Exosomes as Reconfigurable Therapeutic Systems
TL;DR: Various facets of nanoparticles, namely the isolation and manipulation of exosomes, the construction of synthetic exosome-like particles in vivo, and their potential use in the treatment of various diseases are discussed.
About: This article is published in Trends in Molecular Medicine.The article was published on 2017-07-01 and is currently open access. It has received 165 citations till now.
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TL;DR: Interestingly, adipose tissue expansion through the generation of new adipocytes (adipogenesis), rather than through increasing adipocyte size, can prevent this metabolic decline, and a better understanding of adipogenesis can inform new strategies to increase metabolic health in humans.
Abstract: Obesity is characterized by increased adipose tissue mass and has been associated with a strong predisposition towards metabolic diseases and cancer. Thus, it constitutes a public health issue of major proportion. The expansion of adipose depots can be driven either by the increase in adipocyte size (hypertrophy) or by the formation of new adipocytes from precursor differentiation in the process of adipogenesis (hyperplasia). Notably, adipocyte expansion through adipogenesis can offset the negative metabolic effects of obesity, and the mechanisms and regulators of this adaptive process are now emerging. Over the past several years, we have learned a considerable amount about how adipocyte fate is determined and how adipogenesis is regulated by signalling and systemic factors. We have also gained appreciation that the adipogenic niche can influence tissue adipogenic capability. Approaches aimed at increasing adipogenesis over adipocyte hypertrophy can now be explored as a means to treat metabolic diseases.
724 citations
TL;DR: A detailed review of exosomes engineering through genetic and chemical methods for targeted drug delivery is presented in this article, where the authors show that exosome-mediated drug delivery boasts low toxicity, low immunogenicity, and high engineerability and holds promise for cell-free therapies for a wide range of diseases.
Abstract: Exosomes are cell-derived nanovesicles that are involved in the intercellular transportation of materials. Therapeutics, such as small molecules or nucleic acid drugs, can be incorporated into exosomes and then delivered to specific types of cells or tissues to realize targeted drug delivery. Targeted delivery increases the local concentration of therapeutics and minimizes side effects. Here, we present a detailed review of exosomes engineering through genetic and chemical methods for targeted drug delivery. Although still in its infancy, exosome-mediated drug delivery boasts low toxicity, low immunogenicity, and high engineerability, and holds promise for cell-free therapies for a wide range of diseases.
369 citations
TL;DR: It is shown that neighboring endothelial cells (ECs) transfer cav1-containing EVs to adipocytes in vivo, which reciprocate by releasing EVs to ECs, which facilitates transfer of plasma constituents from ECs to the adipocyte.
238 citations
TL;DR: Comparative assessment of TFF and UC of conditioned cell culture media revealed that the former concentrates EVs of comparable physicochemical characteristics, but with higher yield, less single macromolecules and aggregates, and improved batch-to-batch consistency in half the processing time.
Abstract: Concentration of extracellular vesicles (EVs) from biological fluids in a scalable and reproducible manner represents a major challenge. This study reports the use of tangential flow filtration (TFF) for the highly efficient isolation of EVs from large volumes of samples. When compared to ultracentrifugation (UC), which is the most widely used method to concentrate EVs, TFF is a more efficient, scalable, and gentler method. Comparative assessment of TFF and UC of conditioned cell culture media revealed that the former concentrates EVs of comparable physicochemical characteristics, but with higher yield, less single macromolecules and aggregates (<15 nm in size), and improved batch-to-batch consistency in half the processing time (1 h). The TFF protocol was then successfully implemented on fluids derived from patient lipoaspirate. EVs from adipose tissue are of high clinical relevance, as they are expected to mirror the regenerative properties of the parent cells.
231 citations
TL;DR: This review will highlight the collagen species produced during the different therapeutic approaches, and new developments in scaffold design and delivery of therapeutic molecules will be described.
171 citations
References
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TL;DR: It is shown that exosomes contain both mRNA and microRNA, which can be delivered to another cell, and can be functional in this new location, and it is proposed that this RNA is called “exosomal shuttle RNA” (esRNA).
Abstract: Exosomes are vesicles of endocytic origin released by many cells. These vesicles can mediate communication between cells, facilitating processes such as antigen presentation. Here, we show that exosomes from a mouse and a human mast cell line (MC/9 and HMC-1, respectively), as well as primary bone marrow-derived mouse mast cells, contain RNA. Microarray assessments revealed the presence of mRNA from approximately 1300 genes, many of which are not present in the cytoplasm of the donor cell. In vitro translation proved that the exosome mRNAs were functional. Quality control RNA analysis of total RNA derived from exosomes also revealed presence of small RNAs, including microRNAs. The RNA from mast cell exosomes is transferable to other mouse and human mast cells. After transfer of mouse exosomal RNA to human mast cells, new mouse proteins were found in the recipient cells, indicating that transferred exosomal mRNA can be translated after entering another cell. In summary, we show that exosomes contain both mRNA and microRNA, which can be delivered to another cell, and can be functional in this new location. We propose that this RNA is called "exosomal shuttle RNA" (esRNA).
