BACKGROUND: Transplantation of olfactory ensheathing cells (OEC) to regenerate damaged spinal tracts and induce functional recovery following spinal cord injury (SCI) has been trialed in the clinic. Evidence suggests that the regenerative capacity of OEC is induced by soluble, secreted factors that influence their microenvironment. These factors may regulate OEC self-renewal and/or induce their capacity to augment spinal cord regeneration. Profiling of secreted factors through a high-throughput expression proteomics approach was undertaken to identify secreted proteins in the conditioned media of OEC under serum-free conditions. RESULTS: Both extracellular matrix and secreted proteins were identified in OEC conditioned media. OEC secrete pro-regulatory and survival factors that modulate nerve nascence and anti-angiogenic factors that regulate functional maturation of nervous tissues. Notable proteins identified include retinoic acid binding proteins and suggest that OEC utilise retinoic acid and other vitamins in their molecular pathways to augment their microenvironment and achieve their regenerative capacities. CONCLUSIONS: Proteins expressed and secreted by OEC indicate that dynamic molecular pathways regulate and influence their cellular self-renewal and regenerative capacities. OEC provide microenvironmental cues that trigger a dynamic switch between modulating pathways in their cell signaling network. Understanding OEC biology will aid in translation of OEC to the clinic in order to develop improved therapeutic modalities for the treatment of SCI. (c) 2008 Society of Chemical Industry.