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: 9311008
• 负责人: Arun Sharma
• 金额: $ 69.73万
• 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/9311008
• 关键词: Acute Kidney Failure; Address; Adverse effects; 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; Stem cells; 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; stem; stem cell biology; 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.

项目总结/摘要 患有病理性膀胱的患者具有尿失禁、感染和尿失禁的慢性医学问题。 潜在的肾衰竭病理性膀胱的常规外科治疗使用去管化的肠 作为一个补丁（肠膀胱成形术），以扩大膀胱。虽然肠膀胱成形术提供了功能性的 改善，它与显着的短期和长期并发症。因此，替代方法， 通过将培养的膀胱细胞接种在 生物支架作为一个增强补丁。使用这些技术，已经注意到边际成功， 尚未实现完全功能正常膀胱组织的再生。目前有几个障碍限制了 该研究领域的进展，包括相关动物模型的选择; 接种、接种移植物的充分新血管形成、组织神经支配和原始生物支架设计。 因此，需要替代的细胞来源、生物支架设计的进步和适用的动物模型 来满足这些未满足的临床需求。骨髓干/祖细胞（BMSPCs）代表了高度的 所述细胞是易于获得的并且可用于膀胱再生的限定的细胞群。BMSPC是 非排他性地由间充质干细胞（MSC）和造血干/祖细胞组成 （HSPC）。已经显示MSC能够分化为平滑肌细胞（SMC），并且参与平滑肌细胞的分化。 在膀胱再生过程中，虽然HSPCs已经证明了促进新细胞生长的能力， 血管再生组织，同时帮助周围神经和尿道再生。最近 弹性体化学和支架设计的发展使得合成的 具有对再生过程重要的生长因子的受控动力学释放的支架 并且可以模拟膀胱的机械性能。最后，我们建立了一种独特的动物 非人类灵长类动物膀胱增大模型。该模型与其人类高度同源 解剖学和生理学方面的同行。该提案将利用这些最新进展， 干细胞生物学和弹性体化学沿着与我们新建立的膀胱模型，以确定 自体骨髓间充质干细胞和HSPC与新型弹性体支架的联合使用是否可以增强 目前的组织工程技术，以促进膀胱再生。这些包括肌肉和外周 神经再生、血管生成和快速尿道生长。初步数据显示， 两种细胞类型可以实现这些目标，如在体内证实的。