Peripheral Blood Mesenchymal Stem Cell–Derived Exosomes Improve Renal Sympathetic Denervation Efficacy Through β-Catenin-Mediated Cardiac Reprogramming

Objectives To explore the role of self-peripheral blood mesenchymal stem cell (PBMSC)-derived exosomes (Exos) in enhancing renal sympathetic denervation (RD)-mediated cardiac repair following myocardial infarction (MI) in a porcine model. Methods Pigs (EF < 40% post-MI) were randomized 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 × 10¹³ particles) or PBS and were followed until 90 days. Another cohort underwent myocardial biopsy at 14 days post-MI to assess PBMSC-Exos effects on ischemic cardiomyocyte (CM) reprogramming, followed by AAV therapy with miR-141-200-429 sponges or negative control (NC) 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 < 0.001), with improved survival and reduced fibrosis. Exos therapy enhanced RD effects by inhibiting the renin-angiotensin-aldosterone system and transferring the miR-141-200-429 cluster into ischemic CMs. CMs from RD-treated hearts co-cultured 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 Dkk1 expression and activated GSK3β phosphorylation, thereby stimulating the Wnt/β-catenin pathway. Conclusions PBMSC-Exos ^RD enhances RD-mediated cardiac repair by activating the Wnt/β-catenin pathway via miR-141-200-429 cluster, 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.