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.