Extracellular vesicles (EVs), membrane vesicles that are secreted by a variety of mammalian cell types, have been shown to play an important role in intercellular communication. The contents of EVs, ...including proteins, microRNAs, and mRNAs, vary according to the cell type that secreted them. Accordingly, researchers have demonstrated that EVs derived from various cell types play different roles in biological phenomena. Considering the ubiquitous presence of mesenchymal stem cells (MSCs) in the body, MSC‐derived EVs may take part in a wide range of events. In particular, MSCs have recently attracted much attention due to the therapeutic effects of their secretory factors. MSC‐derived EVs may therefore provide novel therapeutic approaches. In this review, we first summarize the wide range of functions of EVs released from different cell types, emphasizing that EVs echo the phenotype of their parent cell. Then, we describe the various therapeutic effects of MSCs and pay particular attention to the significance of their paracrine effect. We then survey recent reports on MSC‐derived EVs and consider the therapeutic potential of MSC‐derived EVs. Finally, we discuss remaining issues that must be addressed before realizing the practical application of MSC‐derived EVs, and we provide some suggestions for enhancing their therapeutic efficiency.
Brain metastasis is an important cause of mortality in breast cancer patients. A key event during brain metastasis is the migration of cancer cells through blood-brain barrier (BBB). However, the ...molecular mechanism behind the passage through this natural barrier remains unclear. Here we show that cancer-derived extracellular vesicles (EVs), mediators of cell-cell communication via delivery of proteins and microRNAs (miRNAs), trigger the breakdown of BBB. Importantly, miR-181c promotes the destruction of BBB through the abnormal localization of actin via the downregulation of its target gene, PDPK1. PDPK1 degradation by miR-181c leads to the downregulation of phosphorylated cofilin and the resultant activated cofilin-induced modulation of actin dynamics. Furthermore, we demonstrate that systemic injection of brain metastatic cancer cell-derived EVs promoted brain metastasis of breast cancer cell lines and are preferentially incorporated into the brain in vivo. Taken together, these results indicate a novel mechanism of brain metastasis mediated by EVs that triggers the destruction of BBB.
Recent important progress in cancer biology was the identification of the significant roles played by extracellular vesicles (EVs). EVs are secreted by a variety of mammalian cell types and have been ...revealed to play important roles in intercellular communications. EVs serve as unique communication vehicles in many ways. First, unlike cytokine signaling, EVs enable transportation not only of proteins, but also of nucleic acids, including mRNAs and microRNAs. Recent reports showing the functionality of these nucleic acids in the recipient cells have opened up a new avenue of cell‐to‐cell communication research. Second, EVs have been revealed to transport membrane components including receptors, such as epithelial growth factor receptor. These findings have provided significant insights into understanding the molecular mechanisms of cancer development. Third, EVs protect their contents from clearance by degrading enzymes present in the extracellular space, which allows for remote transportation of the contents, even between organs. This concept is highlighted by recent reports that suggest the deep involvement of cancer cell derived EVs in metastasis. From these points of view, we will summarize recent studies on the relevance of EVs in cancer biology. We will also highlight the possibility of novel diagnostic technologies using circulating EVs in body fluid.
Extracellular vesicles (EVs) play important roles in intercellular communications via their content molecules, and mimic, at least in part, the roles that are played by their originating cells. ...Consistent with this notion, an increasing number of reports have suggested that EVs derived from mesenchymal stem cells (MSCs), which are therapeutically beneficial to a wide range of diseases, can serve as drugs to treat multiple diseases. EVs contain a variety of molecules, including proteins, microRNAs, and mRNAs, and are associated with biological processes in a content molecule-dependent manner. In this article, we review the latest reports regarding the therapeutic potential of MSC-EVs by focusing on the underlying molecular mechanisms of their effects. Specifically, we feature the effects of MSC-EVs in terms of their content molecules and of the tissue recovery processes endowed by these molecules.
One of the pathological hallmarks of Alzheimer's disease (AD) is the presence of extracellular plaques resulting from the accumulation of beta-amyloid peptide (Aβ). To date, a definitive cure for ...this disease is still lacking as the currently approved drugs used are mainly symptomatic treatments. The revolutionary discovery of extracellular vesicles (EVs) has shed new light on the development of disease-modifying treatments for AD, owing to their potential in delivering the therapeutic agents to the brain. The feasibility of harnessing EVs for clinical applications is highly dependent on the donor cell, which determines the intrinsic properties of EVs. The merit of mesenchymal stem cells (MSCs) as therapeutic delivery vehicles, and the proven therapeutic effects of the EVs derived from these cells, make researchers esteem MSCs as ideal producers of EVs. Therefore, MSC-derived EVs (MSC-EVs) emerge to be an appealing therapeutic delivery approach for the treatment of AD. Here, we discuss perspectives on the therapeutic strategies using MSC-EVs to treat AD and the associated challenges in clinical application.
Bipotent liver progenitor cells (LPCs) are promising cell sources for cell transplantation therapy in hepatic disorders as well as biliary dysfunctions. Using a cocktail of small molecules, we ...recently reported a novel approach to generate bipotent LPCs, named chemically induced liver progenitors (CLiPs), from adult rat hepatocytes. In this chapter, we describe a detailed protocol for the induction of rat CLiPs. We first describe the method to isolate primary rat hepatocytes and then describe how to induce CLiPs from the hepatocytes. In addition, we describe methods to induce the generated CLiPs to differentiate into hepatocytes and biliary epithelial cells.
Hepatocytes are regarded as the only effective cell source for cell transplantation to treat liver diseases; however, their availability is limited due to a donor shortage. Thus, a novel cell source ...must be developed. We recently reported that mature rodent hepatocytes can be reprogrammed into progenitor-like cells with a repopulative capacity using small molecule inhibitors. Here, we demonstrate that hepatic progenitor cells can be obtained from human infant hepatocytes using the same strategy. These cells, named human chemically induced liver progenitors (hCLiPs), had a significant repopulative capacity in injured mouse livers following transplantation. hCLiPs redifferentiated into mature hepatocytes in vitro upon treatment with hepatic maturation-inducing factors. These redifferentiated cells exhibited cytochrome P450 (CYP) enzymatic activities in response to CYP-inducing molecules and these activities were comparable with those in primary human hepatocytes. These findings will facilitate liver cell transplantation therapy and drug discovery studies.
The immediate deterioration of primary human hepatocytes (PHHs) during culture limits their utility in drug discovery studies. Here, we report that a cocktail of four small molecule signaling ...inhibitors, termed YPAC, is useful for maintaining various hepatic functions of PHHs, including albumin and urea productivity, glycogen storage, and cytochrome P450 (CYP) expression. Most importantly, we found that YPAC allows PHHs to retain enzymatic activities of CYP1A2, CYP2B6, and CYP3A4 even after 40 days of culture, and that inducibility of CYP3A4 activity in response to the prototypical inducers rifampicin and phenobarbital is also maintained. Our novel approach could facilitate drug discovery studies.
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