Anti-inflammatory Cell Based Repair of Intervertebral Disc Degeneration

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.

Grant Number: 5R01AR077760-05
NIH Institute/Center: NIH
Principal Investigator: NADEEN CHAHINE