Encyclopedia
Please note this is a comparison between Version 1 by Giuseppe Sangiorgi and Version 3 by Lindsay Dong.
Vasculogenic erectile dysfunction (ED) due to endothelial dysfunction and atherosclerosis of penile arteries is the most common cause of ED, especially in men over fifty. Cell-based regenerative therapies include platelet-rich plasma (PRP), both heterologous and autologous stem cell therapy (SCT), and peripheral blood mononuclear cells (PBMNC), highlighting the role played by immune cell populations, which may represent the new frontier of vasculogenic erectile dysfunction treatment.
- immune cells
- erectile dysfunction
- cell therapy
1. Introduction
The first-line treatment for vasculogenic erectile dysfunction (ED) consists initially of lifestyle changes, followed by oral phosphodiesterase 5 inhibitors (PDE5is) as first-line medical management [1][2][2,3]. However, about 35% of patients do not respond to oral PDE5i; on the other side, in patients who are responders, the compliance may be poor for the onset of side effects [3][4]. Moreover, in patients affected by diabetes mellitus, vasculogenic ED is more severe and refractory than in non-diabetic patients [4][5]. If PDE5i fails, second- and third-line treatment can be offered, including low-intensity shockwave therapy, intracavernosal injections therapy, vacuum erection devices, and intraurethral or topical application of prostaglandin E1 analogues, such as Alprostadil® (Figure 1).
Figure 1.
Current approaches to the treatment of erectile dysfunction.
However, even with the expansion of available treatments for ED, some patients still cannot achieve adequate performance. Surgical management with penile prosthesis implantation may be offered in patients who do not respond to second-line therapies [1][2]. In this setting, diabetic patients are more than twice as likely to undergo penile prosthesis surgery than non-diabetics [1][2][2,3]. Recently, alternative therapeutic strategies have been explored to treat non-responsive patients with vasculogenic ED effectively.
2. Erectile Dysfunction in Patients Affected by Diabetes
Diabetes mellitus (DM) is one of the major traditional cardiovascular (CV) risk factors promoting vasculogenic ED, together with hypercholesterolemia, hypertension, and cigarette smoking [5][6]. According to multivariate analyses, DM determines the highest risk for ED among all CV risk factors [6][7][7,8]. It has been reported that the prevalence of ED in the diabetic population is about three times greater than that in non-diabetic individuals [8][9]. Among diabetic patients, ED is more common than retinopathy or nephropathy [9][10]. In 12% of type 1 diabetic men, ED was the first symptom of DM [10][11]. Moreover, ED also develops earlier in diabetic patients than in non-diabetic patients. In fact, within ten years of DM onset, more than 50% of patients develop ED [11][12].
The pathogenesis of diabetes erectile dysfunction (DED) is much more complex than in non-diabetic men. In fact, DM accelerates endothelial dysfunction and the atherosclerotic process through several alterations in molecular pathways, resulting in an inability to vasodilate the small penile arterioles.
Decreased endothelial nitric oxide synthesis (eNOS) [12][13][13,14], selective degeneration of NO-dependent nitrergic nerves [14][15], increased advanced glycation end products (AGEs) and increased oxygen free radical content [15][16], decreased NO/cGMP signalling [16][17][17,18], increased endothelin B receptor binding sites [18][19], and an upregulated RhoA/Rho pathway [19][20] are just some of the mechanisms involved in the development of ED in diabetics. In addition to these known molecular pathways, NO mediates many of the antiatherogenic functions of the endothelium in patients with DED by blocking the expression of proinflammatory cytokines, chemokines, and leukocyte adhesion molecules [20][21]. Thus, loss of eNOS biological activity increases inflammation and cell proliferation. Indeed, increased expression of inflammatory markers was observed in these patients.
Moreover, AGEs themselves stimulate the expression of cytokines on monocytes and macrophages, while chronic hyperglycaemia leads to inflammation and contributes to the production of reactive oxygen species (ROS) [21][22][22,23]. In this context, the growing interest in the possible role of drugs that lower blood glucose levels, and thus chronic hyperglycaemia and AGEs, in erectile dysfunction is noteworthy. The recent review by Cignarelli et al. examined the mechanism of action of antidiabetic drugs in the possible remission of ED. Further studies are needed to define the role of these drugs in the treatment of ED [23][24].
