Comparative study of different transplantation methods of adipose tissue-derived stem cells in the treatment of erectile dysfunction caused by cavernous nerve injury

We aimed to compare intracavernosal injection (ICI), tail vein injection (IV), and periprostatic injection (PPI) of adipose-derived stem cells (ADSCs) for their ability to improve erectile function in cavernous nerve injury-induced erectile dysfunction (CNIED) rats and to explore the possible mechanism. Eighty-four male SD rats were divided into the sham group (n = 6), BCNI group (bilateral CN crush injury, n = 6), PBS-ICI group (n = 6), PBS-IV group (n = 6), PBS-PPI group (n = 6), ADSC-ICI group (n = 18), ADSC-IV group (n = 18) and ADSC-PPI group (n = 18). ADSCs were labelled with 5-ethynyl-2′-deoxyuridine (EdU), and six rats each in the ADSC-ICI group, ADSC-IV group, and ADSC-PPI group were sacrificed 2, 7, and 28 days after injection. EdU-labelled ADSCs were tracked by immunofluorescence staining. The intracavernosal pressure (ICP)/mean arterial pressure (MAP) ratio, neuronal nitric oxide synthase (nNOS)-positive nerve fibres in the dorsal penile nerve and the smooth muscle/collagen ratio in the cavernosum between groups were also evaluated. ADSCs can significantly improve erectile function through ICI or IV. The two are similar in efficacy and superior to PPI. The mechanism may be that after CN injury, ADSCs are recruited to around the MPG and secrete a variety of neurotrophic factors that promote the repair of the CN, thereby improving erectile function.     

Recent advances in andrology-related stem cell research

Stem cells hold great promise for regenerative medicine because of their ability to self-renew and to differentiate into various cell types. Although embryonic stem cells （BSC） have greater differentiation potential than adult stem cells, the former is lagging in reaching clinical applications because of ethical concerns and governmental restrictions. Bone marrow stem cells （BMSC） are the best-studied adult stem cells （ASC） and have the potential to treat a wide variety of diseases, including erectile dysfunction （ED） and male infertility. More recently discovered adipose tissuederived stem cells （ADSC） are virtually identical to bone marrow stem cells in differentiation and therapeutic potential, but are easier and safer to obtain, can be harvested in larger quantities, and have the associated benefit of reducing obesity. Therefore, ADSC appear to be a better choice for future clinical applications. We have previously shown that ESC could restore the erectile function of neurogenic ED in rats, and we now have evidence that ADSC could do so as well. We are also investigating whether ADSC can differentiate into Leydig, Sertoli and male germ cells. The eventual goal is to use ADSC to treat male infertility and testosterone deficiency. （Asian JAndrol 2008 Mar; 10： 171-175）     

干细胞治疗阴茎勃起功能障碍的研究进展

阴茎勃起功能障碍(ED)是指男性反复或者持续性的难以达到和维持充分的阴茎勃起,无法完成性交或满意性活动的病理现象。海绵体神经(CN)损伤引起的勃起神经反射中断,是患者出现ED的直接原因,此外,CN损伤后,阴茎海绵体组织平滑肌细胞和内皮细胞凋亡增加,海绵体平滑肌纤维数量减少加重了ED的发生。因此,尽早干预CN损伤的病理过程,促进CN再生是治疗CN损伤性ED的关键。近年来,干细胞在ED治疗中的应用日益成为临床研究热点。现对胚胎干细胞(ESC)、间充质干细胞(MSCs)、肌源性干细胞(MDSCs)、脂肪干细胞(ADSCs)在ED治疗中的研究综述如下。     

大鼠脂肪干细胞体外诱导为神经元样细胞的研究

目的 建立将大鼠脂肪干细胞体外诱导分化为神经元样细胞的方法.方法 取SD大鼠腹股沟处的皮下脂肪,分离出脂肪干细胞并培养传代.使用诱导剂IBMX诱导ADSCs向神经元样细胞分化,检测神经前体细胞标志Nestin和神经元标志NF200、MAP2,以明确分化结果,而且榆测Nestin在诱导过程中的表达阳性率的变化情况,采用SPSS11.0软件进行统计学分析.结果 从大鼠脂肪组织中分离出脂肪干细胞,经诱导剂IBMX诱导后,ADSCs表现出神经无样细胞形态,大部分细胞表达nestin,少部分细胞表达MAP2和NF200,随着诱导的进行,nestin的表达是升高的.结论 成功地建立了一种将大鼠脂肪干细胞体外诱导分化为神经元样细胞的方法,ADSCs有希望成为治疗神经性勃起功能障碍的、理想的组织工程种子细胞.     

