Stem cell-derived smooth muscle progenitor cells for vaginal wall prolapse

项目摘要 盆腔器官脱垂是一种使人衰弱的疾病，其特征是阴道壁向下移动 和/或通过阴道口进入子宫其他盆腔结构，如膀胱、肠和直肠 也可以下降到阴道和子宫后面，导致各种泌尿生殖系统和肠道症状 严重影响生活质量。阴道结缔组织和平滑肌细胞中的缺陷 与盆腔器官脱垂有关因此，人们认为，缺乏阴道壁 可能是盆腔器官脱垂进展的重要因素。 正常和受损的组织通常被组织的不断补充和分化所取代- 干细胞在体内的分布然而，这一过程受到老化的影响， 退行性疾病的患病率增加，尤其是在受伤后。阴道分娩创伤和年龄- 依赖性组织变化是盆腔器官脱垂的主要原因。手术治疗为主 再次手术风险为30%。显然需要采取预防和新的治疗战略。 在过去的十年中，基于干细胞的疗法已经成为改善生物相容性和生物相容性的有吸引力的选择。 组织整合最常研究的干细胞类型是成体间充质干细胞（MSC） 因为这些细胞可以从患者的脂肪组织、骨髓中收获并在培养物中扩增， 子宫内膜组织虽然初步结果似乎很有希望，但临床结果并不可靠。鉴于 干细胞技术的巨大进步，特别是能够引入一组基因， 来自体细胞的多能干细胞（a.k.a.诱导多能干细胞或iPSC），现在有 在将这种细胞类型转化为多种疾病的临床疗法方面正在进行重大努力。iPSCs可以 分化成具有再生特性的所有谱系的体细胞。 一个分化方案已被优化，以产生一个均匀的人口平滑肌 来自患者iPSC的祖细胞（pSMC）。首要假设是pSMC来源于患者 iPSC将在受损的盆腔组织中发挥双重作用：1. pSMC将诱导细胞外基质蛋白 由宿主结缔组织沉积，和2. pSMC的植入将改善细胞的收缩特性， 阴道壁变弱这些作用将导致受影响的阴道壁缺陷的修复， 盆腔器官脱垂在R21提案中，概述了测试这些假设的动物和细胞研究。

Project Summary Pelvic organ prolapse is a debilitating condition characterized by the downward movement of the vaginal wall and/or the uterus through the vaginal opening. Other pelvic structures such as the bladder, bowel, and rectum can also descend behind the vagina and uterus resulting in a variety of genito-urinary and bowel symptoms that severely impact quality of life. Deficiencies in connective tissue and smooth muscle cells of the vagina have been associated with pelvic organ prolapse. Consequently, it is thought that the deficient vaginal wall may be a significant factor in the progression of pelvic organ prolapse. Normal and damaged tissues are generally replaced by continuous recruitment and differentiation from tissue- specific stem cell populations in the body. However, this process is compromised with aging, resulting in an increase in prevalence of degenerative conditions especially after injury. Vaginal birth trauma and age- dependent tissue changes are major contributors to pelvic organ prolapse. Surgical treatment is the main option with a 30% risk of reoperation. There is a clear need for preventive and new treatment strategies. In the past decade, stem cell-based therapies have become attractive options to improve biocompatibility and tissue integration. The most commonly studied stem cell type is the adult mesenchymal stem cell (MSC) because these can be harvested and expanded in culture from patient’s adipose tissue, bone marrow, and endometrial tissue. While preliminary results appear promising, clinical results are not robust. Given the tremendous advances in stem cell technologies, specifically the ability to introduce a set of genes to derive pluripotent stem cells from somatic cells (a.k.a. induced pluripotent stem cells or iPSCs), there is now significant effort underway in translating this cell type into clinical therapies for multiple diseases. iPSCs can be differentiated into somatic cells of all lineages with rejuvenated properties. A differentiation protocol has been optimized to produce a homogenous population of smooth muscle progenitor cells (pSMC) from patient iPSCs. The overarching hypothesis is that pSMC, derived from patient iPSCs, will exert dual effects in damaged pelvic tissues: 1. pSMC will induce extracellular matrix protein deposition by host connective tissue, and 2. engraftment of pSMC will improve contractile properties of a weakened vaginal wall. These effects will result in restoration of the defects in the vaginal wall affected by pelvic organ prolapse. In this R21 proposal, animal and cell studies to test these hypotheses are outlined.