Scientists at the University of Edinburgh have been investigating an intriguing question: can RNA molecules, the messengers inside our cells, travel between organs in mammals and help them communicate? While it is well-known that extracellular RNA (exRNA) plays important signalling roles in simpler animals, whether this happens naturally in mammals has remained uncertain.

To explore this, the researchers focused on two vital organs, the liver and the kidney, in mice. They used a special chemical called 4-thiouracil to label newly made RNA specifically in liver cells. This labeling “tags” the RNA, allowing scientists to track whether these RNA molecules end up somewhere else in the body. To detect the tagged RNA in the kidney, the team used an advanced method called SLAMseq, short for SH-Linked Alkylation for Metabolic RNA sequencing, which precisely identifies metabolically labelled RNA molecules.

SLAMseq labels RNA in the liver in a small initial experiment

a Biotinylation dotblot. Flox-stop-UPRT mice were treated with AAV8-TBG-Cre and then injected with 4-thiouracil as either intraperitoneal or subcutaneous injections (n = 3 biological replicates in each group). Incorporation of the 4TU label into liver RNA was assessed using a biotinylation assay. b Mutation rates in SLAMseq data. Increased rates of T > C conversion were detected on the positive strand; increased rates of A > G conversion were detected on the negative strand. Box plot shows median (central line) and 1^st and 3^rd quartiles (lower and upper limits of box); whiskers define the lowest and highest values within a range extending beyond the box by 1.5x the interquartile range. c T > C conversion rates in mRNA SLAMseq data. Rates were higher in the RNA labelling group (p < 2^–16 for comparison with each of the negative control groups by Kruskal-Wallis test and post hoc Wilcoxon signed rank test). d Labelled mRNAs in SLAMseq data were detected by comparing gene-wise T > C conversion rates between Cre-positive (RNA labelling) and Cre-negative (control) groups using the beta-binomial method and setting a significant false discovery rate of 0.05. Each point represents a single gene mRNA; genes for which there was a significant between-group difference in T > C conversion rate are shown in red. e T > C conversion rates in known hepatocyte marker genes. f T > C conversion rates in small RNA SLAMseq data. Rates were higher in the RNA labelling group (p < 2^–16 for comparison with each of the negative control groups by Kruskal-Wallis test and post hoc Wilcoxon signed rank test). g T > C conversion rates stratified by small RNA biotype. h Labelled small RNAs in SLAMseq data. i Labelling of small RNA in liver, stratified by RNA biotype (mean and bootstrapped 95% CI). j miR-122, miR-126a and miR-23a labelling. T > C conversion rates in the known hepatocyte-enriched miRNA, miR-122, and the known endothelial-enriched miRNAs, miR-126a and miR-23a. Data from male and female mice, n = 3 in each experimental group. Source data are provided as a Source Data file.

The results were surprising and exciting. Even under healthy conditions, about 5% of the messenger RNA (mRNA) transcripts found in the kidney carried the liver’s RNA label. This suggests a natural movement or transfer of RNA from liver cells to kidney cells. When the liver was damaged, the transfer increased dramatically, with up to 34% of kidney mRNA transcripts labelled from the liver. This points to a heightened communication or molecular exchange between these organs during injury or stress.

Interestingly, while the team did not observe transfer of small RNAs in general, they did find increased levels of a specific liver microRNA called miR-122 in the kidney after liver injury. MicroRNAs are small RNA molecules that regulate gene expression, and miR-122 is known to be highly abundant in the liver and important for liver function. Its presence in the kidney after injury further supports the idea of RNA moving between organs as a potential signal.

The study does have some limitations. The researchers could not pinpoint exactly which RNA transcripts were being transferred, and they did not test what biological effects this RNA transfer might have on the kidney or overall physiology. Despite these gaps, the discovery raises fascinating possibilities. For example, RNA travelling from one organ to another could influence how organs respond to injury or disease, coordinate repair processes, or regulate metabolism across the body.

Understanding how RNA acts as a molecular messenger between organs could open new avenues for diagnosing diseases, developing treatments, or even creating therapies that mimic or enhance this natural communication system. The use of RNA sequencing methods like SLAMseq offers powerful tools to unravel these complex interactions and deepen our knowledge of how the body maintains health and responds to injury.