己酮可可碱治疗勃起功能障碍的临床研究

目的　为探讨己酮可可碱治疗勃起功能障碍 (ED)的有效性。方法　以勃起功能国际问卷 (IIEF 5 )的量表作为指标 ,对 30例ED患者进行了临床观察。结果　服用己酮可可碱后阴茎勃起功能明显改善 ,有效率为6 3.33%。结论　己酮可可碱可以用于ED的临床治疗     

Endovascular treatment of vasculogenic erectile dysfunction

The treatment of erectile dysfunction (ED) has been a fascination involving multiple medical specialities over the past century with urologic, cardiac and surgical experts all contributing knowledge toward this multifactorial disease. With the well-described association between ED and cardiovascular disease, angiography has been utilized to identify vasculogenic impotence. Given the success of endovascular drug-eluting stent (DES) placement for the treatment of coronary artery disease, there has been interest in using this same technology for the treatment of vasculogenic ED. For men with inflow stenosis, DES placement to bypass arterial lesions has recently been reported with a high technical success rate. Comparatively, endovascular embolization as an approach to correct veno-occlusive dysfunction has produced astonishing procedural success rates as well. However, after a thorough literature review, arterial intervention is only recommended for younger patients with isolated vascular injuries, typically from previous traumatic experiences. Short-term functional outcomes are less than optimal with long-term results yet to be determined. In conclusion, the hope for a minimally invasive approach to ED persists but additional investigation is required prior to universal endorsement.     

Prevalence of erectile dysfunction in Thailand

A study of the prevalence rate of erectile dysfunction (ED) in the Thai population has never been done previously, except for a small study in the hospital. The project was carried out across the whole country, including in the north, south, eastern and central plains, and there were representatives from one small and one large province and the Bangkok metropolitan area. There were 250 males in each area, giving as total of 1250 males. The interviews were carried out in urban areas, so that the questions and answers could produce good data. The interviewer was trained by one of our EDACTT members, before going to the interview locations, and the supervisor were also onsite to clarify any the questions that might occur. The questions and pretest were carried out stringently, to help in term of statistics.
All the health questions were asked taking care to accommodate the interviewee's feelings, so as not to cause embarrassment. The interviews were held individually and strictly privately, so that the interviewees could speak freely The interviewees were between 40 and 70-years old, to match with MMAS. The rate of ED in this age group is increasing gradually, and the relationship between ED and hypertension, diabetics or heart disease, and lifestyle factors, including smoking habits, alcohol consumption, caffeine and risk factors is of interest.¹     

多剂量伐地那非治疗男性勃起功能障碍的临床研究

目的评估不同剂量新型磷酸二酯酶5（PED5）抑制剂伐地那非治疗男性勃起功能障碍（ED）的有效性和安全性。方法采用随机、双盲、安慰剂平行对照、3个药物剂量（5、10和20mg）的方法，对88例ED患者进行为期12周的临床研究。结果伐地那非5mg、10mg和20mg组均能改善患者国际勃起功能指数（IIEF）中勃起功能部分的得分、患者日记中插入和保持勃起的成功率，改善程度优于安慰剂组。伐地那非20mg组对IIEF问卷中勃起功能部分得分的改善优于伐地那非5mg组。伐地那非组不良事件的发生率高于安慰剂组，但多为轻中度，且可自行缓解。结论伐地那非是治疗男性勃起功能障碍的安全、有效药物。     

