Nonhuman Primate Model of Bladder Regeneration Using Autologous Bone Marrow Cells

使用自体骨髓细胞的非人灵长类动物膀胱再生模型

• 批准号: 9898353
• 负责人: Arun Sharma
• 金额: $ 67.05万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-15 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9898353
• 关键词: Acute Kidney Failure; Address; Affect; Anatomy; Animal Model; Animals; Autologous; Bladder; Bladder Tissue; Blood Vessels; Bone Marrow; Bone Marrow Cells; CD34 gene; Canis familiaris; Cell Count; Cell Differentiation process; Cells; Chemistry; Chronic; Clinical; Clinical Trials; Conduct Clinical Trials; Congenital Abnormality; Data; Development; Disease; Elastomers; Electrolytes; Extravasation; Goals; Growth; Growth Factor; Hematopoietic stem cells; Human; Infection; Interstitial Cystitis; Intestines; Kidney Failure; Kinetics; Label; Malignant - descriptor; Mechanics; Medical; Mesenchymal Stem Cells; Methods; Modeling; Motivation; Muscle; Natural regeneration; Operative Surgical Procedures; Papio; Pathologic; Patients; Perforation; Peripheral Nerves; Phylogenetic Analysis; Physiological; Physiology; Population; Process; Proxy; Radiation therapy; Rattus; Replacement Therapy; Research; Role; Serious Adverse Event; Small Intestinal Submucosa; Smooth Muscle Myocytes; Source; Surgical Management; Techniques; Testing; Thick; Tissue Engineering; Tissues; Trauma; United States; Urinary Incontinence; Urine; Urologic Cancer; Urothelium; angiogenesis; base; cell type; clinically relevant; clinically translatable; design; elastomeric; functional improvement; improved; in vivo; innovation; mechanical properties; neovascularization; nerve supply; new growth; nonhuman primate; novel; peripheral nerve regeneration; regenerative; response; scaffold; sham surgery; side effect; stem; stem cell biology; stem cells; success; tissue regeneration

PROJECT SUMMARY/ABSTRACT Patients with a pathologic bladder have chronic medical problems with urinary incontinence, infections, and potential renal failure. Conventional surgical management of the pathologic bladder uses detubularized bowel as a patch (enterocystoplasty) to enlarge the bladder. Although enterocystoplasty provides functional improvement, it is associated with significant short- and long-term complications. Thus, alternative methods to enterocystoplasty have been explored through tissue engineering by seeding cultured bladder cells on bioscaffolds as an augmentation patch. With these techniques, marginal success has been noted but regeneration of fully functional normal bladder tissue has yet to be achieved. Several obstacles currently limit advancement in this research field including the choice of a relevant animal model; appropriate cell types for seeding, adequate neovascularization of the seeded graft, tissue innervation, and primitive bioscaffold design. Thus, alternative cell sources, advancements in bioscaffold design, and applicable animal models are needed to address these unmet clinical needs. Bone marrow stem/progenitor cells (BMSPCs) represent a highly defined population of cells that are easily accessible and may be used for bladder regeneration. BMSPCs are non-exclusively comprised of mesenchymal stem cells (MSCs) and hematopoietic stem/progenitor cells (HSPCs). MSCs have been shown to be capable of smooth muscle cell (SMC) differentiation and are involved in the bladder regenerative process, while HSPCs have demonstrated the ability to facilitate the growth of new blood vessels in regenerating tissue while aiding in peripheral nerve and urothelium regeneration. Recent developments in elastomer chemistry and scaffold design have allowed for the development of synthetic scaffolds that have controlled kinetic release of growth factors that are important for the regenerative process and that can mimic the mechanical properties of the bladder. Lastly, we have established a unique animal model of bladder augmentation in a nonhuman primate. This model is highly homologous to its human counterparts with regards to anatomy and physiology. This proposal will utilize these recent advancements in stem cell biology and elastomer chemistry along with our newly established bladder model to determine whether the use of autologous MSCs and HSPCs in conjunction with novel elastomer scaffolds can enhance current tissue engineering techniques to promote bladder regeneration. These include muscle and peripheral nerve regeneration, angiogenesis, and rapid urothelium growth. Preliminary data strongly suggests that these two cell types can accomplish these goals as demonstrated in vivo.

项目摘要/摘要 病理性膀胱的患者有慢性医学问题，如尿失禁、感染和 潜在的肾功能衰竭。病理性膀胱的传统外科治疗使用拔管的肠管 作为补丁(小肠膀胱成形术)来扩大膀胱。尽管小肠膀胱成形术提供了功能 改善，它与重大的短期和长期并发症有关。因此，替代方法是 通过将培养的膀胱细胞种植到组织工程学中，肠膀胱成形术已经被探索 生物支架作为增强贴片。通过这些技术，已经注意到了微不足道的成功，但 全功能正常膀胱组织的再生尚未实现。目前有几个障碍限制了 这一研究领域的进展包括选择相关的动物模型；适当的细胞类型 种植、种植移植物足够的新生血管、组织神经支配和原始生物支架设计。 因此，替代细胞来源、生物支架设计的进步和适用的动物模型是必要的。 以解决这些未得到满足的临床需求。骨髓干/祖细胞(BMSPC)是一种高度 定义的细胞群，易于获取，可用于膀胱再生。BMSPC是 非排他性包括间充质干细胞(MSCs)和造血干/祖细胞 (HSPC)。已证实间充质干细胞具有向平滑肌细胞分化的能力，并参与 在膀胱再生过程中，HSPC已经证明有能力促进新生的 再生组织中的血管，同时帮助周围神经和尿路上皮再生。近期 弹性体化学和支架设计的发展使合成材料的开发成为可能 具有控制生长因子动态释放的支架，这些生长因子对再生过程非常重要 这可以模仿膀胱的机械性能。最后，我们建立了一种独特的动物 非人灵长类动物的膀胱增大模型。这个模型与它的人类高度同源 在解剖学和生理学方面与之相对应。这项提议将利用这些最新的进展 干细胞生物学和弹性体化学以及我们新建立的膀胱模型 自体MSCs和HSPC与新型弹性体支架联合使用是否可以增强 目前的组织工程技术可以促进膀胱再生。包括肌肉和外周 神经再生、血管生成和尿路上皮快速生长。初步数据强烈表明，这些 有两种细胞类型可以实现这些目标，正如在体内证明的那样。