3. Stem Cell Therapy and Erectile Dysfunction
Stem cells (SCs) are undifferentiated cells capable of unlimited proliferation, multi-differentiation potency, and perpetual self-renewal. The specific mechanisms underlying the effectiveness of SCs in the treatment of ED are not yet understood. Since pre-clinical studies have shown that few stem cells can be detected after transplantation, and almost no direct evidence supports the theory that transplanted stem cells have differentiated into vascular endothelial cells, smooth muscle cells, or nerves, the main mechanisms of action of stem cell transplantation would seem to be related to their paracrine action [24][30].
Moreover, preclinical research has shown that SCs exert their therapeutic effects on the basis of active factors contained in their secretions that can act as messengers. Indeed, the effect of SCs has been shown to persist after their disappearance, and even cell-free treatments have shown benefits [25][26][31,32]. Bioactive factors may represent a future treatment option for ED due to their pro-angiogenic, anti-inflammatory, anti-apoptotic, and anti-fibrotic properties [25][26][31,32].
Notably, the peripheral blood mononuclear cell (PBMNC) secretome differs only slightly from the stem cell secretome in its ability to promote cell proliferation [27][33]. These active paracrine factors, represented by different types of protein molecules, lipid mediators, microRNAs, and exosomes, underlie the regenerative effects of both stem cells and PBMNCs. The proteins are mainly growth factors, cytokines, and chemokines (e.g., CXCL8, CXCL5, CXCL1, CCL5, and VEGF). Lipids and especially oxidised phospholipids (e.g., PLPC-OOH, PAPC-OOH, SGPC, and PGPC) have also shown pleiotropic biological effects, such as neoangiogenesis, but also inflammation modulation by acting on Toll-like receptors (TLRs) and neutrophil granulocytes. Exosomes that arise intracellularly may contain a mixture of proteins, lipids, messenger RNA (mRNA), and micro RNA (miRNA). Due to the complexity of cellular paracrine activity, other factors also play an active role in this process, but these are the biological factors that have been most extensively studied both in vivo and in vitro [28][34]. Apoptotic PBMNCs have been shown to induce angiogenesis and vasodilation, enhance re-epithelialisation, promote macrophage polarization, and modulate the immune system through their paracrine factors. Since the isolation and cultivation of stem cells is not easy, while the secretome is easier to obtain, the latter could take on a central role in regenerative therapy [28][34] (Figure 23).Figure 23. Immune-centric revolution: vasculogenic repair ED. PBMNCs: peripheral blood mononuclear cells. GFs: growth factors. PBMNCs based on monocytes/macrophages and lymphocytes are a novel autologous cell therapy that has shown efficacy in angiogenesis and tissue regeneration through the action of bioactive substances with paracrine effects represented by different types of protein molecules such as growth factors, chemokines and cytokines, lipid mediators as oxidized phospholipids, microRNAs, and exosomes.
4. Platelet-Rich Plasma Therapy
Although PRP is an emerging treatment option in several fields of medicine, including ED, there are limited studies that support its efficacy. Ding et al. [29][56] studied the PRP effect on regeneration and restoring the cavernous nerve function after its damage in a rat model. Animals were divided into three groups receiving either sham operation, bilateral cavernous nerve (CN) crush injury with immediate injection of PRP at the site of injury, or bilateral CN crush injury with no further intervention. Intracavernous pressure (ICP) was measured to evaluate erectile function. In the PRP group, the ICP was significantly higher than in the non-treated group but lower than in the placebo group (p < 0.05).
Furthermore, in the PRP treatment group compared to the other injured group, they found more CN myelinated axons and more NADPH-diaphorase-positive nerve fibres.
In 2012, Wu et al. [30][57] reported that rats in the experimental group receiving intralesional PRP therapy immediately after the CN damage improved erectile function (p < 0.05) and improved preservation of myelinated axons of the CN significantly (p < 0.05) compared with animals that did not receive PRP therapy. PRP administration significantly reduced the level of apoptotic markers, as a reduction in TGF-b1 staining. The absence of the type III collagen and the prevalence of the type I collagen was observed in the histologic study of penile tissue from the treated group. Wu Thet al. authors believe that PRP accelerated the nerve repair processes through its neuro-regenerative and neuroprotective effects, and it also inhibited the fibrosis process in the corpora cavernosa. The limit of the study was the small sample of rats; this did not allow peopleus to consider the use of PRP therapy as an effective treatment method, despite the positive results.
In conclusion, although it seems to be a promising therapy, more extensive studies are needed to understand PRP’s mechanism of action better before PRP therapy enters clinical practice.