Pathophysiology and treatment of diabetic erectile dysfunction

The pathophysiology of diabetes is multifactorial and no single etiology is at the forefront.The proposed mecha-nisms of erectile dysfunction(ED)in diabetic patients includes elevated advanced glycation end-products(AGEs)andincreased levels of oxygen free radicals,impaired nitric oxide(NO)synthesis,increased endothelin B receptor bindingsites and ultrastructural changes,upregulated RhoA/Rho-kinase pathway,NO-dependent selective nitrergic nervedegeneration and impaired cyclic guanosine monophosphate(cGMP)-dependent kinase-1(PKG-1).The treatment ofdiabetic ED is multimodal.Treatment of the underlying hyperglycemia and comorbidities is of utmost importance toprevent or halt the progression of the disease.The peripherally acting oral phosphodiesterase type 5(PDE5)inhibitorsare the mainstay of oral medical treatment of ED in diabetics.Vacuum erection devices are an additional treatment asa non-invasive treatment option.Local administration of vasoactive medication via urethral suppository or intracorporalinjection can be effective with minimal side-effects.Patients with irreversible damage of the erectile mechanism arecandidates for penile implantation.Future strategies in the evolution of the treatment of ED are aimed at correcting ortreating the underlying mechanisms of ED.With an appropriate vector,researchers have been able to transfectdiabetic animals with agents such as neurotrophic factors and nitric oxide synthase(NOS).Further studies in genetherapy are needed to fully ascertain its safety and utility in humans.(Asian J Androl 2006 Nov;8:675-684)     

Surgical niche for the treatment of erectile dysfunction

Penile erection implicates arterial inflow, sinusoidal relaxation and corporoveno-occlusive function. By far the most widely recognized vascular etiologies responsible for organic erectile dysfunction can be divided into arterial insufficiency, corporoveno-occlusive dysfunction or mixed type, with corporoveno-occlusive dysfunction representing the most common finding. In arteriogenic erectile dysfunction, corpora cavernosa show lower oxygen tension, leading to a diminished volume of cavernosal smooth muscle and consequential corporoveno-occlusive dysfunction. Current studies support the contention that corporoveno-occlusive dysfunction is an effect rather than the cause of erectile dysfunction. Surgical interventions have consisted primarily of penile revascularization surgery for arterial insufficiency and penile venous surgery for corporoveno-occlusive dysfunction, whatever the mechanism. However, the surgical effectiveness remained debatable and unproven, mostly owing to the lack of consistent hemodynamic assessment, standardized select patient and validated outcome measures, as well as various surgical procedures. Penile vascular surgery has been disclaimed to be the treatment of choice based on the currently available guidelines. However, reports on penile revascularization surgery support its utility in treating arterial insufficiency in otherwise healthy patients aged <55 years with erectile dysfunction of late attributable to arterial occlusive disease. Furthermore, it is noteworthy that penile venous surgery might be beneficial for selected patients with corporoveno-occlusive dysfunction, especially with a better understanding of the innovated venous anatomy of the penis. Penile vascular surgery might remain a viable alternative for the treatment of erectile dysfunction, and could have found its niche in the possibility of obtaining spontaneous, unaided and natural erection.     

Transplantation KCNMA1 modified bone marrow‐mesenchymal stem cell therapy for diabetes mellitus‐induced erectile dysfunction

This study assessed the effect of KCNMA1 transfected bone marrow‐mesenchymal stem cells (BM‐MSCs) on the improvement of erectile function in diabetic rats. Sixty male Sprague–Dawley rats were injected with streptozotocin (STZ) and screened with apomorphine (APO) to establish diabetes mellitus‐induced erectile dysfunction (DMED). DMED rats were randomly divided into four groups: rats in each group underwent intracavernous injection with either phosphate buffer solution (DMED+PBS), nontransfected MSCs (DMED+MSCs), empty vector transfected MSCs (DMED+null‐MSCs) or KCNMA1 transfected MSCs (DMED+KCNMA1‐MSCs). Before injection, high levels of KCNMA1 expression were confirmed in KCNMA1‐MSCs using RT‐PCR and Western blotting. The lentivirus transfected MSCs maintained their potential for multidirectional differentiation. Four weeks after injection, erectile function was ascertained by measuring intracavernous pressure (ICP). Penile tissues were collected for immunohistochemical analysis. The expression of KCNMA1 in the corpus cavernosum was increased, and the DMED+KCNMA1‐MSCs group displayed a significant improvement of erectile function. We concluded that KCNMA1 was able to enhance the positive effect of MSCs in the treatment of diabetes‐associated erectile dysfunction.     

