About this Research Topic

Background

Extracellular RNAs (exRNAs) are a heterogeneous group of RNAs ranging from small and long non-coding to coding RNAs and ribosomal RNAs. ExRNAs travel all over the body via the bloodstream and other fluids embedded in lipid membranes referred to as extracellular vesicles (EVs) or bound to non-vesicular (lipoprotein and ribonucleoprotein) carriers. Recent progress in the field of exRNA biology raises the question whether exRNAs and their carriers, mainly EVs, can mediate cell-to-cell communication and regulate cellular functions from the outside. EVs contain a highly specific set of proteins, nucleic acids, lipids, and other molecules, specific for particular physiological functions. EVs connect signaling cells and target cells and change their gene expression via transcription factors, epigenetic signals, and regulatory RNAs. EVs are enriched with microRNA, tRNA, long non-coding RNAs, and other types of non-coding RNAs. Among the various RNA classes present in EVs, miRNAs have been most intensively studied because of their known gene-regulatory functions. However, other types of non-coding RNAs are shown to be also abundantly present in EVs. The molecular composition of EVs is specific for the cell of origin, its viability, cell activation, or stimulation. Thus, the RNA pattern within EVs might be a subject of regulation.

Better understanding of the cellular communications encoded by exRNAs could reveal early signs of diseases such as cancer, fibrosis, diabetes, cardiovascular, neurological, and immunological disorders. Several studies showed that ribosomal exRNAs released by cells upon inflammatory stimulation or by damaged cells constitute proinflammatory and prothrombotic alarmins. Moreover, tumor cells produce EVs that suppress the immune reaction, stimulate angiogenesis, and promote tumor growth and metastasis. On the other hand, EVs derived from stem cells inhibit tumor growth by multiple mechanisms. These and many other examples point out the critical role of secreted RNAs in homeostasis and regulation of the extracellular microenvironment.

RNA-carrying EVs might offer a safer and simpler alternative to stem cell therapy for cardiovascular, neurological and immunological disorders due to their pro-regenerative potential and immunoregulatory activity. Apart from stimulatory proteins, such as HLA, TLRs, CD47 etc., EVs transferring exRNAs play an important role in immune regulation. EVs exhibit both pro-inflammatory and immunosuppressive activities, depending on EV releasing cell. EVs secreted by stem cells were shown to be mostly immunosuppressive, but cell viability, age, activation status can revert the properties of EVs. Regulatory non-coding RNAs can act as tumor suppressors or as oncogenes, depending on their targets and co-factors. It has been shown that a single RNA could have a contradictory role in different cell contexts. Since one EV contains a specifically composed and adjusted set of RNAs involved in a particular function, we believe that EVs might be the key to understand and translate the language of exRNAs.

This Research Topic focuses on the functional role of exRNAs, mainly as a cargo of EVs, in both physiological and pathological circumstances. Additionally, we would like to discuss the emerging role of circulating RNAs as potential biomarkers with a possible role as novel mediators of intercellular communication and gene expression regulation coming from outside. Altered expression of exRNAs and their function as crucial contributor of various cellular pathways in normal and pathological conditions are widely implicated. We are particularly interested in novel exRNAs detection technologies, along with their advantages and limitations, to evaluate different types of exRNAs in tissues and body fluids and explore their functions, both known and unknown. Finally, this Research Topic aims to highlight the recent advances in using exRNAs for the treatment of various diseases and validate their promising therapeutic potential.

We welcome Original Research and Review articles based on experimental and clinical results. We encourage particularly contributions that include, but are not limited to, the following topics:

• Extracellular RNAs in cellular physiology and cell-to-cell communication.
• Elucidating the functions of different types of RNAs revealed in extracellular vesicles.
• Extracellular RNAs as mediators of the targeted horizontal gene transfer (dietary RNA, RNA from breast milk, RNA regulating human gut miocrobiome and other symbionts).
• Extracellular RNAs as biomarkers.
• Extracellular RNAs in cell renewal and tissue regeneration.
• Regulation of immune response by exRNA.
• Extracellular RNAs in pathogenesis of various diseases, including cancer, fibrosis, diabetes, cardiovascular, neurological, and immunological disorders.
• Types of exRNA: mRNA, microRNA, tRNA, rRNA, lncRNA.
• Novel approaches to explore and regulate extracellular RNA functions.
• Extracellular RNAs as therapeutic modality.

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

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