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The use of stem cell therapies for erectile dysfunction (ED) and Peyronie’s disease (PD) in clinical practice and research studies has been increasing with favorable preliminary findings. The availability of various cell sources and differentiation protocols makes stem cell therapy a promising treatment option for ED and PD.
In this focused review, we first overview the properties and application types of stem cells and the appropriate donor selection for this therapeutic approach. The information related to adipose tissue, bone marrow, placental tissue, mesenchymal stem cells, exosomes, and other stem cell subtypes used in erectile tissue was summarized in the literature search. Lastly, we discuss the use of stem cell therapies in the clinical setting and detail the many challenges involved in using these therapies for ED and PD.
Stem cells, through conditions that activate complex differentiation pathways and produce these specific regulatory mediators, inhibit the development of damage and can also govern and regulate cell conversion, immune responses, and inflammatory phenomena.
Many publications describe various sources for mesenchymal stem cell (MSC), but great criteria for progenitors that promote regeneration processes are the source, the differentiation is the “using” tissue for transplantation, and so the driver. MSC can be isolated from many fetal, infant, perinatal, and adult organs and tissues with a self-renewal and multi-lineage differentiation ability, such as bone marrow (BM), umbilical cord blood (UC), umbilical cord, adipose, endometrial, dental pulp, peripheral blood, and so on.
From the numerous MSC populations that are currently available, those from adult bone marrow stroma, and more recently, those from fatty tissue (adipose-derived stem cells, ADSC), endometrium (E-MSC), and umbilical cord appear to be the most promising cell types for regenerative medicine.
Stem cell-based therapies represent a promising approach in regenerative medicine, offering targeted treatment strategies for a variety of human health maladies. Stem cells possess two principal characteristics that make them unique among all the stem cells in the body: they can both regenerate themselves and differentiate into a variety of specialized cells.
The main advantage of stem cell therapy is that it is able to accelerate or jump-start the healing process, renew tissue that is damaged, and repair that tissue. Moreover, the immune response that may be associated with the transfer of a heterogeneous mixture of cells is always milder than that associated with allogeneic transplantation of cellular transplants.
The most promising source of MSC for pro-regenerative therapy is hemangioblast. This, selected by testing for CD34 marker, could be able to differentiate in vivo after the transplantation in any stromal line investing also angio- or vasculogenesis programs. These multipotent, tissue-derived MSC can be easily cultured, manipulated, and reintroduced into the same donor autologously, thus overcoming many of the potential obstacles to the successful application of regenerative medicine.
Although many preclinical studies confirmed the viability and functions of stem cells in different pro regenerative procedures and in some clinical trials, the role of tissue-resident stem cells in physiological repair remains largely unknown. The mechanisms responsible for the signals that recruit tissue-resident stem cells to participate in tissue repair are equally poorly understood.
Stem cells are considered the next-generation treatment for impotence, with higher demand among patients. Through these techniques, autologous stem cells can be used in both Peyronie’s disease and vasculogenic erectile dysfunction.
After the decline of the first enthusiasm for fibroblast injections in Peyronie’s plaque and conformal radiation therapy, penile revascularization using the patient’s autologous platelets and leukocyte-enriched plasma is proposed as a treatment guaranteeing better patient selection.
Erectile dysfunction diagnosis should not exclude stem cell usage, since several preclinical animal studies are positive in cavernous tissue remodeling. Complete informed consent in patients should always underline that the method is still experimental and not without criticisms, applied when standard guidelines are exhausted.
Erectile Dysfunction and Peyronie’s Disease treatment represents a goal for several andrological urologists. The prolonged sexual activity, proposed by both andrology guidelines and popular magazines for the prevention of aging, has increased the demand for these combined preventive-reconstructive treatments. Increasing demand for reconstructive surgery in patients with low customs, due to continuous information on civil and criminal complaints, and a classic low tolerance for side effects – so-called “andromedical mentality” – have increased the demand for conservative procedures suitable for patients without anatomical or functional limits.
This is the reason for the continuous and growing interest in the use of autologous stem cells as regenerative therapy in urology. Several preclinical animal studies are offering great hope for regenerative therapy in impotence for the removal of problem-affected tissues, with reconnecting tissue in its original anatomical site, or be replaced by an artificial tissue-like micronetwork of nanofiber material. Cavernous tissue remodeling in the case of full anatomical absence of corpora cavernosa.
Erectile dysfunction (ED) is a growing medical disorder in males. It affects sexual intercourse and has a significant socioeconomic and psychological effect. In recent years, many experimental therapies and surgical means, such as localized hormone therapy, phosphodiesterase V (PDE5) inhibitors, endothelial growth factors, and hormone replacement therapy, have been employed to treat ED.