10,484 citations
TL;DR: Exosomes were described as vesicles of endosomal origin secreted from reticulocytes in the 1980s as discussed by the authors, and their biogenesis, their secretion, and their subsequent fate are discussed, as their functions rely on these important processes.
Abstract: In the 1980s, exosomes were described as vesicles of endosomal origin secreted from reticulocytes. Interest increased around these extracellular vesicles, as they appeared to participate in several cellular processes. Exosomes bear proteins, lipids, and RNAs, mediating intercellular communication between different cell types in the body, and thus affecting normal and pathological conditions. Only recently, scientists acknowledged the difficulty of separating exosomes from other types of extracellular vesicles, which precludes a clear attribution of a particular function to the different types of secreted vesicles. To shed light into this complex but expanding field of science, this review focuses on the definition of exosomes and other secreted extracellular vesicles. Their biogenesis, their secretion, and their subsequent fate are discussed, as their functions rely on these important processes.
3,959 citations
TL;DR: It is shown that exosomes—endogenous nano-vesicles that transport RNAs and proteins—can deliver short interfering (si)RNA to the brain in mice, and the therapeutic potential of exosome-mediated siRNA delivery was demonstrated by the strong mRNA and protein knockdown of BACE1, a therapeutic target in Alzheimer's disease, in wild-type mice.
Abstract: To realize the therapeutic potential of RNA drugs, efficient, tissue-specific and nonimmunogenic delivery technologies must be developed. Here we show that exosomes-endogenous nano-vesicles that transport RNAs and proteins-can deliver short interfering (si)RNA to the brain in mice. To reduce immunogenicity, we used self-derived dendritic cells for exosome production. Targeting was achieved by engineering the dendritic cells to express Lamp2b, an exosomal membrane protein, fused to the neuron-specific RVG peptide. Purified exosomes were loaded with exogenous siRNA by electroporation. Intravenously injected RVG-targeted exosomes delivered GAPDH siRNA specifically to neurons, microglia, oligodendrocytes in the brain, resulting in a specific gene knockdown. Pre-exposure to RVG exosomes did not attenuate knockdown, and non-specific uptake in other tissues was not observed. The therapeutic potential of exosome-mediated siRNA delivery was demonstrated by the strong mRNA (60%) and protein (62%) knockdown of BACE1, a therapeutic target in Alzheimer's disease, in wild-type mice.
3,442 citations
National Taiwan University1, University of Porto2, University of Tokyo3, Rockefeller University4, Memorial Sloan Kettering Cancer Center5, Karolinska Institutet6, Linköping University7, Lawrence Berkeley National Laboratory8, Cornell University9, Alberta Children's Hospital10, Columbia University11, University of Oslo12, University of Nebraska Medical Center13, University of Hamburg14, University of Pennsylvania15, Princeton University16, Rutgers University17, Fred Hutchinson Cancer Research Center18, Carlos III Health Institute19
TL;DR: It is demonstrated that exosomes from mouse and human lung-, liver- and brain-tropic tumour cells fuse preferentially with resident cells at their predicted destination, namely lung fibroblasts and epithelial cells, liver Kupffer cells and brain endothelial cells.
Abstract: Ever since Stephen Paget's 1889 hypothesis, metastatic organotropism has remained one of cancer's greatest mysteries. Here we demonstrate that exosomes from mouse and human lung-, liver- and brain-tropic tumour cells fuse preferentially with resident cells at their predicted destination, namely lung fibroblasts and epithelial cells, liver Kupffer cells and brain endothelial cells. We show that tumour-derived exosomes uptaken by organ-specific cells prepare the pre-metastatic niche. Treatment with exosomes from lung-tropic models redirected the metastasis of bone-tropic tumour cells. Exosome proteomics revealed distinct integrin expression patterns, in which the exosomal integrins α6β4 and α6β1 were associated with lung metastasis, while exosomal integrin αvβ5 was linked to liver metastasis. Targeting the integrins α6β4 and αvβ5 decreased exosome uptake, as well as lung and liver metastasis, respectively. We demonstrate that exosome integrin uptake by resident cells activates Src phosphorylation and pro-inflammatory S100 gene expression. Finally, our clinical data indicate that exosomal integrins could be used to predict organ-specific metastasis.
3,399 citations
01 Jan 2014
TL;DR: The definition of exosomes and other secreted extracellular vesicles, which mediating intercellular communication between different cell types in the body, and thus affecting normal and pathological conditions are focused on.
Abstract: In the 1980s, exosomes were described as vesicles of endosomal origin secreted from reticulocytes. Interest increased around these extracellular vesicles, as they appeared to participate in several cellular processes. Exosomes bear proteins, lipids, and RNAs, mediating intercellular communication between different cell types in the body, and thus affecting normal and pathological conditions. Only recently, scientists acknowledged the difficulty of separating exosomes from other types of extracellular vesicles, which precludes a clear attribution of a particular function to the different types of secreted vesicles. To shed light into this complex but expanding field of science, this review focuses on the definition of exosomes and other secreted extracellular vesicles. Their biogenesis, their secretion, and their subsequent fate are discussed, as their functions rely on these important processes.
3,321 citations