Regenerative Adjuvant Therapy for Stress Urinary Incontinence

描述(由申请人提供)： 压力性尿失禁(SUI)是指因劳累或劳累导致的非自愿性尿漏失，是最常见的尿失禁形式。Sui是一种常见的疾病，尤其是在女性中，40岁以上的女性中约有35%受到影响，并且与阴道分娩密切相关，阴道分娩可能会损伤负责维持节制的神经、肌肉和胶原组织。对产妇分娩损伤的唯一康复方法是盆底(Kegel)练习，它可以加强盆底肌肉，防止空洞之间的渗漏。然而，有一半的患者在盆底锻炼中没有取得成功。因此，需要对Kegel康复训练进行辅助治疗。干细胞参与正常的修复过程，因此有可能被利用来促进分娩和其他损伤的修复。损伤组织产生的细胞因子梯度将循环干细胞吸引或归巢到损伤部位，在那里它们促进修复过程，有时通过参与归巢的相同受体介导的机制。最近的研究表明，干细胞促进损伤后修复的机制是通过分泌旁分泌作用蛋白，如生长因子。在啮齿类动物中，用阴道扩张模拟人类分娩的母体损伤，以研究其损伤和恢复的机制。作为SUI的证据，VD可显著降低尿漏的抵抗力。干细胞归巢细胞因子在VD后上调，尤其是那些吸引成人间充质干细胞(MSCs)的细胞因子，而在VD后输注MSCs可加速SUI的恢复。然而，这种改进的功能修复的机制尚不清楚。这项建议的目的是为了研究模拟分娩损伤后应用MSCs治疗加速康复的机制，为未来的临床试验做准备。本项目中要检验的假设是，成年MSCs通过分泌浓缩条件培养液(CCM)中的旁分泌因子来促进模拟分娩损伤后SUI的恢复，这种治疗益处可以通过细胞因子受体介导的机制将这些细胞归巢到尿路和盆腔器官而全身输送到MSCs来实现。这一假设将通过3个具体目标(SO)进行检验。SO1的实验旨在确定MSC或CCM的最有效剂量和时机，以促进VD的康复。SO2实验旨在确定受体介导的MSC归巢和促进VD患者功能恢复的机制。SO3的实验旨在确定旁分泌因子介导的VD加速功能恢复的机制。产后SUI对数年后的SUI有很高的预测性，即使产后SUI最初得到解决。因此，没有哺乳的产后SUI女性可能是潜在的主要干预对象，既可以治疗她们目前的尿失禁，又可以防止以后生活中尿失禁的复发。全身细胞疗法可以为需要治疗的部位提供治疗，副作用很少。此外，非细胞方法是可能的，因为干细胞分泌的旁分泌因子可能在没有细胞的情况下被用来加速恢复，就像CCM治疗一样。这项工作也直接适用于多发伤和其他多因素创伤，因为分娩的母体损伤同样是弥漫的，通过各种机制涉及神经、肌肉和结缔组织，包括直接创伤、缺血、拉伸和撕脱。因此，这项研究的结果可以用于其他弥漫性和多因素创伤的治疗，包括多发伤。因此，这项工作既适用于OIF/OEF退伍军人，也适用于妇女，并可提供一种方法，改善这些难以康复的复合损伤的康复。

DESCRIPTION (provided by applicant): Stress urinary incontinence (SUI) is the involuntary urine leakage on effort or exertion and is the most common form of urinary incontinence. SUI is a common condition, particularly among women, affecting about 35% of women over the age of 40, and is strongly correlated with vaginal delivery, which can injure the nerve, muscle, and collagenous tissues responsible for maintaining continence. The only rehabilitation method for the maternal injuries of childbirth is pelvic floor (Kegel) exercises which strengthen the muscles of the pelvic floor and prevent leakage between voids. However, one half of patients do not achieve success with pelvic floor exercises. Therefore an adjuvant treatment to Kegel rehabilitative exercises is needed. Stem cells participate in normal repair processes and therefore have the potential to be harnessed to facilitate repair of childbirth and other injuries. Cytokine gradients produced by the injured tissues attract or home circulating stem cells to sites of injury, where they facilitate the repair process, sometimes via the same receptor-mediated mechanisms involved in homing. Recent research has demonstrated that the mechanism by which stem cells facilitate repair after injury is by secreting paracrine-acting proteins such as growth factors. Vaginal distension (VD) has been used in rodents to simulate the human maternal injuries of childbirth for investigations of the mechanisms of injury and recovery. VD results in a significant decrease in urethral resistance to leakage, taken as evidence of SUI. Stem cell homing cytokines are upregulated after VD, particularly those that attract adult mesenchymal stem cells (MSCs), and infusion of MSCs after VD results in accelerated recovery of SUI. However, the mechanisms of this improved functional repair are not known. The goal of this proposal is to investigate the mechanisms of accelerated recovery by treatment with MSCs after simulated childbirth injury, in preparation for future clinical trials. The Hypothesis to be tested in this project is that adult MSCs facilitate recovery from SUI after simulated childbirth injury via secretion of paracrine factors as are in concentrated conditioned media (CCM), and this therapeutic benefit can be achieved through the systemic delivery of MSCs due to homing of these cells to the urethra & pelvic organs via a cytokine-receptor-mediated mechanism. The hypothesis will be tested with 3 Specific Objectives (SO). The experiments of SO1 are designed to determine the most effective dosage and timing of MSC or CCM delivery to facilitate recovery from VD. The experiments of SO2 are designed to determine the receptor-mediated mechanisms of MSC homing & accelerated functional recovery from VD. The experiments of SO3 are designed to determine the paracrine factor-mediated mechanisms of accelerated functional recovery from VD. Postpartum SUI is highly predictive of SUI years later even if the postpartum SUI resolves initially. Therefore, women with postpartum SUI who are not nursing could be a population of potential primary candidates for an intervention that would both treat their current incontinence and prevent recurrence of incontinence later in life. Systemic cellular therapy could provide treatment to the site where it is needed with few side effects. In addition, noncellular methods are possible, since the paracrine factors secreted by stem cells could potentially be used to accelerate recovery in the absence of cells, as with CCM treatment. This work also has direct application to polytrauma and other multi-factorial traumatic injuries since the maternal injuries of childbirth are similarly diffuse and involve nerves, muscles, connective tissue by a variety of mechanisms including direct trauma, ischemia, stretch, and avulsion. Therefore, results from this study could be used to propose treatment for other diffuse and multi-factorial traumatic injuries, including polytrauma. As a result this work has application to veterans of OIF/OEF as well as to women and could provide a method of improving rehabilitation from these combinatorial injuries for which recovery is difficult.