However, there are frequent or serious side effects, and the effectiveness and safety remain doubtful. On the other hand, stem cell therapy has become a remarkable breakthrough in regenerative medicine for repairing injured tissues such as the heart, cartilage, bone, and nerve. Studies have shown the potency of stem cells on erectile function, even in large animal models.
Most stem cell sources for treating ED are mesenchymal stem cells (MSCs). Recently, scientists have known that the efficacy of MSCs for treating ED is based on paracrine secretion of angiogenic and neurotrophic factors into the injured tissue, or direct differentiation into cured tissues.
To our knowledge, the treatments using stem cells to cure ED that have been studied include stem cell transplantation, stem cell stemness, and cell-free stem cell-derived therapeutic molecular agents. Stem cell transplantation is the most common method for treating ED. Homing of stem cells into injured or damaged tissues and releasing autocrine cytokines, paracrine signaling, and secretomes are beneficial in repairing.
Stem cell stemness and the lack of differentiation for kidney stem cells can also repair erectile function to cure ED in the prostatectomized rat. Cell-free stem cell-derived therapeutic molecular agents have curative effects on injured tissues that support relaxed vascular smooth muscles, such as PDE5i and sildenafil. The experimental models of ED included diabetes mellitus (DM) and postprostatectomy (PP).
The therapeutic effects of stem cell therapy for treating the normal and injured ED model have been studied for animal and clinical trials. Although morbidities, treatments, and therapies are different between males and females, we have reviewed most studies that have good application of male and female animal therapies.
The main attraction of using stem cells to treat sexual dysfunction and cosmetic procedures of the penis is that the cells are already in the patient’s body. This means that the stem cells used are the patient’s own and the patient’s body will not reject the cells when used in treatment.
Remarkably, most patients continue on anti-rejection medication and because of the procedure of using the patient’s own stem cells into the patient himself, there are no known negative side effects from the treatment. This treatment doesn’t have the complications related to plastic surgery procedures, is done in one day, and the results can last for many years.
With very few medical, surgical, or drug options, stem cell injections increase the potential of the patient’s sexual capabilities. No prior specialized preparation or specialized problems is necessary. Unlike other things, the male does not have to worry about a missed dose or missed procedure because one lump sum of cells was taken before the procedure.
Although there are thousands of stem cell populations in the body, they can be mainly divided into embryonic, which exist only in the earliest stages of life and are used to give rise to the body, and postnatal or adult stem cells, which have other more specific functions in each group of organs or tissues.
Postnatal mesenchymal stem cells, such as those that have different types of mesenchymal stem cells, which are those most generally used in the treatments for ED. These cells possess the main capacity to renew by making new cell actions with which they can specifically regenerate diseased tissue.
Stem cell therapy can be performed on an outpatient basis with local anesthesia or mild sedation administered as deemed necessary by the treating physician. After a caregiver collects stem cells from bone marrow and fat that have been harvested from both ‘love handles’ or ‘abdomen’, penile shaft injections are performed in the office under local anesthesia by the physician. Immediately following the cell preparation, a simple penile injection is administered.
With the help of a small insulin needle, pain is minimal since adipose-derived cells are harvested and concentrated without exposure to heat, centrifugation, or other conditions that may damage the cells. This is combined with non-activated PRP, which is capable of initiating the regeneration of new tissue while providing a positive inflammatory response.
This typically takes from 15 to 20 minutes. Patients can immediately return to routine activities including work and sexual relations. There is typically no significant recovery period and very minimal post-procedure pain, if any. Mild bruising, which disappears within a week, at the extraction sites is the primary side effect due to the use of local anesthesia.
The immunosuppressive properties of fat-derived MSCs have been demonstrated in a number of studies. These properties of fat-derived MSCs are linked to increased heterogeneity in this cell population, as well as the fact that SVF contains various cell types with macrophage-related characteristics, including regulatory T cells and M2 macrophages, which probably play a synergistic role in the therapeutic effects.
Peyronie’s disease is a disorder of the tunica albuginea (TA) involving collagen deposition and transformation of fibroblastic cells. It ultimately leads to abnormal, ventrally or laterally bent erections, as a consequence of fibrotic plaques within the TA. Other erectile abnormalities associated with PD include indentation, hourglass deformities, and shortening, which are associated with flaccid or partial erections. The most characteristic feature of Peyronie’s disease is the presence of Peyronie’s plaques, which manifest as penile deformities in 95% of patients.
