Regeneration of the Pelvic and Urethral Supports by Muscle Derived Stem Cells

描述（由申请人提供）：最近的证据表明，骨盆肌肉（如提肛肌、尿道支撑和尿道括约肌）的功能受损或萎缩是女性压力性尿失禁（SUI）的原因。SUI是一种常见的疾病，发病率很高，治疗方案包括骨盆底锻炼、药物治疗和手术。目前，外科治疗是真正SUI的主要治疗方法，治愈率最高。然而，它们是侵入性的，并且与术中和术后的并发症相关。因此，人们一直在寻找治疗SUI的更好方法。使用肌肉来源的成体干细胞（肌源性干细胞，MDSC）的基于细胞的疗法有望用于组织修复，最终目标是再生和恢复骨盆对膀胱，尿道膀胱连接处和尿道的正常功能。近年来，成人干细胞植入已被证明可以再生萎缩或受伤骨骼肌中的肌纤维。平滑肌的再生也已得到证实。成人干细胞移植修复有缺陷的组织负责SUI是一种新的和有前途的选择，这种情况的治疗。 我们这项研究的总体目标是调查，在大鼠模型中，自体肌源性干细胞植入萎缩的提肛肌，同时植入或不植入横纹泌尿生殖器括约肌或尿道平滑肌，是否可以逆转萎缩，随后改善或治愈SUI。长期目标是最终设计一个临床试验，在妇女中使用自体干细胞来纠正SUI。这项研究涉及两个目标。第一个目标涉及大鼠肌肉来源的干细胞的体外分离、纯化和表征。结果将包括肌管形成、平滑肌细胞分化和肌成纤维细胞形成的测定。这些测试将确定正在进行的细胞培养是否在不存在肌成纤维细胞的情况下仍然具有生成骨骼肌和平滑肌的活性。第二个目的是确定将自体干细胞植入雌性大鼠萎缩的肛提肌中，同时植入或不植入横纹泌尿生殖括约肌或尿道平滑肌中的效果。结果包括尿动力学测量、应激试验、骨骼肌重量、植入干细胞的命运和细胞谱系测定。

DESCRIPTION (provided by applicant): Recent evidence demonstrates that the functional impairment or atrophy of pelvic muscles, such as levator ani, urethral supports and urethral sphincter, are responsible for stress urinary incontinence (SUI) in women. SUI is a common condition with significant morbidity, and treatment options include pelvic floor exercises, pharmacological treatment, and surgery. Currently, surgical management is the main treatment of genuine SUI and offers the highest cure rates. However, they are invasive and associated with complications, both intra- and post-operatively. There is, therefore, a constant search for a better approach to treat SUI. Cell-based therapies with adult stem cells of muscle origin (muscle-derived stem cells, MDSC) hold promise for tissue repair with the ultimate goal to regenerate and restore normal function of the pelvic support to the bladder, urethrovesical junction, and urethra. In recent years, adult stem cell implantation has been shown to regenerate myofibers in atrophic or injured skeletal muscle. Regeneration of smooth muscle has also been demonstrated. Adult stem cell implantation for the repair of defective tissues responsible for SUI is a novel and promising option for a therapy of this condition. Our overall goal of this study is to investigate, in a rat model, whether the implantation of autologous muscle-derived stem cells into the atrophic levator ani, with or without concurrent implantation into the striated urogenital sphincter or urethral smooth muscles, can reverse the atrophy and subsequently improve or cure SUI. The long-term objective is to eventually devise a clinical trial for the use of autologous stem cells in women for the correction of SUI. This study involves two aims. The first aim involves the in vitro isolation, purification, and characterization of rat muscle derived stem cells. The outcomes will include the determination of myotube formation, smooth muscle cell differentiation, and myofibroblast formation. These tests will determine whether the ongoing cell culture is still active in generating skeletal and smooth muscles in the absence of myofibroblasts. The second aim is to determine the effects of implanting autologous stem cells into the atrophic levator ani of female rats, with or without concurrent implantation into the striated urogenital sphincter or urethral smooth muscles. The outcomes include urodynamic measurements, stress test, skeletal muscle weight, fate of the implanted stem cells, and cell lineage determination.