Stem Cell Therapy Combined with Growth Factors for Stress Urinary Incontinence

干细胞疗法联合生长因子治疗压力性尿失禁

• 批准号: 8915847
• 负责人: YUANYUAN no ZHANG
• 金额: $ 11.56万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-18 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8915847
• 关键词: Adverse event; Affect; Alginates; American; Autologous; Binding; Biocompatible Materials; Biological; Biopsy; Blood; Bone Marrow; Bone Marrow Stem Cell; Cell Proliferation; Cell Survival; Cell Therapy; Cells; Cellular Stress; Characteristics; Chronic; Cleaved cell; Clinical Trials; Conditioned Culture Media; Cytoprotection; Disease; Encapsulated; Fatty acid glycerol esters; Female; Genes; Goals; Growth; Growth Factor; Health; Human; IGF1R gene; IGFBP3 gene; Implant; In Vitro; Injection of therapeutic agent; Injury; Insulin-Like Growth Factor I; Insulin-Like Growth Factor Receptor; Insulin-Like Growth-Factor Binding Protein 1; Lead; Longevity; Mediating; Methods; Microspheres; Modeling; Muscle; Natural regeneration; Nerve Regeneration; Nerve Tissue; Nude Rats; Operative Surgical Procedures; Outcome; Pathologic Processes; Pathway interactions; Patients; Pharmacotherapy; Play; Procedures; Protocols documentation; Quality of life; Rattus; Recovery; Recruitment Activity; Risk; Role; Safety; Signal Pathway; Signal Transduction; Skeletal Muscle; Source; Sphincter; Stem cells; Stress Urinary Incontinence; System; Techniques; Testing; Therapeutic; Tissues; Transfection; Urethra; Urethral sphincter; Urinary Incontinence; Urine; Vagina; Vascular Endothelial Growth Factors; Vascular blood supply; adult stem cell; angiogenesis; base; caspase-3; cell growth; controlled release; cost; improved; improved functioning; in vivo; inhibitor/antagonist; knock-down; myogenesis; nerve injury; nerve supply; novel; paracrine; pressure; response; small hairpin RNA; small molecule; stem cell niche; stem cell therapy; success; tissue regeneration; tissue repair; tool

DESCRIPTION (provided by applicant): Stress urinary incontinence (SUI) severely affects the quality of life of up to 13 million people in the USA. Its pathological processes include dysfunctional sphincter muscle tissue, chronic nerve injury, and poor regional blood supply. Some current therapeutic approaches are pharmacotherapy, sling surgery, and injection of bulking agents. Cellular-based therapy is a promising alternative method to restore deficient urethral sphincter function in the treatment of SUI. We have demonstrated that adult stem cells exist in human urine. These cells, termed urine-derived stem cells (USCs), possess stem cell characteristics with robust proliferative potential and multi-potential differentiation. These cell can be obtained using simple, safe, non-invasive and low-cost procedures, thus avoiding the adverse events associated with obtaining stem cells from other sources. Improving the urethral sphincter microenvironment by angiogenesis is critical for success of stem cell therapy determined by cell survival, ingrowth and differentiation, and host cell recruitment to aid urethra sphincter tissue repair. It is desirable to employ a safer approach to growth factor delivery to enhance the stem cell niches (microenvironment). Insulin-like growth factor 1 (IGF-1) promotes myogenesis and induces nerve regeneration after injury, and it also stimulates angiogenesis. Our recent studies demonstrated that USCs secreted high levels of IGF1 and IGF binding protein 1, and implanted USCs significantly enhanced sphincter function after vaginal distention in vivo. Moreover, we demonstrated that an alginate microbead delivery system is feasible to control growth factor release and thereby enhance survival and differentiation of grafted stem cells in vivo. Thus, the ultimate goal of this project is to develop a therapeutic approach to improve the outcomes of stem cell therapy and eventually lead to treatments and possibly cures for urinary incontinence. To do so, we will develop coherent experimental protocols to study a combination of stem cells and growth factor delivery to enhance angiogenesis and promote cell survival, growth, myogenic differentiation, and innervation in vivo. We hypothesize that IGF1 released from alginate microbeads can improve cell survival, enhance ingrowth and differentiation of USCs, and recruit resident cells to take part in urethral sphincter tissue repai via Akt-mediated signaling pathways. To test these hypotheses, we propose the following Specific Aims: Aim 1. Elucidate the mechanisms by which USCs improve sphincter tissue repair in an athymic rat model of SUI. Aim 2. Determine the effects of controlled release of IGF1 from alginate microbeads on sphincter tissue repair in vivo. Aim 3. Determine the impact of USCs and IGF1 in combination on urethral sphincter regeneration after vaginal distention. The systematic approach will provide us with a critical tool to investigate how to manipulate biological interactions between stem cells and IGF1 that impair urethral tissue regeneration. Successful completion of this project will develop a therapeutic strategy for clinical trials of autologous USCs for urinary incontinence.