Penile traction, vacuum erection devices, various mechanical stretching treatments, and drugs such as collagenase, corticosteroids, and Verapamil are used in the early stages to reduce associated symptoms. Meanwhile, methodic follow-up is recommended for patients in the acute phase or those with relatively low severity degrees. Surgery serves as the last stage of the treatment process to reduce or remove fibrotic plaques, placing a graft, or prosthetic implantation where necessary. In contradistinction to any other options used by patients, stem cell therapies aim at reconstructing TA tissue disrupted by the build-up and resolving repaired tissue strength.
In case of advantageous mesenchymal stem cells being non-recruited to the site of interest, several pathological conditions occur; conversely, one of the regenerative therapy approaches is the focal, intracorporal pertinently directed delivery of mesenchymal stem cells. Consequently, an attempt was made to administer stem cells in combination with other materials for better specific localization of applied cell populations.
With a little coculture, activating and enhancing microenvironments without a necessity to isolate stem cells will be possible. To optimize a mesenchymal stem cell medical product without using genetic manipulation, given the recognition of relevant factors in each corresponding clinical trial, validated stem cell activity maintenance at the site of action is highly preferable. Treatment of Peyronie’s disease with stem cells is well-grounded and is supported quite well by robust preclinical evidence.
Moreover, the efficiency of using stem cells in combination with heterologous materials in different animal experimental models was clearly demonstrated. It is the combination of stem cells with a matrix that helps to avoid uncontrolled, scattered cell expansion, migration, or differentiation that should be of particular attention. Furthermore, it contributes to the substantial stem cell maintenance at the site of action.
The mentioned studies are quite straightforward, and their purpose was to implant experimental sites with a cell-matrix system. Researchers assume that since Duramatrix is washed out by body fluids, the material serves as a timely scaffold. The stem cell sizes are of the same order as prolyl-4-hydroxylase polymers, which are formed with a typical tissue turnover dynamics. Due to Duramatrix structural enzyme digestion, that would lead to improved interaction between mesenchymal stem cells and TA near the Peyronie plaque.
Applying stem cell therapy in urological applications has just recently started, and in some instances, yielded promising results. Stem cells are reported to regenerate smooth muscle cells, endothelial cells, and nerve cells in the corpus cavernosum, making them a good choice for erectile dysfunction treatment. There is much attention on the use of stem cells, also known as multipotent mesenchymal stromal cells, obtained from adult tissue, such as bone marrow, fat, and blood, for cell replacement and regenerative therapy.
Stem cells can be preemptively isolated from the patient and then expanded in the laboratory before being injected. These adult stem cells are a newer type of treatment since they are derived from non-embryonic tissue. Although they are found in some tissues more than others, each adult type is multipotent and can differentiate to produce a myriad of specialized cell types.
Furthermore, hematopoietic stem cells derived from peripheral blood or bone marrow, mesenchymal stromal cells derived from bone marrow or adipose tissue, and endothelial progenitor cells obtained from peripheral blood or umbilical cord blood have been widely studied and applied for treatment of ED, diabetes mellitus, and other diseases, as well as tissue recovery or repair in various organs.
Obviously, stem cell treatments for erectile dysfunction are still in their early days. Although several leading doctors and researchers have been working on it, a consensus on how to administer stem cell treatment for erectile dysfunction will naturally take some time to form.
For patients currently seeking stem cell treatment, the dose of stem cells that most doctors use is 1-5 million mesenchymal stem cells per kilogram of body weight. If adipose-derived autologous stem cells are being used, expect something closer to the lower end of that range. The route of administration will depend on the stem cells you use. For bone marrow-derived autologous stem cells, injection into the corpus cavernosum appears to be the most popular method.
For bio-active amniotic-derived stem cells (which are available in larger numbers), intravenous administration is possible, as is the catheter method preferred by doctors who specialize in placental tissue. If you are not getting placental tissue, it is generally better to have more stem cells and to deliver them directly, so you do not have to worry about them reaching your penis in high enough numbers. All methods that work will sooner or later find competition and compatibility.
Different people will have different preferences. Unfortunately, this is an area in which common sense and a lot of imagination might as well be the final guide. There currently don’t appear to be conclusive studies proving which stem cell sources, processing techniques, or dosage levels work best.
In contrast to current engorged models, regenerative models seek to use stem cells to return the damaged tissue to its original state as much as possible, rather than simply relying on the original tissue of the patient to support the virility under the support of stem cell-derived new tissue.
Restore erectile function by repairing various pathologically damaged tissues through the action of stem cells. It will be of great significance and higher value to distinguish the disease stages that the ED and PD can accept for optimal efficacy and better carry out research. Both ED and PD are mainly divided into acute phase and chronic phase, regardless of whether it is used for ED or PD.
