Anti-inflammatory Cell Based Repair of Intervertebral Disc Degeneration

椎间盘源性背痛是残疾的主要原因，涉及椎间盘的退行性变化。 椎间盘（IVD），包括导致生物力学不稳定性的结构缺陷， 炎症由于只有一小部分患者对常规治疗反应良好， 这些方法解决了症状，但没有解决疾病，因此需要再生疗法， 治疗椎间盘退变（DD）。间充质干细胞移植治疗DD 可以通过旁分泌信号恢复椎间盘高度和组织结构。的 退行性IVD小生境代表了基于细胞的修复的恶劣微环境，其特征在于 通过椎间盘内动态静水压力（HP）的变化，促炎性细胞因子水平的增加， 细胞因子和巨噬细胞的积累。虽然在这些因素上没有达成共识， 增强治疗效果，研究表明促炎性IVD环境抑制ECM 生产我们的目标是确定减少促炎性和增强抗炎性的策略， 骨髓来源的MSC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动态机械负荷增强MSC 免疫调节和增强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中抗炎性串扰的影响- MSC-巨噬细胞培养物。在目标2中，我们将研究应用负载调制作为一种策略 以增强IVD压缩负荷器官培养模型中的MSC免疫调节。在Aim中 3、我们将评估抗炎细胞在体内的治疗潜力。成功 这项研究的完成将确定MSC对免疫调节的负载作用， 巨噬细胞，并建立DD，一种促炎微环境，对细胞的反应， 基于修复，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.