Peripheral blood mesenchymal stem cell‐derived exosomes improve renal sympathetic denervation efficacy through β‐catenin‐mediated cardiac reprogramming

Background To investigate the role of self‐peripheral blood mesenchymal stem cell (PBMSC)‐derived exosomes (Exos) in enhancing renal sympathetic denervation (RD)‐mediated heart regeneration following myocardial infarction (MI) in a porcine model. Methods Pigs (ejection fraction [EF] < 40% post‐MI) were randomised to early sham RD or RD. At 2 weeks post‐MI, autologous PBMSC‐Exos were collected. At 30 days post‐MI, pigs received either PBMSC‐Exos (2 × 10 13 particles) or phosphate‐buffered saline and were followed until 90 days. Another cohort underwent myocardial biopsy at 14 days post‐MI to assess PBMSC‐Exos effects on ischaemic cardiomyocyte (CM) reprogramming, followed by adeno‐associated viral therapy with miR‐141‐200‐429 sponges or negative control sponges to explore the role of miR‐141‐200‐429 clusters in reprogramming. Results Two weeks post‐MI, RD hearts showed increased Exos uptake and inhibited the sympathetic nervous system. By 90 days, the RD+Exos group had 11%–26% higher EF than single‐treatment groups (all p < .001), with improved survival and reduced fibrosis. Exos therapy enhanced RD effects by suppressing the renin‒angiotensin‒aldosterone system and transferring the miR‐141‐200‐429 cluster into ischaemic CMs. CMs from RD‐treated hearts cocultured with PBMSC‐Exos RD exhibited a more immature state, promoting reprogramming. β‐Catenin overexpression further enhanced PBMSC‐Exos RD effects, while miR‐141‐200‐429 inhibition blocked RD‐induced CM reprogramming and survival. Ultimately, PBMSC‐Exos RD reduced dickkopf‐1 (Dkk1) expression and activated GSK3β phosphorylation, thereby stimulating the Wnt/β‐catenin pathway. Conclusions PBMSC‐Exos RD enhances RD‐mediated cardiac repair through miR‐141‐200‐429 cluster‐dependent activation of the Wnt/β‐catenin pathway, offering a novel therapeutic strategy for MI‐induced heart failure. Our findings unveil a novel therapeutic strategy, highlighting that RD maintains its efficacy and safety when integrated with complementary approaches over extended periods. Key points Myocardial infarction triggers cardiomyocyte depletion and sympathetic overactivation, culminating in irreversible heart failure. Renal denervation (RD) attenuates sympathetic signalling, modulating catecholamine‒B‐type natriuretic peptide (BNP) homeostasis. We newly demonstrate RD‐enhanced peripheral blood mesenchymal stem cell exosomal secretion enriched with miR‐141‐200‐429 clusters. These exosomal miRNAs suppress dickkopf‐1 (Dkk1), activating GSK3β/Wnt/β‐catenin signalling to enhance myocardial survival and regeneration. Our findings establish a combined therapeutic paradigm wherein RD maintains durable efficacy and safety alongside complementary interventions for heart failure management.