直肠癌治疗术后勃起功能障碍的发病机制

直肠癌是常见的消化道恶性肿瘤之一,近年来发病率逐年上升。目前治疗方法包括手术治疗、放化疗以及多种方式联合的综合治疗。性功能障碍尤其是勃起功能障碍(ED)是男性直肠癌治疗术后最常见的并发症之一,严重降低了患者术后的生活质量,既往公认其主要原因是损伤了盆腔自主神经。近年的研究发现其发病机制不仅如此,而是一个复杂的病理生理过程,包括神经、血管、心理因素等。现就直肠癌治疗术后ED的发病机制作一综述,为临床上预防和治疗术后ED提供理论依据,从而降低其发生率,提高患者的生活质量。     

经尿道注入前列地尔治疗勃起功能障碍的研究

为评价经尿道使用前列地尔（PGE1）对ED的治疗作用。作者对40例年龄29－65岁的ED患者，在门诊选用4种剂量的前列地尔进行测试（125、250、500、1000μg），对前列地尔有充分反应者被指定接受有效剂量的前列地尔，在家治疗1个月。结果40例中32例在家使用前列地尔治疗时，至少有1次成功的性交。平均反应时间在7－9min，恢复到完全无勃起状态在50－72min。最常见的副反应是阴茎有轻微的疼痛，但没有人因此而退出研究。没有阴茎异常勃起和阴茎纤维化发生。作者认为尿道使用前列地尔能使大部分ED病人产生阴茎勃起，而且能进行性交。     

Psychosomatic aspects in the diagnosis and treatment of erectile dysfunction

After a critical review of prevalence data, psychosocial determinants and psychosomatic aspects in the diagnosis and treatment of erectile dysfunction are discussed (with reference to age-related changes). Widely used laboratory assessments are responsive to psychological factors (e.g. anxiety). Inclusion of the partner in the diagnostic process may change the clinical picture and the treatment recommendations considerably. As illustrated by penile prosthetis treatment and self-injection of vasoactive substances, acceptance and success of widely used surgical and medical treatments depend largely upon the patient's expectations, and the adaptation of the couple to the procedure. Even in cases with a clear organic pathology, fluctuations in erectile functioning may be attributable to psychological influences. As recent psychotherapeutic and psychoeducational approaches underscore, erectile failure is best conceived as a final common pathway of somatic, lifestyle, psychological and partnership determinants. These should be taken into account in comprehensive diagnostic and treatment formulations if the goal of therapy is not only to produce rigid erections, but to increase sexual satisfaction.     

不同方法分离的大鼠骨髓间充质干细胞增殖活性和成脂分化能力的比较

目的：通过比较密度梯度离心和贴壁筛选两种方法所获MSCs的增殖活性和成脂分化能力，探索MSCs体外分离和纯化的较好方法。方法：应用密度梯度离心和贴壁筛选两种方法分离纯化骨髓MSCs，并通过MTT法检测其增殖活性，用第三代MSCs进行成脂诱导，以观察两种方法所获MSCs的成脂分化能力。结果：密度梯度离心法所获MSCs纯度高，呈纺缍形或小三角形，增殖快，约7～10天融合；贴壁筛选法分离的原代细胞中红细胞。破骨细胞等杂质细胞较多，增殖速度相对较慢，且经数次传代仍有较多杂质细胞存在，经成脂诱导后，两种方法所获MSCs表现出相似的成脂能力，油红O染色细胞计数值与光密度值比较两组无显著差异（P值〉0．05）。结论：密度梯度离心法是体外分离和纯化MSCs较好的方法，所获细胞增殖活性高，与贴壁筛选法所获MSCs具有相似的成脂分化能力。     

Extracorporeal shock wave therapy combined with engineered mesenchymal stem cells expressing stromal cell-derived factor-1 can improve erectile dysfunction in streptozotocin-induced diabetic rats

