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

基本信息

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
项目类别：
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

项目摘要

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）：压力尿失禁（SUI）严重影响了美国多达1300万人的生活质量。它的病理过程包括功能失调的括约肌肌肉组织，慢性神经损伤和区域血液供应不良。一些当前的治疗方法是药物治疗，吊索手术和注射散装剂。基于细胞的治疗是恢复SUI治疗中尿道括约肌功能不足的一种有希望的替代方法。我们已经证明了成年干细胞存在于人类尿液中。这些细胞称为尿液衍生的干细胞（USC），具有具有牢固增殖电势和多势分化的干细胞特征。可以使用简单，安全，非侵入性和低成本程序获得这些细胞，从而避免与从其他来源获得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通过细胞存活，向内生长和分化确定的干细胞治疗以及宿主细胞募集以帮助尿道括约肌修复至关重要。希望采用更安全的生长因子递送方法来增强干细胞壁ni（微环境）。胰岛素样生长因子1（IGF-1）促进肌发生并诱导损伤后神经再生，并且还刺激了血管生成。我们最近的研究表明，USC分泌高水平的IGF1和IGF结合蛋白1，并植入USC在体内阴道延伸后显着增强了括约肌功能。此外，我们证明了藻酸盐微粒递送系统可用于控制生长因子释放，从而增强了体内移植干细胞的存活和分化。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疗法的结果，并最终导致治疗，并可能治愈尿失禁。为此，我们将开发一致的实验方案，以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细胞存活，生长，肌原性分化和体内神经支配。我们假设从藻酸盐微珠释放的IGF1可以改善细胞的存活，增强USC的向内生长和分化，并募集居民细胞以通过AKT介导的信号传导途径参与尿道括约肌组织repai。为了检验这些假设，我们提出了以下特定目的：目标1。阐明USC在SUI的无胸腺大鼠模型中改善括约肌组织修复的机制。 AIM 2。确定IGF1从藻酸盐微粒受控释放对体内括约肌修复的影响。 AIM 3。确定阴道延伸后USC和IGF1对尿道括约肌再生的影响。系统的方法将为我们提供一个关键工具，以研究如何操纵干细胞与IGF1之间的生物学相互作用，从而损害尿道组织再生。该项目的成功完成将制定一种治疗策略，以用于自体USC的临床试验，以解决尿失禁。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Tissue-specific extracellular matrix promotes myogenic differentiation of human muscle progenitor cells on gelatin and heparin conjugated alginate hydrogels.

DOI：
10.1016/j.actbio.2017.08.022
发表时间：
2017-10-15
期刊：
Acta biomaterialia
影响因子：
9.7
作者：
Yi H;Forsythe S;He Y;Liu Q;Xiong G;Wei S;Li G;Atala A;Skardal A;Zhang Y
通讯作者：
Zhang Y

* Tissue-Specific Extracellular Matrix Enhances Skeletal Muscle Precursor Cell Expansion and Differentiation for Potential Application in Cell Therapy.

DOI：
10.1089/ten.tea.2016.0489
发表时间：
2017-05
期刊：
Tissue engineering. Part A
影响因子：
0
作者：
De‐ying Zhang;Yong Zhang;Yuanyuan Zhang;Hualin Yi;Zhan Wang;Rongpei Wu;D. He;G. Wei;Shicheng Wei;Yun Hu;Junhong Deng;T. Criswell;J. Yoo;Yu Zhou;A. Atala
通讯作者：
De‐ying Zhang;Yong Zhang;Yuanyuan Zhang;Hualin Yi;Zhan Wang;Rongpei Wu;D. He;G. Wei;Shicheng Wei;Yun Hu;Junhong Deng;T. Criswell;J. Yoo;Yu Zhou;A. Atala

Controlled release of insulin-like growth factor 1 enhances urethral sphincter function and histological structure in the treatment of female stress urinary incontinence in a rat model.

DOI：
10.1111/bju.13985
发表时间：
2018-03
期刊：
BJU international
影响因子：
4.5
作者：
Yan H;Zhong L;Jiang Y;Yang J;Deng J;Wei S;Opara E;Atala A;Mao X;Damaser MS;Zhang Y
通讯作者：
Zhang Y

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