Abstract
Microvesicles are plasma membrane-derived vesicles released into the extracellular environment by a variety of cell types. Originally characterized from platelets, microvesicles are a normal constituent of human plasma, where they play an important role in maintaining hematostasis. Microvesicles have been shown to transfer proteins and RNA from cell to cell and they are also believed to play a role in intercellular communication. We characterized the RNA and protein content of embryonic stem cell microvesicles and show that they can be engineered to carry exogenously expressed mRNA and protein such as green fluorescent protein (GFP). We demonstrate that these engineered microvesicles dock and fuse with other embryonic stem cells, transferring their GFP. Additionally, we show that embryonic stem cells microvesicles contain abundant microRNA and that they can transfer a subset of microRNAs to mouse embryonic fibroblasts in vitro. Since microRNAs are short (21–24 nt), naturally occurring RNAs that regulate protein translation, our findings open up the intriguing possibility that stem cells can alter the expression of genes in neighboring cells by transferring microRNAs contained in microvesicles. Embryonic stem cell microvesicles may be useful therapeutic tools for transferring mRNA, microRNAs, protein, and siRNA to cells and may be important mediators of signaling within stem cell niches.
Highlights
Circulating platelet-derived vesicles were first identified in human plasma in the 1960’s [1]
We isolated mouse embryonic stem cell microvesicles (ESMVs) and determined their total RNA profile by gel electrophoresis and capillary electrophoresis (Figures 1A and 1B). 4.7760.7 mg (n = 10) of total RNA can be obtained over a 48 hour period from ESMVs released by 3.56106 embryonic stem cells (ESCs) plated on a T175 culture flask and cultured to,70% confluence in serum-free media
We observed an overall reduction of several orders of magnitude in the levels of all transcripts tested from ESMVs when compared with the levels of the same mRNAs in ESCs, including that encoding the cytoskeletal protein, b-actin (Figure 1C)
Summary
Circulating platelet-derived vesicles were first identified in human plasma in the 1960’s [1]. These vesicles, called microvesicles or microparticles, are heterogeneous in size and range from ,30 nm to 1 mm. Believed to be inert cellular debris, microvesicles are gaining acceptance as important mediators of intercellular communication [2,3,4,5,6,7,8,9]. Microvesicles may mediate intercellular communication by transporting bioactive lipids, mRNA, or proteins between cells. Microvesicles were isolated from embryonic stem cells. A reduction in the number of platelet microvesicles causes a bleeding disorder called Scott Syndrome [14]. Elevated levels of microvesicles are associated with a variety of disorders including acute coronary syndrome, hypertension, diabetes, and pulmonary embolism (reviewed in [15])
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