BackgroundFor erectile dysfunction (ED) in diabetes mellitus (DM) patients who have poor response to drugs, extracorporeal shock wave therapy (ESWT) and engineered mesenchymal stem cell (MSC) therapy have been studied as alternative treatment options. The objective of this study is to investigate whether ESWT in combination with stromal cell-derived factor-1 expressing engineered mesenchymal stem cell (SDF-1 eMSC) therapy can have synergistic effects on ED in streptozotocin-induced diabetic rats.MethodsFifty 8-week-old male Sprague-Dawley rats were randomly divided into five groups (N=10 per group): (I) Normal group, (II) DM ED, (III) DM ED + ESWT group, (IV) DM ED + SDF-1 eMSC group, and (V) DM ED + ESWT + SDF-1 eMSC group. Each groups were treated with bilateral injections of SDF-1 eMSC or ESWT following the experiment protocol for eight weeks.ResultsThe ratio of ICP/MAP was distinctly higher in the DM ED + ESWT + SDF-1 eMSC group than that in the DM ED group. Concentration of α-smooth muscle actin (α-SMA) was elevated the highest in the DM ED + ESWT + SDF-1 eMSC group. Additionally, ESWT increased the intensity of SDF-1 expression in the corpus cavernosum. ESWT + SDF-1 eMSC treatment also induced neuronal nitric oxide synthase (nNOS) and NO/cGMP expression in the corpus cavernosum. Furthermore, numbers of penile progenitor cells were increased in DM ED rats.ConclusionsCombined treatment of ESWT with SDF-1 eMSC treatment is more effective than by a single therapy. It could be used as a potential and effective synergistic treatment for DM ED.     

Transplantation of adipose tissue‐derived stem cell‐derived exosomes ameliorates erectile function in diabetic rats

Mesenchymal stem cells (MSCs) have been considered as an attractive tool for the therapy of diseases. Accumulating evidence indicates that the healing effects of MSCs are mainly related to paracrine action rather than transdifferentiation. Exosomes excreted from MSCs have emerged as physiologically relevant and powerful components of the MSC secretome. However, whether MSC‐derived exosomes can improve erectile function of streptozotocin‐induced diabetic rats and its mechanism remains unknown. Our previous work showed that adipose tissue‐derived stem cells (ADSCs) transplantation could increase endothelial and smooth muscle contents and improve erectile function of diabetic rats. In this study, ADSC‐derived exosomes (ADSC‐Exo) exhibited in vitro proangiogenic properties, induced the proliferation of endothelial cells and restored erectile function in vivo, as well as decreased fibrosis of corpus cavernosum. In further experiments, we found that ADSC‐Exo contained some proangiogenic (miR‐126, miR‐130a and miR‐132) microRNAs and an antifibrotic microRNA family (miR‐let7b and miR‐let7c). Thus, it is reasonable to postulate that ADSC‐Exo transports key functional miRNAs to target cells in a specific manner to improve functional recovery or to activate endogenous repair mechanisms. This proof‐of‐concept study provides a novel approach for the treatment of diabetic erectile dysfunction.     

盐酸曲唑酮治疗勃起功能障碍的临床研究(附32例报告)

观察盐酸曲唑酮对勃起功能障碍(ED)患者治疗的有效性和安全性,本组设计ED症状评分表对32例患者进行开放式多中心临床研究,结果获得59.4%的有效率,并发现在勃起时间、性交频率、性交满意度方面用药后均有明显改善,不良反应主要为头晕、嗜睡和口干、疲劳,程度均较轻微.认为在累积更多病例更长时间的观察基础上,本药有望成为治疗ED的选择性用药.     

盐酸伐地那非治疗男性勃起功能障碍临床研究

目的 观察盐酸伐地那非治疗男性勃起功能障碍的安全性和有效性。方法 随机、双盲、安慰剂对照，对88例勃起功能障碍口服伐地那非治疗的患者进行了为期7个月的观察随访。结果 主要疗效指标的统计学分析结果，显示出5mg、10mg和20mg三个剂量组的伐地那非疗效均优于安慰剂组。次要疗效指标的分析结果与主要疗效指标一致。与药物相关的不良事件依次为潮红、头痛、眼胀、鼻塞、头晕和背痛，多为轻度，且可以自行缓解。结论 盐酸伐地那非治疗勃起功能障碍安全、有效、耐受性好。