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，盆腔肌的功能损伤或萎缩，如提肛肌、尿路支架和尿路括约肌，是导致女性压力性尿失禁(SUI)的原因。自闭症是一种常见的疾病，发病率很高，治疗方法包括盆底锻炼、药物治疗和手术。目前，手术治疗是真正意义上的SUI的主要治疗方法，且治愈率最高。然而，它们是侵袭性的，并与术中和术后的并发症有关。因此，人们一直在寻找更好的治疗SUI的方法。以肌肉来源的成体干细胞(肌源性干细胞，MDSC)为基础的细胞疗法有望实现组织修复，最终目标是再生和恢复骨盆对膀胱、尿路膀胱连接和尿路的正常支持功能。近年来，成体干细胞移植被证明可以在萎缩或受损的骨骼肌中再生肌纤维。平滑肌的再生也已被证实。成人干细胞移植修复导致SUI的缺陷组织是治疗这种疾病的一种新的和有前途的选择。 我们这项研究的总体目标是，在大鼠模型中，将自体肌源性干细胞植入萎缩的肛提肌，同时或不同时植入横纹泌尿生殖括约肌或尿道平滑肌，是否可以逆转萎缩并随后改善或治愈SUI。长期目标是最终设计一项临床试验，在女性中使用自体干细胞来矫正SUI。这项研究涉及两个目的。第一个目标是体外分离、纯化和鉴定大鼠肌源性干细胞。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。这些测试将确定在没有肌成纤维细胞的情况下，正在进行的细胞培养是否仍然活跃于生成骨骼肌和平滑肌肉。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，同时或不同时植入横纹泌尿生殖器括约肌或尿道平滑肌的效果。结果包括尿动力学测量、压力测试、骨骼肌重量、移植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.