RT Journal Article
SR Electronic
T1 A Multilevel Screening Strategy Defines a Molecular Fingerprint of Proregenerative Olfactory Ensheathing Cells and Identifies SCARB2, a Protein That Improves Regenerative Sprouting of Injured Sensory Spinal Axons
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 11116
OP 11135
DO 10.1523/JNEUROSCI.1002-13.2013
VO 33
IS 27
A1 Kasper C. D. Roet
A1 Elske H. P. Franssen
A1 Frederik M. de Bree
A1 Anke H. W. Essing
A1 Sjirk-Jan J. Zijlstra
A1 Nitish D. Fagoe
A1 Hannah M. Eggink
A1 Ruben Eggers
A1 August B. Smit
A1 Ronald E. van Kesteren
A1 Joost Verhaagen
YR 2013
UL http://www.jneurosci.org/content/33/27/11116.abstract
AB Olfactory ensheathing cells (OECs) have neuro-restorative properties in animal models for spinal cord injury, stroke, and amyotrophic lateral sclerosis. Here we used a multistep screening approach to discover genes specifically contributing to the regeneration-promoting properties of OECs. Microarray screening of the injured olfactory pathway and of cultured OECs identified 102 genes that were subsequently functionally characterized in cocultures of OECs and primary dorsal root ganglion (DRG) neurons. Selective siRNA-mediated knockdown of 16 genes in OECs (ADAMTS1, BM385941, FZD1, GFRA1, LEPRE1, NCAM1, NID2, NRP1, MSLN, RND1, S100A9, SCARB2, SERPINI1, SERPINF1, TGFB2, and VAV1) significantly reduced outgrowth of cocultured DRG neurons, indicating that endogenous expression of these genes in OECs supports neurite extension of DRG neurons. In a gain-of-function screen for 18 genes, six (CX3CL1, FZD1, LEPRE1, S100A9, SCARB2, and SERPINI1) enhanced and one (TIMP2) inhibited neurite growth. The most potent hit in both the loss- and gain-of-function screens was SCARB2, a protein that promotes cholesterol secretion. Transplants of fibroblasts that were genetically modified to overexpress SCARB2 significantly increased the number of regenerating DRG axons that grew toward the center of a spinal cord lesion in rats. We conclude that expression of SCARB2 enhances regenerative sprouting and that SCARB2 contributes to OEC-mediated neuronal repair.