Effects of stem cell–derived exosome therapy on erectile dysfunction: a systematic review and meta-analysis of preclinical studies

Abstract

Introduction Erectile dysfunction (ED) is a common disease among elderly men, and novel therapy methods are needed for drug-refractory ED. As an extracellular vesicle, stem cell–derived exosomes displayed erectile function improvement in rat ED models in some preclinical studies. However, the therapeutic efficacy has not been comprehensively evaluated. Aim To study the therapeutic effects of stem cell–derived exosomes on ED in preclinical studies and to investigate the potential mechanisms responsible for the efficacy. Methods The systematic literature search was conducted in Web of Science, PubMed, and Embase to retrieve studies utilizing stem cell–derived exosomes for ED treatment. We extracted data of intracavernous pressure/mean artery pressure (ICP/MAP), and cavernosum structural changes in rat ED models before and after stem cell-derived exosome therapy. RevMan 5.3 was used to perform meta-analyses of ICP/MAP and cavernosum microstructural changes. Publication bias was assessed with the Egger test and funnel plot by Stata 15.0 (StataCorp). Main Outcome Measures Outcomes included ICP/MAP, smooth muscle, and endothelial markers—such as the ratio of smooth muscle to collagen and the expression of α-SMA (alpha smooth muscle actin), CD31 (cluster of differentiation 31), nNOS and eNOS (neuronal and endothelial nitric oxide synthase), TGF-β1 (transforming growth factor β1), and caspase 3 protein-to evaluate erectile function and microstructural changes. Forest plots of effect sizes were performed. Results Of 146 studies retrieved, 11 studies were eligible. Pooled analysis showed that stem cell–derived exosomes ameliorated damaged ICP/MAP (standardized mean difference, 3.68; 95% CI, 2.64-4.72; P < .001) and structural changes, including the ratio of smooth muscle to collagen and the expression of α-SMA, CD31, nNOS, eNOS, TGF-β1, and caspase 3 protein. Subgroup analysis indicated that exosome type and ED model type made no difference to curative effects. Conclusion This meta-analysis suggests the therapeutic efficacy of stem cell–derived exosomes for ED. Exosomes may restore erectile function by optimizing cavernosum microstructures.

Bibliometric and Visualization Analysis of Stem Cell Therapy for Erectile Dysfunction

“…In addition, the advancement of research on exosomes in recent years uncovered that stem cell-secreted exosomes also play a fundamental role in penile tissue repair. 60 Compared with the injection of stem cells, exosomes have many benefits, such as higher stability, no risk of tumorigenesis, and lower immunogenicity. 61 Exosomes secreted by stem cells seem to be a promising novel direction for the research of ED.…”

Erectile Dysfunction: Treatments, Advances and New Therapeutic Strategies

“…The majority of studies that have used these regenerative treatments for ED have been made with stem cells of different type (e.g., mesenchymal stem cells, placental-matrixderived stem cells, mesenchymal-stem-cell-derived exosomes, adipose-derived stem cells, bone-marrow-derived mononuclear stem cells, umbilical cord tissue or blood stem cells, and urine derived stem cells) ( [202][203][204][205][206][207][208][209][210][211][212][213] and references therein). In these studies, different animals, mainly rat models of ED, have been used.…”

“…The more recent studies describe combinatory treatment approaches, with stem cells having been modified or supplemented with angiogenic and/or neurotrophic genes and proteins, such as those present in platelet-enriched plasma itself, depending on the animal model used or bioengineered with particular substances (i.e., hydrogels), with the aim to facilitate stem cell adherence in the damaged penile tissues and improve their therapeutic efficacy [207,214,215]. In these studies a positive synergic effect between stem cells and the modification added to them, usually confirming a good efficacy on ED and a safety profile [203][204][205][206][207]213]. However, due to the complications added to the stem cells preparation by the procedures required for modifying stem cells, it has yet to be determined if these modifications really increase the success of this already complex ED therapy when compared to the use of stem cells alone.…”

“…In fact, in spite of a large amount of experimental work in animal, mainly rat models, of ED (from aged and diabetic rats to radical prostatectomy rat models) with the intracavernous injection of stem cells obtained from numerous tissues, these studies have only shown that stem cells improve ED by acting with a paracrine mechanism (e.g., by releasing humoral agents that allow damaged tissue components to recover, at least in part, their physiological function) rather than after being transplanted and differentiated in penile tissues. Not much better results have been obtained with stem cells modified or supplemented with angiogenic and/or neurotrophic genes, proteins such as those present in platelet-enriched plasma and with the intracavernous injection of platelet-enriched plasma itself, or stem cells bioengineered with particular substances (i.e., hydrogels), aimed to facilitate stem cell adherence and implant in damaged penile tissues to improve their therapeutic efficacy [206,213,214207,214,215). So far, data from only about one hundred patients who underwent stem cell therapy are available.…”

Current Advances in Corneal Stromal Stem Cell Biology and Therapeutic Applications

“…Additionally, exosome therapy offers a new, non-invasive means of modulating corneal cell behavior, potentially revolutionizing treatment strategies [27]. Exosome-based approaches have already proven popular with various stem cell-related diseases and conditions, from myocardial infarctions to Alzheimer's [28][29][30][31][32]. The use of autologous stem cells and stem cell stimulation techniques has the potential to alleviate donor cornea scarcity but can also improve transplant procedures by targeting relevant stem cell behavior, such as immunomodulation, differentiation, or anti-vascularization.…”