Using the autologous adipose stem cell or muscle stem cell should be in the chronic disease stage. The general proliferation and fusion capacity of stem cells isolated from chronic disease tissues is higher than that of acute tissue-derived stem cells, and the choice of treatment time is the most important in the regeneration treatment of maximal histologic appearance of normal or nonacute tissues.
In particular, tumor growth factors are best for use in chronic diseases. In ED treatment, tumor growth factor-derived products are useful for cell survival and tissue regeneration. Despite the fact that tumor growth factors have antiapoptotic and antiapoptotic effects, the net effect of tumor growth factors on survival is still in balance. Therefore, we surmised—especially for PD—the use of inhibitor of apoptosis protein in combination with tumor growth factor or HEALOS or hyaluronic acid would promote increased quantities of cells.
In general, transplantation should be considered only if the corresponding external factors are added, and both lack of the factor and overexpression of the factor would affect the repair. Whatever treatment plan you choose, do not use hormones or other prostaglandins that form because they are not the most direct treatment for the transplanted cells to achieve better results.
The most common efficacy assessment was the application of the IIEF questionnaire. After the administration of stem cells, a significant improvement in EF domain scores was demonstrated in most clinical trials. Only a few clinical trials found no statistically significant difference in the IIEF scores before and after erectile dysfunction treatment.
Apart from the IIEF, the visual analog scale (VAS), international index of erectile function, and nocturnal penile tumescence tests were applied. They showed very good treatment outcomes in 58% to 100% of the cases. One particular study was based on the injection of stem cells into the corpus cavernosum.
When the results for erectile function based on the IIEF-5 at pre- and post-treatment were compared, the average values increased by 4 points, and statistical significance was observed. Another group of patients received stem cells in combination with low-intensity shockwave therapy, and the improvement in IIEF-5 at post-intervention was 3 points.
In the case of Peyronie’s disease, the most common IIEF-EF domain scores showed higher efficiency in the treatment of Peyronie’s disease using stem cells in comparison with the placebo injection. Apart from the IIEF, angle deviation, plaque size, and pain improvement were evaluated using patient’s questionnaires. Embryonic mesenchymal stem cells in combination with hyaluronic acid were also found to be effective in patients with Peyronie’s disease.
There are cases that report no improvement in the pain, curvature, length, and girth of the penis and plaque volume while receiving stem cells. The volume limit of the plaque was the criteria for their inclusion in the trial, and ADSCT was performed. The most frequently reported source of stem cells for erectile dysfunction treatment was bone marrow aspirate concentrate.
The second choice was bone marrow mononuclear cells. Olmi et al. preferred adipose-derived SVFs as the third choice. Most of these treatments were delivered intracavernously. If there is intracavernous therapy, all procedures consist of two stem cell doses, and bone marrow-mononucleated cells are used in many cases. For patients assigned under penile implants, body weight and the number of utilized stem cells accounted.
It seems that stem cell therapy has been shown to be very effective in treating ED as well as Peyronie’s disease using a multi-modal mechanism of action. In animal studies and absence of adjuvant compounds that interfere, we were able to demonstrate extracellularly secreted factors in amniotic epithelial stem cells recovered by a commercially available way.
It was proven to be anti-apoptotic, anti-inflammatory, and regenerative. Partial discovery of its individual components has been made, providing yet more interest. One of the reasons the stem cell treatment for other conditions has been very effective is because it provides the essential stimuli for regeneration and repair of body organs. Furthermore, scientists have discovered over 800 proteins, peptides, lipids, steroid receptors, etc., which together can provide cell replacement, stimulation, anti-inflammatory, and immunomodulatory benefits.
In the flaccid state, the α2A-adrenergic receptors and cavernosal sympathetic innervations are responsible for the contraction of the cavernosal smooth muscles and associated veno-occlusive mechanism. In the presence of AADC, dopamine can be produced and released by the murine amniotic fluid stem cells (cAFSC).
Dopamine is an inhibitor of norepinephrine release from nerve fibers by activating the presynaptic D2 receptor and postsynaptically at allelic D2 receptors, inhibiting depolarization and resultant muscle contraction, thus maintaining sexual activity. In mice, the neurons that innervate the corporal tissue reside in the major pelvic ganglia (MPG). If the specific 6-hydroxydopamine is neurotoxic, neurodegeneration occurs in the MPG dopamine production, and sexual function are reduced. However, following the transplantation of cAFSC into the MPG, both parameters can be enhanced by the increasing recruitment, retention, and trpc1+-mature dopaminergic neurons.
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