Intervertebral disc repair with Mesenchymal Stem Cells

间充质干细胞修复椎间盘

• 批准号: 6956433
• 负责人: JEFFREY C. LOTZ
• 金额: $ 31.99万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-20 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6956433
• 关键词: athymic mouse; bioreactors; bone marrow; cartilage development; cell differentiation; chondrocytes; gel; human tissue; intervertebral disk; laboratory rat; mesenchyme; musculoskeletal regeneration; nonhuman therapy evaluation; spine disorder; stem cell transplantation; stem cells; tissue /cell culture

DESCRIPTION (provided by applicant): Degeneration of the intervertebral disc is a common problem in the adult population, arid leads to significant morbidity and health care expenditure. Current treatment options are limited to conservative care or a relatively few surgical procedures, all of which have less than optimal outcomes. With recent advances in minimally-invasive surgical procedures and biological methods for guiding tissue healing, the prospect of biologic disc repair has gained significant clinical interest. Current efforts have focused on stimulating disc cells with growth factors, transfecting disc cells using gene therapy procedures, or transplanting autologous disc cells that have been expanded ex vivo. These approaches are limited due to the inherent low cellularity of degenerated discs (limiting the efficacy of in situ growth factor or gene therapy), and graft procurement and harvest site morbidity (limiting the practicality of autologous cell transplantation). We hypothesize that mesenchymal stem cells (MSCs) derived from bone marrow have the capacity to differentiate appropriately within the disc environment and thereby initiate a significant repair response. MSCs have the advantage of being readily available (from bone marrow) and can differentiate into a number of relevant cell types. To test the feasibility of using MSCs for disc repair, we propose two specific aims. First, we will characterize how human MSCs (at two different differentiation stages) respond to bioreactor culture under conditions that mimic the in vivo disc environment (low pH, low oxygen concentration, high pressure). We will compare the response of these MSCs to disc cells cultured under the same conditions. In aim 2, the MSC stage that most closely matches disc cells will be injected into degenerated athymic rat-tail discs. The response of the tail discs tc cell injection will be monitored at various time points up to 28 days by assessing histology, matrix production, and biomechanical properties. We anticipate that the results of this research will establish feasibility of using MSCs to guide disc remodeling and repair. Upon successful completion, we will extend this work to a large animal model of disc degeneration where surgical, biological, and mechanical challenges more closely match those anticipated with human use.

描述（由申请人提供）：椎间盘退变是成年人群中的常见问题，并导致显着的发病率和医疗保健支出。目前的治疗选择仅限于保守治疗或相对较少的外科手术，所有这些都没有达到最佳效果。随着微创外科手术和引导组织愈合的生物方法的最新进展，生物椎间盘修复的前景引起了临床的广泛关注。目前的工作重点是用生长因子刺激椎间盘细胞，使用基因治疗程序转染椎间盘细胞，或移植已离体扩增的自体椎间盘细胞。由于退变椎间盘固有的低细胞结构（限制了原位生长因子或基因治疗的功效）以及移植物获取和收获部位发病率（限制了自体细胞移植的实用性），这些方法受到限制。我们假设源自骨髓的间充质干细胞（MSC）具有在椎间盘环境中适当分化的能力，从而启动显着的修复反应。间充质干细胞具有易于获得（来自骨髓）的优点，并且可以分化成许多相关的细胞类型。为了测试使用 MSC 进行椎间盘修复的可行性，我们提出了两个具体目标。首先，我们将描述人类 MSC（处于两个不同分化阶段）在模拟体内椎间盘环境（低 pH、低氧浓度、高压）的条件下如何对生物反应器培养做出反应。我们将比较这些 MSC 对相同条件下培养的椎间盘细胞的反应。在目标 2 中，与椎间盘细胞最匹配的 MSC 阶段将被注射到退化的无胸腺鼠尾椎间盘中。通过评估组织学、基质产生和生物力学特性，将在长达 28 天的不同时间点监测尾盘 tc 细胞注射的反应。我们预计这项研究的结果将确立使用间充质干细胞指导椎间盘重塑和修复的可行性。成功完成后，我们将把这项工作扩展到椎间盘退变的大型动物模型，其中手术、生物和机械挑战更接近于人类使用的预期挑战。