SPARC from Olfactory Ensheathing Cells Stimulates Schwann Cells to Promote Neurite Outgrowth and Enhances Spinal Cord Repair

Abstract

Olfactory ensheathing cells (OECs) transplanted into the lesioned CNS can stimulate reportedly different degrees of regeneration, remyelination, and functional recovery, but little is known about the mechanisms OECs may use to stimulate endogenous repair. Here, we used a functional proteomic approach, isotope-coded affinity tagging and mass spectrometry, to identify active components of the OEC secreteome that differentially stimulate outgrowth. SPARC (secreted protein acidic rich in cysteine) (osteonectin) was identified as an OEC-derived matricellular protein that can indirectly enhance the ability of Schwann cells to stimulate dorsal root ganglion outgrowth in vitro. SPARC stimulates Schwann cell-mediated outgrowth by cooperative signal with laminin-1 and transforming growth factor ␤. Furthermore, when SPARC-null OECs were transplanted into lesioned rat spinal cord, the absence of OEC-secreted SPARC results in an attenuation of outgrowth of specific subsets of sensory and supraspinal axons and changes the pattern of macrophage infiltration in response to the transplanted cells. These data provide the first evidence for a role for SPARC in modulating different aspects of CNS repair and indicate that SPARC can change the activation state of endogenous Schwann cells, resulting in the promotion of outgrowth in vitro, and in vivo.

SPARC is expressed by macroglia and microglia in the developing and mature nervous system

“…SPARC promotes axon outgrowth indirectly, by enhancing the ability of Schwann cells to support neurite outgrowth (Bampton et al, 2005;Au et al, 2007). When SPARC null OECs are transplanted into the injured rat spinal cord, the outgrowth of specific subsets of sensory and supraspinal axons is reduced, and the immune response is altered (Au et al, 2007). Furthermore, in the absence of OECderived SPARC, we found that SPARC is present in endogenous glia surrounding the lesion site (Au et al, 2007), which further supports a potential role for SPARC in CNS repair.…”

“…This suggests that SPARC may be involved in regulating plasticity and repair in the CNS. In support of this, we have shown that SPARC is a major component of the neurite outgrowth-promoting activity of OEC-conditioned medium in a dorsal root ganglion assay (Au et al, 2007). SPARC promotes axon outgrowth indirectly, by enhancing the ability of Schwann cells to support neurite outgrowth (Bampton et al, 2005;Au et al, 2007).…”

“…6; Table 1) (Au et al, 2007), which migrate in tandem with their developing nerves (Tennent and Chuah, 1996;Jessen and Mirsky, 2005). Later, SPARC is ideally positioned to play a role in the formation and maintenance of the basal lamina that is necessary for Schwann cell myelination (Fig.…”

“…In support of this, we have shown that SPARC is a major component of the neurite outgrowth-promoting activity of OEC-conditioned medium in a dorsal root ganglion assay (Au et al, 2007). SPARC promotes axon outgrowth indirectly, by enhancing the ability of Schwann cells to support neurite outgrowth (Bampton et al, 2005;Au et al, 2007). When SPARC null OECs are transplanted into the injured rat spinal cord, the outgrowth of specific subsets of sensory and supraspinal axons is reduced, and the immune response is altered (Au et al, 2007).…”

“…OECs that are derived from the peripheral olfactory system, lamina propria (LP)-OECs, can minimize glial scar and cavity formation, stimulate axon sprouting and invasion of Schwann cells, and promote directed angiogenesis (Ramer et al, 2004;Richter et al, 2005). Since the cellular mechanisms underlying these effects are not well understood, we recently applied a proteomics screen to identify secreted factors produced by OECs that support neural tissue repair (Au et al, 2007). Our analysis revealed high levels of the glycoprotein, secreted protein acidic and rich in cysteine (SPARC), also known as osteonectin and basement membrane .…”