Structured co-culture of stem cells and chondrocytes for spinal disc repair

干细胞和软骨细胞的结构化共培养用于椎间盘修复

• 批准号: 8354655
• 负责人: JEFFREY C. LOTZ
• 金额: $ 17.38万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8354655
• 关键词: Adoption; Adult; Animal Model; Animals; Back Pain; Behavior; Biological Response Modifier Therapy; Biomechanics; Bone necrosis; Cartilage; Cell Culture Techniques; Cell Nucleus; Cell Therapy; Cell physiology; Cells; Chondrocytes; Chronic low back pain; Clinical; Coculture Techniques; Collagen; Data; Degenerative polyarthritis; Developmental Process; Disease; Drug Formulations; Ensure; Environment; Equilibrium; Fibrin; Functional disorder; Future; Gene Expression; Goals; Gold; Grant; Growth Factor; Healed; Hypertrophy; Hypoxia; Immune response; In Vitro; Inflammation; Inflammatory; Injection of therapeutic agent; Injury; Intervertebral disc structure; Lead; Matrix Metalloproteinases; Mechanics; Mesenchymal Stem Cells; Methods; Modeling; Motion; Musculoskeletal; Needles; Nutrient; Operative Surgical Procedures; Osteoporosis; Outpatients; Pain; Patients; Phenotype; Physical condensation; Physiological; Pre-Clinical Model; Procedures; Process; Production; Property; Proteoglycan; Proteolysis; Rattus; Rejuvenation; Research; Safety; Signal Transduction; Source; Spinal; Spinal Fusion; Spinal Injections; Stem cells; Structure; System; Techniques; Testing; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Tissue Engineering; Tissues; Translations; United States National Institutes of Health; Water; bone; cell behavior; cell type; cytokine; density; deprivation; disability; disc regeneration; healing; improved; in vivo; injured; intervertebral disk degeneration; minimally invasive; novel; nucleus pulposus; preclinical study; prevent; repaired; resilience; response; restoration; spine bone structure; stem cell differentiation; stem cell therapy; therapy design; therapy development; three dimensional structure; treatment strategy; trend

DESCRIPTION (provided by applicant): The overall goal of this grant is to develop improved methods of treating axial back pain via intervertebral disc tissue engineering. Our previous research indicates that disc degeneration is a manifestation of poor nucleus cell function. Adult mesenchymal stem cells (MSCs) are an attractive cell source for nucleus rejuvenation, however, their differentiation and function need to be optimized to thrive in the challenging degenerate disc environment. To improve MSC resilience in vivo, we discovered a novel co-culture system where MSCs are packaged in a spherical configuration with chondrocytes. This bi-laminar structure allows for homotypic and heterotypic cellular interactions that mimic the developmental processes of condensation (where cell aggregates form) and induction (where a mature tissue layer directs the differentiation of a na¿ve one). Our ongoing studies demonstrate that bi-laminar cell pellets (BCPs) have superior matrix synthesis and gene expression under in vitro conditions like those of the degenerate disc. Given the promising BCP results, we now propose in Aim 1 to optimize a small BCP configuration to for minimally-invasive intradiscal injection. In Aim 3 we will determine whether optimized BCPs lead to morphologically-relevant improvements (as compared to appropriate control conditions) within a small animal model of disc injury. PUBLIC HEALTH RELEVANCE: The goals of this new R21 application are to: 1) optimize a stem cell therapy for intervertebral disc degeneration; and 2) demonstrate disease modifying activity in a small animal model. This research will have substantial impact by providing a minimally- invasive therapy for the management of patients with the most common and costly musculoskeletal condition - chronic low back pain. The proposed therapeutic approach may also have future applications for treatment of cartilage and bone conditions, such as osteoarthritis and osteonecrosis.

描述(由申请者提供)：这笔赠款的总体目标是通过椎间盘组织工程开发治疗轴性背痛的改进方法。我们先前的研究表明，椎间盘退变是核细胞功能低下的表现。成体间充质干细胞(MSCs)是一种有吸引力的核再生细胞来源，但其分化和功能需要优化，才能在具有挑战性的退变椎间盘环境中茁壮成长。为了提高MSC在体内的弹性，我们发现了一种新的联合培养系统，将MSCs与软骨细胞包装成球形结构。这种双层结构允许同型和异型细胞相互作用，模拟凝聚(细胞聚集体形成)和诱导(成熟组织层指导幼稚组织层分化)的发育过程。我们正在进行的研究表明，双层细胞颗粒(BCP)在类似于退变椎间盘的体外条件下具有优越的基质合成和基因表达。鉴于前景看好的BCP结果，我们现在在目标1中建议优化一种小型BCP配置，以用于微创椎间盘内注射。在目标3中，我们将确定优化的BCP是否在小动物椎间盘损伤模型中导致与形态相关的改善(与适当的控制条件相比)。 公共卫生相关性：这一新的R21应用程序的目标是：1)优化针对椎间盘退变的干细胞疗法；以及2)在小动物模型中展示疾病修改活性。这项研究将为患有最常见和最昂贵的肌肉骨骼疾病--慢性下腰痛的患者提供一种微创疗法，从而产生重大影响。拟议的治疗方法也可能在未来应用于软骨和骨骼疾病的治疗，如骨关节炎和骨坏死。