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.
Erectile dysfunction (ED) is a common, debilitating complication of diabetes mellitus, driven by endothelial dysfunction, neurovascular injury, and oxidative stress. Although mesenchymal stem cells confer benefit, concerns regarding safety, scalability, and standardization have shifted interest to cell-free therapies. Umbilical cord blood–derived extracellular vesicles (UCB-EVs) are protein-rich with regenerative potential, but their efficacy in diabetic ED remains unknown. We isolated and characterized UCB-EVs and evaluated them across in vitro, ex vivo, and in vivo platforms: human umbilical vein and mouse cavernous endothelial cells under high glucose; aortic ring, dorsal root ganglion, and major pelvic ganglion explants; and streptozotocin-induced diabetic mice. Erectile function was quantified by intracavernous pressure after intracavernous UCB-EV delivery (5–20 µg). Mechanistic assays included immunofluorescence, terminal deoxynucleotidyl transferase dUTP nick end labeling, phospho-histone H3, reactive oxygen species staining, western blotting, RNA sequencing, and gene set enrichment analysis. UCB-EVs enhanced tube formation, migration, and microvessel sprouting under high glucose and promoted neurofilament-positive neurite extension in dorsal root ganglion and major pelvic ganglion explants. In diabetic mice, UCB-EV treatment improved 90
Inflammatory bowel disease (IBD) is a chronic and currently incurable intestinal disorder, with existing treatments often being limited and burdened by challenges. Mesenchymal stem cell (MSC) therapy has emerged as a highly promising therapeutic strategy, primarily due to its profound immunomodulatory and tissue-reparative capabilities. Autophagy, an essential cellular homeostatic process, is deeply implicated in both the pathogenesis of IBD and the biological functions of MSCs. This review consolidates current knowledge on the critical role of autophagy within MSC-based treatment paradigms for IBD. We examine how MSCs and their derived extracellular vesicles (EVs) alleviate intestinal inflammation, and conversely, how autophagy regulates vital MSC properties such as cellular survival, differentiation potential, and immunomodulatory activity. A deeper understanding of this bidirectional interaction provides innovative insights for enhancing the therapeutic efficacy of MSCs. Ultimately, strategically modulating autophagy in conjunction with MSC therapy represents a meaningful and promising frontier for developing novel and effective treatments against IBD.
Mesenchymal stromal cells (MSCs) are widely investigated as immunomodulatory therapies for inflammatory and immune‑mediated diseases, yet the mechanisms underlying their in vivo efficacy remain poorly defined. Despite their ability to modulate immune cells in vitro, intravenously delivered MSCs are rapidly trapped in the lungs and cleared, with minimal engraftment at target tissues. This disconnect between limited MSC persistence and their broad therapeutic effects represents a longstanding paradox in the field. Evidence suggests that MSC apoptosis, rather than sustained survival, may be central to their activity. Apoptotic MSCs can induce immunosuppression through uptake by host phagocytes, highlighting efferocytosis as a potential mechanistic driver of therapeutic benefit. However, the extent to which MSC apoptosis contributes to the beneficial outcomes observed across preclinical disease models, or to the variable efficacy reported in clinical trials, remains unclear. In this review, we synthesise emerging insights into MSC apoptosis, its immunological consequences and remaining knowledge gaps, and present an updated framework for re‑evaluating mechanistic paradigms in MSC therapy.
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic liver disorder characterized primarily by excessive lipid accumulation in liver cells. It affects nearly a quarter of the global population and significantly impairs quality of life. Recent studies shown that mesenchymal stem/stromal cells (MSCs) have the potential to improve hepatic lipid metabolism, offering a novel therapeutic approach for MASLD. However, the mechanisms by which MSCs ameliorate MASLD remain unclear. Human hepatocellular carcinoma cells and primary hepatocytes from mice were used to establish a cellular model of MASLD by incubating them with oleic acid and palmitic acid. Additionally, a MASLD mouse model was created using a high-fat diet. The effects of human umbilical cord MSCs on hepatocyte lipid metabolism and the underlying mechanisms were evaluated in vitro using Transwell co-culture systems. The therapeutic efficacy of MSCs in MASLD mice was assessed via tail vein injection. MSC-mediated effects on hepatocyte lipid metabolism were analyzed using Oil Red O staining, RT-qPCR, Western blotting, and immunofluorescence. Both MSC co-culture using the Transwell system and supplementation with MSC-conditioned medium effectively ameliorate hepatic lipid droplet accumulation and enhance lipid oxidation in hepatocytes. Additionally, tail vein injection of either MSCs or concentrated MSC-conditioned medium markedly attenuates lipid deposition and hepatic damage in MASLD mice. Mechanistically, MSC-secreted lipoprotein lipase (LPL) was identified as a key regulator of hepatocyte lipid metabolism, promoting lipid oxidation and reducing intrahepatic lipid accumulation through interaction with low-density lipoprotein receptor-related protein 1 (LRP1) on hepatocytes. This study identifies the LPL-LRP1 axis as a novel paracrine mechanism driving MSC-mediated amelioration of MASLD. By establishing LPL-dependent engagement of hepatocyte LRP1 as the central functional mechanism for enhancing lipid oxidation and reducing intrahepatic lipid accumulation, these findings provide a mechanistic foundation for targeted therapeutic strategies in MASLD and related metabolic disorders. Not applicable.
