Low-intensity pulsed ultrasound reverses erectile dysfunction by targeting and expanding stem-like PDGFRa⁺Sca1⁺ fibroblasts

Low-intensity pulsed ultrasound (LIPUS) is an effective therapy for erectile dysfunction, yet its precise cellular mechanisms remain elusive. Meanwhile, fibroblasts (FBs) are increasingly recognized for their highly specialized and multifaceted functions across various tissues. We investigated the mechanobiological effects of LIPUS on corpus cavernosum FBs utilizing in vitro primary cell cultures, in vivo diabetic rat models, and single-cell RNA sequencing (scRNA-seq) analyses. Mechanistically, in vitro assays revealed that LIPUS significantly stimulated FB proliferation via activation of the AMPK-WNT/β-catenin signaling pathway. In vivo evaluations demonstrated that LIPUS effectively ameliorated erectile function and repaired damaged cavernous vasculature in diabetic rats. Furthermore, scRNA-seq analysis indicated that LIPUS treatment altered FB subpopulation dynamics, markedly expanding a specific endogenous PDGFRa⁺Sca1⁺ FB subset that is highly enriched in angiogenic signaling. This study unveils a novel mechanobiological mechanism by which LIPUS facilitates cavernous vascular regeneration through the modulation of specific FB subpopulations, providing crucial biological evidence to support its clinical application.