Regenerative Adjuvant Therapy for Stress Urinary Incontinence

描述（由申请人提供）： 压力性尿失禁（SUI）是指在用力或用力时不自主的尿液泄漏，是最常见的尿失禁形式。SUI是一种常见的疾病，特别是在女性中，影响约35%的40岁以上的女性，并且与阴道分娩密切相关，阴道分娩可能会损伤负责维持子宫的神经，肌肉和胶原组织。产妇分娩损伤的唯一康复方法是骨盆底（凯格尔）练习，这种练习可以加强骨盆底的肌肉，防止空隙之间的渗漏。然而，有一半的患者在骨盆底练习中没有取得成功。因此，需要凯格尔康复训练的辅助治疗。 干细胞参与正常的修复过程，因此有潜力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吸引或归巢循环干细胞到损伤部位，在那里它们促进修复过程，有时通过与归巢相同的受体介导机制。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。 阴道扩张（Vaginal diffusion，VD）是一种模拟人类分娩损伤的动物模型，旨在探讨其损伤和恢复的机制。VD导致尿道对渗漏的抵抗力显著降低，作为SUI的证据。干细胞归巢细胞因子在VD后上调，特别是那些吸引成体间充质干细胞（MSC）的细胞因子，并且VD后MSC的输注导致SUI的加速恢复。然而，这种改善功能修复的机制尚不清楚。本提案的目的是研究模拟分娩损伤后用MSC治疗加速恢复的机制，为未来的临床试验做准备。 在该项目中要测试的假设是，成人MSC通过分泌浓缩条件培养基（CCM）中的旁分泌因子促进模拟分娩损伤后SUI的恢复，并且这种治疗益处可以通过全身递送MSC来实现，因为这些细胞通过精氨酸受体介导的机制归巢到尿道和盆腔器官。该假设将通过3个特定目标（SO）进行检验。SO 1的实验旨在确定MSC或CCM递送的最有效剂量和时间，以促进VD的恢复。SO2实验旨在研究受体介导的MSC归巢机制及加速VD功能恢复的机制。SO 3实验旨在探讨旁分泌因子介导的加速VD功能恢复的机制。 产后SUI是高度预测SUI年后，即使产后SUI解决最初。因此，患有产后SUI的未哺乳妇女可能是干预的潜在主要候选人群，该干预既可以治疗其当前的尿失禁，又可以预防以后生活中尿失禁的复发。全身性细胞治疗可以为需要治疗的部位提供治疗，副作用很少。此外，非细胞方法也是可能的，因为干细胞分泌的旁分泌因子可能在没有细胞的情况下用于加速恢复，如CCM治疗。 这项工作也直接应用于多发性创伤和其他多因素创伤性损伤，因为产妇分娩损伤同样是弥漫性的，并涉及神经，肌肉，结缔组织的各种机制，包括直接创伤，缺血，拉伸和撕脱。因此，本研究的结果可用于建议治疗其他弥漫性和多因素创伤性损伤，包括多发性创伤。因此，这项工作适用于法语国家组织/持久自由行动的退伍军人以及妇女，可以提供一种方法，改善这些难以康复的组合性损伤的康复。

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.