Advances in studies of circulating microRNAs: origination, transportation, and distal target regulation

Abstract

In the past few years, numerous advances emerged in terms of circulating microRNA(miRNA) regulating gene expression by circulating blood to the distal tissues and cells. This article reviewed and summarized the process of circulating miRNAs entering the circulating system to exert gene regulation, especially exogenous miRNAs (such as plant miRNAs), from the perspective of the circulating miRNAs source (cell secretion or gastrointestinal absorption), the transport form and pharmacokinetics in circulating blood, and the evidence of distal regulation to gene expression, thereby providing a basis for their in-depth research and even application prospects.

Evidence of Cross-Kingdom Gene Regulation by Plant MicroRNAs and Possible Reasons for Inconsistencies

“…EV-borne plant miRNAs can be specifically internalized by intestinal cells via caveolin-mediated endocytosis and micropinocytosis. 12,58,64 Notably, the types of plant lipids contained in EV may play different roles in the absorption of plant miRNAs, as suggested by the finding that phosphatidic acid lipids prefer to maintain the duration and amount of EV-borne plant miRNAs accumulation in the gut, whereas phosphatidylcholine lipids prefer to enhance the migration of EV-borne plant miRNAs from the intestine to the liver. 16 The current evidence reveals that EV-borne plant miRNAs can enter the body through the gastrointestinal tract 16 and respiratory tract.…”

“…Furthermore, EV can be artificially generated from plant lipids, ,, and plant miRNAs can be artificially packaged into EV , for delivery into body cells. EV-borne plant miRNAs can be specifically internalized by intestinal cells via caveolin-mediated endocytosis and micropinocytosis. ,, Notably, the types of plant lipids contained in EV may play different roles in the absorption of plant miRNAs, as suggested by the finding that phosphatidic acid lipids prefer to maintain the duration and amount of EV-borne plant miRNAs accumulation in the gut, whereas phosphatidylcholine lipids prefer to enhance the migration of EV-borne plant miRNAs from the intestine to the liver …”

“…In addition to EV-borne plant miRNAs, total plant small RNAs (sRNAs, including miRNAs), termed extracted plant miRNAs, have also been extracted from plant tissues to study their cross-kingdom gene regulation. − The extracted plant miRNAs can be absorbed into the blood by systemic RNA interference defective protein 1 (SID-1) . In our previous review, we summarized that the stability of plant miRNAs, which makes them resistant to high temperatures during cooking, exposure to strong acid conditions and digestion in the gastrointestinal tract, and degradation in the blood circulation system, is generally attributed to the protection of EV and RNA-binding proteins (e.g., Argonaute 2), 3′ end methylation, and some special sequences (e.g., those rich in cytosine and guanine) in plant miRNAs and perhaps plant metabolites . Based on the principle of nucleic acid extraction, the extracted plant miRNAs are free or naked (Figure ), without the protection of EV or RNA-binding proteins (e.g., Argonaute 2).…”

“…In our previous review, we summarized that the stability of plant miRNAs, which makes them resistant to high temperatures during cooking, exposure to strong acid conditions and digestion in the gastrointestinal tract, and degradation in the blood circulation system, is generally attributed to the protection of EV and RNA-binding proteins (e.g., Argonaute 2), 3′ end methylation, and some special sequences (e.g., those rich in cytosine and guanine) in plant miRNAs and perhaps plant metabolites . Based on the principle of nucleic acid extraction, the extracted plant miRNAs are free or naked (Figure ), without the protection of EV or RNA-binding proteins (e.g., Argonaute 2). However, existing studies suggest that free plant miRNAs can enter the animal circulation system via gastrointestinal absorption , and intravenous injection to exert cross-kingdom gene regulation, for instance, by modifying the host microbiome composition, inhibiting virus replication by targeting viral mRNA, and reducing the severity of experimental autoimmune encephalomyelitis (EAE) by dampening Th1 and Th17 cells .…”

Regulatory mechanisms of microRNAs in endocrine disorders and their therapeutic potential

“…Moreover, miRNAs can target hormone receptors and intracellular signaling molecules to alter target cell responses ( Derghal et al, 2016 ; Bayraktar et al, 2017 ). Recently, evidence postulated that miRNAs could be secreted to the extracellular milieu and act as endocrine factors, performing endocrine and paracrine crosstalk between cells and tissues ( Wu et al, 2022 ).…”