Abstract
Stem cell–based regenerative strategies are promising for intervertebral disc degeneration. Stimulation of bone-marrow- and adipose-derived multipotent stem cells with recombinant human growth differentiation factor 6 (rhGDF6) promotes anabolic nucleus pulposus like phenotypes. In comparison to mesenchymal stem cells, adipose-derived multipotent stem cells exhibit greater NP-marker gene expression and proteoglycan-rich matrix production. To understand these response differences, we investigated bone morphogenetic protein receptor profiles in donor-matched human mesenchymal stem cells and adipose-derived multipotent stem cells, determined differences in rhGDF6 signalling and their importance in NP-like differentiation between cell populations. Bone morphogenetic protein receptor expression in mesenchymal stem cells and adipose-derived multipotent stem cells revealed elevated and less variable expression of BMPR2 in adipose-derived multipotent stem cells, which corresponded with increased downstream pathway activation (SMAD1/5/8, ERK1/2). Inhibitor studies demonstrated SMAD1/5/8 signalling was required for rhGDF6-induced nucleus-pulposus-like adipose-derived multipotent stem cell differentiation, while ERK1/2 contributed significantly to critical nucleus pulposus gene expression, aggrecan and type II collagen production. These data inform cell regenerative therapeutic choices for intervertebral disc degeneration regeneration and identify further potential optimisation targets.
Highlights
Intervertebral disc (IVD) degeneration is a leading cause of low back pain, for which at present, few effective management options are available
Type I and type II BMP receptor subunit protein expression was profiled in donor-matched MSCs and ASCs (n = 6) through western blot (Figure 1). recombinant human growth differentiation factor 6 (rhGDF6) is known to have the ability to bind to the type I receptors BMPR1A and BMPR1B
The expression of ACVR2A, a hypothesized GDF6 receptor, appeared higher in ASCs than MSCs, the level of expression was appreciably lower in both populations compared to other type II receptors and variable leading to no statistically significant difference
Summary
Intervertebral disc (IVD) degeneration is a leading cause of low back pain, for which at present, few effective management options are available. Preventative conservative treatments often offer short-term relief from symptomatic pain and improve functionality but fail to address the underlying progressive nature of disc degeneration. In cases of long-term and severe low back pain, costly and invasive surgical interventions, such as vertebral fusions or discectomies, are used as last-resort strategies. Outcomes from such procedures, though often positive, can result in altered spinal loading and degeneration of IVDs adjacent to the intervention site.[1,2] Due to the failure of these conventional therapies to address the underlying pathology, there is a need to develop effective regenerative strategies targeting IVD degeneration. Effective restoration of a healthy and functional extracellular matrix (ECM) in the central portion of the IVD, the nucleus pulposus (NP), has been a focus of research in the field.[3,4,5] Several regenerative medicine strategies have been proposed, but the location and enclosed-nature of the NP within the IVD make adult stem cell therapy alongside small molecule biologics an attractive option.[5,6]
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