Adipose-derived stromal cells improve functional recovery after spinal cord injury through TGF-β1/Smad3/PLOD2 pathway activation

Abstract

Transplantation of mesenchymal stromal cells (MSCs) improves functional recovery in experimental models of spinal cord injury (SCI), but the mechanism is not fully understood. Activation of procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2), a collagen-modifying enzyme, reportedly follows MSC transplantation in an SCI animal model. We investigated the regulation of PLOD2 expression and its potential contribution to the neuroprotective effects of adipose-derived stromal cells (ADSCs) following mechanical injury to neurons in vitro and SCI in vivo. ADSCs enhanced wound healing in vitro and promoted functional recovery after their implantation near injury sites in a rat SCI model. These effects correlated with upregulation of PLOD2, MAP2, NSE and GAP43, and downregulation of GFAP, which is indicative of improved neuronal survival and axonal regeneration as well as reduced glial scar formation. The neurorestorative effect of ADSCs was weakened after inhibition of PLOD2 expression. ADSCs appeared to induce PLOD2 upregulation via TGF-β1 secretion, as ADSC-mediated PLOD2 expression, neuronal survival, and functional recovery after SCI were largely prevented by SB431542, a TGF-β1 receptor inhibitor. These findings indicate that ADSCs reduce lesion size and promote functional recovery after SCI mainly through activation of a TGF-β1/P-Samd3/PLOD2 pathway in spinal cord neurons.