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MiRNA Cargo of Matrix-Bound Extracellular Vesicles Isolated from Human Left Ventricular Tissue Differs with Heart Failure

ABSTRACT: Matrix-bound extracellular vesicles were isolated from the left ventricle tissue of de-identified patients with non-failing (healthy) hearts or with non-ischemi heart failure. mIRNA sequencing was performed on the miRNA cargo sequestered within the extracellular vesicles. Differences in the miRNA signature of healthy versus failing-tissue derived extracellular vesicles suggests that disease progression to heart failure is associated with dynamic changes in vesicular cargo.

ORGANISM(S): Homo sapiens

PROVIDER: GSE248886 | GEO | 2025/05/14

REPOSITORIES: GEO

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Project description:Amyotrophic lateral sclerosis (ALS) is a terminal neurodegenerative disease. Clinical and molecular observations suggest that ALS pathology originates at a single site and spreads in an organized and prion-like manner, possibly driven by extracellular vesicles. Extracellular vesicles transfer cargo molecules associated with ALS pathogenesis, such as misfolded and aggregated proteins and dysregulated microRNAs (miRNAs). However, it is poorly understood whether altered levels of circulating extracellular vesicles or their cargo components reflect pathological signatures of the disease. In this study, we used immuno-affinity-based microfluidic technology, electron microscopy, and NanoString miRNA profiling to isolate and characterize extracellular vesicles and their miRNA cargo from frontal cortex, spinal cord, and serum of sporadic ALS (n=15) and healthy control (n=16) participants. We found larger extracellular vesicles in ALS spinal cord versus controls and smaller sized vesicles in ALS serum. However, there were no changes in the number of extracellular vesicles between cases and controls across any tissues. Characterization of extracellular vesicle-derived miRNA cargo in ALS compared to controls identified significantly altered miRNA levels in all tissues; miRNAs were reduced in ALS frontal cortex and spinal cord and increased in serum. Two miRNAs were dysregulated in all three tissues: miR-342-3p was increased in ALS, and miR-1254 was reduced in ALS. Additional miRNAs overlapping across two tissues included miR-587, miR-298, miR-4443, and miR-450a-2-3p. Predicted targets and pathways associated with the dysregulated miRNAs across the ALS tissues were associated with common biological pathways altered in neurodegeneration, including axon guidance and long-term potentiation. A predicted target of one identified miRNA (N-deacetylase and N-sulfotransferase 4; NDST4) was likewise dysregulated in an in vitro model of ALS, verifying potential biological relevance. Together, these findings demonstrate that circulating extracellular vesicle miRNA cargo mirror those of the central nervous system disease state in ALS, and thereby offer insight into possible pathogenic factors and diagnostic opportunities.

Project description:Heart failure is associated with high morbidity and mortality and its incidence increases worldwide. MicroRNAs (miRNAs) are potential markers and targets for diagnostic and therapeutic applications, respectively. We determined myocardial and circulating miRNA abundance and its changes in patients with stable and end-stage heart failure before and at different time points after mechanical unloading by a left ventricular assist device (LVAD) by small-RNA-sequencing. MiRNA changes in failing heart tissues partially resembled that of fetal myocardium. Consistent with prototypical miRNAM-bM-^@M-^Starget-mRNA interactions, target mRNA levels were negatively correlated to changes in abundance for highly expressed miRNAs in heart failure and fetal hearts. The circulating small RNA profile was dominated by miRNAs, and fragments of tRNAs and small cytoplasmic RNAs. Heart- and muscle-specific circulating miRNAs (myomirs) increased up to 140-fold in advanced heart failure, which coincided with a similar increase in cardiac troponin I protein, the established marker for heart injury. These extracellular changes nearly completely reversed 3 months following initiation of LVAD support. In stable heart failure, circulating miRNAs showed less than 5-fold differences compared to normal, and myomir and cardiac troponin I levels were only captured near the detection limit. These findings provide the underpinning for miRNA-based therapies and emphasize the usefulness of circulating miRNAs as biomarkers for heart injury performing similar to established diagnostic protein biomarkers. Total RNA isolated from human left ventricular myocardium of failing hearts due to dilated or ischemic cardiomyopathy before and after mechanical unloading by a left ventricular assist device, and fetal myocardium compared to non-failing postnatal myocardium was subjected to multiplexed small RNA-sequencing on the Illumina platform. mRNA gene expression data using Illumina HumanHT-12v4 beadarrays for a subset of the myocardial samples is available (GSE52601).

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MiRNA Cargo of Matrix-Bound Extracellular Vesicles Isolated from Human Left Ventricular Tissue Differs with Heart Failure

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