High BMPR2 expression leads to enhanced SMAD1/5/8 signalling and GDF6 responsiveness in human adipose-derived stem cells: implications for stem cell therapies for intervertebral disc degeneration

Stem cell-based regenerative strategies are promising for intervertebral disc (IVD) degeneration. Stimulation of bone marrow- and adipose-derived multipotent stem cells (MSCs; ASCs) with recombinant human growth differentiation factor 6 (rhGDF6) promotes anabolic nucleus pulposus (NP)-like phenotypes. In comparison to MSCs, ASCs exhibit greater NP-marker gene expression and proteoglycan-rich matrix production. To understand these response differences, we investigated bone morphogenetic protein receptor (BMPR) profiles in donor-matched human MSCs and ASCs, determined differences in rhGDF6 signalling and their importance in NP-like differentiation between cell populations. BMP receptor expression in MSCs and ASCs revealed elevated and less variable expression of BMPR2 in ASCs, which corresponded with increased downstream pathway activation (SMAD1/5/8, ERK1/2). Inhibitor studies demonstrated SMAD1/5/8 signalling was required for rhGDF6-induced NP-like ASC differentiation, while ERK1/2 contributed significantly to critical NP gene expression, aggrecan and type II collagen production. This data informs cell regenerative therapeutic choices for IVD regeneration and identifies further potential optimisation targets.