Anti-inflammatory Cell Based Repair of Intervertebral Disc Degeneration

关节盘源性背痛是致残的主要原因之一，涉及腰椎退行性改变。 间盘(IVD)，包括导致生物力学不稳定和 发炎。因为只有一小部分患者对传统治疗有良好的反应 解决症状而不是疾病，需要再生疗法来 治疗椎间盘退行性变(DD)。骨髓间充质干细胞移植治疗糖尿病 可能通过旁分泌信号恢复椎间盘高度和组织结构。这个 退行性IVD小生境代表了基于细胞修复的恶劣微环境，其特征是 通过改变椎间盘内的动态流体静压(HP)，增加促炎水平 细胞因子和巨噬细胞的积聚。虽然没有就以下因素达成共识 增强治疗效果，研究表明，促炎的IVD环境抑制细胞外基质 制作。我们的目标是确定减少促炎和增强抗炎的策略 骨髓间充质干细胞在IVD修复中的炎症反应我们的假设是反- 炎性巨噬细胞和生理性动态机械负荷增强间充质干细胞 免疫调节，提高IVD修复质量。在目标1中，我们将评估 巨噬细胞亚群和静水压力对IVD抗炎交叉反应的影响 MSC-巨噬细胞培养。在目标2中，我们将研究应用负载调制作为一种策略 目的：在IVD压力负荷器官培养模型中增强MSC的免疫调节作用。在AIM 3、我们将评估体内抗炎细胞的治疗潜力。成功 这项研究的完成将确定负荷对MSCs免疫调节的作用 巨噬细胞，并建立致炎微环境DD对细胞的反应 基础修复，优化以增强抗炎活性。

Discogenic back pain, is a leading cause of disability, and involves degenerative changes of the intervertebral disc (IVD), including structural defects that result in biomechanical instability and inflammation. Since only a small subset of patients responds favorably to conventional treatments which address the symptoms but not the disease, there is a need for regenerative therapies to treat disc degeneration (DD). Treatment of DD with mesenchymal stem cell (MSC) transplantation can restore disc height and tissue architecture likely through paracrine signaling. The degenerative IVD niche represents a harsh microenvironment for cell based repair, characterized by changes in intradiscal dynamic hydrostatic pressure (HP), increased levels of pro-inflammatory cytokines, and accumulation of macrophages. While no consensus exists on the factors that enhance treatment efficacy, studies suggest that the pro-inflammatory IVD milieu inhibits ECM production. Our goal is to identify strategies to reduce the pro-inflammatory and enhance the anti- inflammatory responses of bone marrow derived MSCs in IVD repair. Our hypothesis is that anti- inflammatory macrophages and physiological dynamic mechanical loading augment MSC immunomodulation and enhance IVD repair quality. In Aim 1, we will assess the contributions of macrophage subpopulations and hydrostatic pressure on anti-inflammatory cross talk in IVD- MSC-macrophage cultures. In Aim 2, we will investigate applied loading modulation as a strategy to enhance MSC immunomodulation in an IVD compressive loading organ culture model. In Aim 3, we will evaluate the therapeutic potential of anti-inflammatory cells in vivo. Successful completion of this research will identify role of loading on immunomodulation by MSCs and macrophages and establish the response of DD, a pro-inflammatory microenvironment, to cell based repair that is optimized to enhance anti-inflammatory activity.