描述（由申请人提供）：压力性尿失禁 (SUI) 严重影响美国多达 1300 万人的生活质量。其病理过程包括括约肌组织功能障碍、慢性神经损伤和局部血液供应不良。目前的一些治疗方法包括药物治疗、吊带手术和注射填充剂。在 SUI 治疗中，基于细胞的疗法是恢复尿道括约肌功能缺陷的一种有前景的替代方法。我们已经证明人类尿液中存在成体干细胞。这些细胞被称为尿源性干细胞（USC），具有干细胞特性，具有强大的增殖潜力和多向分化潜能。这些细胞可以通过简单、安全、非侵入性和低成本的程序获得，从而避免与从其他来源获取干细胞相关的不良事件。通过血管生成改善尿道括约肌微环境对于干细胞治疗的成功至关重要，干细胞治疗的成功取决于细胞存活、向内生长和分化以及宿主细胞募集以帮助尿道括约肌组织修复。人们希望采用更安全的生长因子递送方法来增强干细胞生态位（微环境）。胰岛素样生长因子 1 (IGF-1) 促进肌肉生成并诱导损伤后的神经再生，并且还刺激血管生成。我们最近的研究表明，USCs分泌高水平的IGF1和IGF结合蛋白1，并且植入的USCs在体内阴道扩张后显着增强括约肌功能。此外，我们证明藻酸盐微珠递送系统可以控制生长因子的释放，从而增强移植干细胞在体内的存活和分化。因此，该项目的最终目标是开发一种治疗方法来改善干细胞治疗的结果，并最终实现尿失禁的治疗和可能治愈。为此，我们将开发连贯的实验方案来研究干细胞和生长因子递送的组合，以增强血管生成并促进体内细胞存活、生长、肌源性分化和神经支配。我们假设海藻酸盐微珠释放的 IGF1 可以提高细胞存活率，增强 USC 的向内生长和分化，并通过 Akt 介导的信号通路招募常驻细胞参与尿道括约肌组织修复。为了检验这些假设，我们提出以下具体目标： 目标 1. 阐明 USC 在无胸腺 SUI 大鼠模型中改善括约肌组织修复的机制。目标 2. 确定藻酸盐微珠控制释放 IGF1 对体内括约肌组织修复的影响。目标 3. 确定 USC 和 IGF1 联合使用对阴道扩张后尿道括约肌再生的影响。该系统方法将为我们提供一个关键工具来研究如何操纵干细胞和 IGF1 之间损害尿道组织再生的生物相互作用。该项目的成功完成将为自体 USC 治疗尿失禁的临床试验制定治疗策略。

项目成果

Functional characterization of the immunomodulatory properties of human urine-derived stem cells.

人尿干细胞免疫调节特性的功能表征。

• 发表时间: 2021-09
• 作者: Wu, Rongpei;Soland, Melisa;Liu, Guihua;Shi, Yingai;Zhang, Chi;Tang, Yiming;Almeida;Zhang, Yuanyuan
• 通讯作者: Zhang, Yuanyuan

Human Urine-Derived Stem Cell Differentiation to Endothelial Cells with Barrier Function and Nitric Oxide Production.

人尿液干细胞分化为具有屏障功能和一氧化氮生成的内皮细胞。

• 发表时间: 2018
• 影响因子: 6
• 作者: Liu, Guihua;Wu, Rongpei;Yang, Bin;Deng, Chunhua;Lu, Xiongbing;Walker, Stephen J;Ma, Peter X;Mou, Steve;Atala, Anthony;Zhang, Yuanyuan
• 通讯作者: Zhang, Yuanyuan

Strategies to Optimize Adult Stem Cell Therapy for Tissue Regeneration.

优化成体干细胞治疗组织再生的策略。

• 发表时间: 2016-06-21
• 影响因子: 5.6
• 作者: Liu, Shan;Zhou, Jingli;Zhang, Xuan;Liu, Yang;Chen, Jin;Hu, Bo;Song, Jinlin;Zhang, Yuanyuan
• 通讯作者: Zhang, Yuanyuan

A cocktail of growth factors released from a heparin hyaluronic-acid hydrogel promotes the myogenic potential of human urine-derived stem cells in vivo.

从肝素透明质酸水凝胶释放的生长因子混合物可促进体内人尿液干细胞的生肌潜力。

• 发表时间: 2020
• 影响因子: 9.7
• 作者: Liu, Guihua;Wu, Rongpei;Yang, Bin;Shi, Yingai;Deng, Chunhua;Atala, Anthony;Mou, Steven;Criswell, Tracy;Zhang, Yuanyuan
• 通讯作者: Zhang, Yuanyuan

Urothelium with barrier function differentiated from human urine-derived stem cells for potential use in urinary tract reconstruction.

具有屏障功能的尿路上皮从人尿来源的干细胞中分化出来，可用于尿路重建。

• 发表时间: 2018
• 影响因子: 7.5
• 作者: Wan, Qian;Xiong, Geng;Liu, Guihua;Shupe, Thomas D;Wei, Guanghui;Zhang, Deying;Liang, Dan;Lu, Xiongbing;Atala, Anthony;Zhang, Yuanyuan
• 通讯作者: Zhang, Yuanyuan