 ηm exhibited many exosome-like biophysical and biochemical properties and carry both proteins and RNAs. Recently, exosome-associated proteins in this MSC EV preparation were found to segregate primarily to those EVs that bind cholera toxin B chain (CTB), a GM1 ganglioside-specific ligand, and pulse-chase experiments demonstrated that these EVs have endosomal origin and carried many of the exosome-associated markers.

Focus on Extracellular Vesicles: Therapeutic Potential of Stem Cell-Derived Extracellular Vesicles.

The intense research focus on stem and progenitor cells could be attributed to their differentiation potential to generate new cells to replace diseased or lost cells in many highly intractable degenerative diseases, such as Alzheimer disease, multiple sclerosis, and heart diseases. However, experimental and clinical studies have increasingly attributed the therapeutic efficacy of these cells to their secretion. While stem and progenitor cells secreted many therapeutic molecules, none of these molecules singly or in combination could recapitulate the functional effects of stem cell transplantations.

Mesenchymal stem cell exosomes.

MSCs are an extensively used cell type in clinical trials today. The initial rationale for their clinical testing was based on their differentiation potential. However, the lack of correlation between functional improvement and cell engraftment or differentiation at the site of injury has led to the proposal that MSCs exert their effects not through their differentiation potential but through their secreted product, more specifically, exosomes, a type of extracellular vesicle.

Therapeutic MSC exosomes are derived from lipid raft microdomains in the plasma membrane.

Background: Mesenchymal stem cell (MSC) was previously shown to secrete lipid vesicles that when purified by high performance liquid chromatography as a population of homogenously sized particles with a hydrodynamic radius of 55-65 nm reduce infarct size in a mouse model of myocardial ischemia/reperfusion injury. As these vesicles exhibit many biophysical and biochemical properties of exosomes, they were identified as exosomes. Here we investigated if these lipid vesicles were indeed exosomes that have an endosomal biogenesis.

Mesenchymal stem cell exosome ameliorates reperfusion injury through proteomic complementation.

The therapeutic efficacy of mesenchymal stem cell (MSC) transplantation has recently been attributed to exosomes when a single bolus of MSC exosomes prior to reperfusion of ischemic myocardium ameliorates reperfusion injury and reduces infarct size. In this article we review the therapeutic efficacy of MSC exosome in ameliorating cell intrinsic factors in reperfusion injury by focusing on the proteome complementation of exosomes and reperfused myocardium. The well-documented ATP deficit and initiation of apoptosis during ischemia and reperfusion were recently found to be underpinned by a proteomic deficit in enzymes critical for fatty acid oxidation, glycolysis and tricarboxylic acid cycle, and a proteomic surplus of proapoptotic proteins.

High glucose predisposes gene expression and ERK phosphorylation to apoptosis and impaired glucose-stimulated insulin secretion via the cytoskeleton.

Chronic high glucose (HG) inflicts glucotoxicity on vulnerable cell types such as pancreatic β cells and contributes to insulin resistance and impaired insulin secretion in diabetic patients. To identify HG-induced cellular aberrations that are candidate mediators of glucotoxicity in pancreatic β cells, we analyzed gene expression in ERoSHK6, a mouse insulin-secreting cell line after chronic HG exposure (six-day exposure to 33.3 mM glucose).

Exosomes for drug delivery - a novel application for the mesenchymal stem cell.

Exosomes are the most extensively characterized class of secreted membrane vesicles that carry proteins and RNAs for intercellular communication. They are increasingly seen as possible alternatives to liposomes as drug delivery vehicles. Like liposomes, they could deliver their cargo across the plasma membrane and provide a barrier against premature transformation and elimination.

Mesenchymal stem cell: an efficient mass producer of exosomes for drug delivery.

Advances in biomedical research have generated an unprecedented number of potential targets for therapeutic intervention to treat disease or delay disease progression. Unfortunately, many of these targets are not druggable as they are intracellular, present in many cell types, poorly soluble or rapidly inactivated. Although synthetic drug vehicles have successfully circumvented many of these problems, natural particulates such as exosomes that intrinsically possess many attributes of a drug delivery vehicle are highly attractive as potentially better alternatives.

Delineating biological pathways unique to embryonic stem cell-derived insulin-producing cell lines from their noninsulin-producing progenitor cell lines.

To identify unique biochemical pathways in embryonic stem cell-derived insulin-producing cells as potential therapeutic targets to prevent or delay beta-cell dysfunction or death in diabetic patients, comparative genome-wide gene expression studies of recently derived mouse insulin-producing cell lines and their progenitor cell lines were performed using microarray technology. Differentially expressed genes were functionally clustered to identify important biochemical pathways in these insulin-producing cell lines. Biochemical or cellular assays were then performed to assess the relevance of these pathways to the biology of these cells.