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

干细胞衍生的平滑肌祖细胞治疗阴道壁脱垂

• 批准号: 10007190
• 负责人: BERTHA CHEN
• 金额: $ 23.78万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10007190
• 关键词: Address; Adipose tissue; Adult; Affect; Age; Aging; American; Animals; Antibodies; Area; Atopobium vaginae; Bathing; Birth trauma; Bladder; Bone Marrow; California; Carbachol; Cell Differentiation process; Cell Line; Cell Therapy; Cells; Chronic; Clinical; Collagen; Collagen Fiber; Connective Tissue; Data; Defect; Degenerative Disorder; Deposition; Disease; Elastin; Elastin Fiber; Endometrial; Engraftment; Extracellular Matrix; Extracellular Matrix Proteins; Fecal Incontinence; Female; Fibroblasts; Funding; Genes; Genitourinary system; Gynecologic; Harvest; Human; Immunofluorescence Immunologic; In Vitro; Injury; Institutes; Intestines; Knowledge; Luciferases; Maintenance; Medicine; Mesenchymal Stem Cells; Modeling; Movement; Myography; Nuclear; Operative Surgical Procedures; Organ; Pathogenesis; Patients; Pelvic Floor Disorders; Pelvic floor structure; Pelvis; Pluripotent Stem Cells; Population; Population Analysis; Prevalence; Preventive; Process; Progenitor Cell Engraftment; Property; Proteomics; Protocols documentation; Ptosis; Quality of life; Rattus; Reconstructive Surgical Procedures; Rectum; Recurrence; Regenerative Medicine; Repeat Surgery; Risk; Rodent Model; Role; Smooth Muscle; Smooth Muscle Myocytes; Somatic Cell; Stains; Stem cell transplant; Structure; Symptoms; Testing; Time; Tissue Differentiation; Tissue-Specific Gene Expression; Tissues; Translating; Urinary Incontinence; Urology; Uterus; Vagina; Vaginal delivery procedure; Western Blotting; Woman; age related; base; bioluminescence imaging; biomaterial compatibility; cell type; collaborative approach; functional restoration; improved; in vivo; induced pluripotent stem cell; insight; lifetime risk; novel; operation; paracrine; pelvic organ prolapse; recruit; repaired; restoration; stem; stem cell biology; stem cell population; stem cell technology; stem cells; treatment strategy

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.

项目概要 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 也可能下降到阴道和子宫后面，导致各种泌尿生殖和肠道症状 从而严重影响生活质量。阴道结缔组织和平滑肌细胞缺乏 与盆腔器官脱垂有关。因此，人们认为阴道壁缺陷 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持续募集和分化所取代。 体内特定的干细胞群。然而，这个过程会因老化而受到损害，从而导致 退化性疾病的患病率增加，尤其是在受伤后。阴道产伤和年龄 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% 的选项。显然需要预防和新的治疗策略。 在过去的十年中，基于干细胞的疗法已成为改善生物相容性和 组织整合。最常研究的干细胞类型是成体间充质干细胞（MSC） 因为这些可以从患者的脂肪组织、骨髓和 子宫内膜组织。虽然初步结果看起来很有希望，但临床结果并不稳健。鉴于 干细胞技术的巨大进步，特别是引入一组基因来衍生的能力 来自体细胞的多能干细胞（又名诱导多能干细胞或 iPSC），现在有 人们正在努力将这种细胞类型转化为多种疾病的临床疗法。 iPSC 可以是 分化成具有复兴特性的所有谱系的体细胞。 分化方案已经过优化，可产生同质的平滑肌群 来自患者 iPSC 的祖细胞 (pSMC)。总体假设是 pSMC，源自患者 iPSCs，将对受损的盆腔组织发挥双重作用： 1. pSMC 诱导细胞外基质蛋白 宿主结缔组织的沉积，以及 2. pSMC 的植入将改善 a 的收缩特性 阴道壁变弱。这些作用将导致受阴道壁影响的缺陷得到恢复。 盆腔器官脱垂。在此 R21 提案中，概述了检验这些假设的动物和细胞研究。