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.