Inhibition of TROY promotes OPC differentiation and increases therapeutic efficacy of OPC graft for spinal cord injury.

Abstract

Endogenous or graft-derived oligodendrocytes promote myelination and aid in the recovery from central nervous system (CNS) injury. Regulatory mechanisms underlying neural myelination and remyelination in response to injury, including spinal cord injury (SCI), are unclear. In the present study, we demonstrated that TROY serves as an important negative regulator of oligodendrocyte development and that TROY inhibition augments the repair potential of oligodendrocyte precursor cell (OPC) graft for SCI. TROY expression was detected by reverse transcriptase-polymerase chain reaction in OPCs as well as in differentiated premature and mature oligodendrocytes of postnatal mice. Pharmacological inhibition or RNAi-induced knockdown of TROY promotes OPC differentiation, whereas overexpression of TROY dampens oligodendrocyte maturation. Further, treatment of cocultures of DRG neurons and OPCs with TROY inhibitors promotes myelination and myelin-sheath-like structures. Mechanically, protein kinase C (PKC) signaling is involved in the regulation of the inhibitory effects of TROY. Moreover, in situ transplantation of OPCs with TROY knockdown leads to notable remyelination and neurological recovery in rats with SCI. Our results indicate that TROY negatively modulates remyelination in the CNS, and thus may be a suitable target for improving the therapeutic efficacy of cell transplantation for CNS injury.

• Authors: Liang Sun, Shengliang Liu, Qi Sun, Zhuying Li, Fengyan Xu, Chunmei Hou, Toshihide Harada, Ming Chu, Kun Xu, Xiaoling Feng, Yongshun Duan, Yafang Zhang, Shuliang Wu
• Journal: Stem cells and development (Stem Cells Dev) Vol. 23 Issue 17 Pg. 2104-18 (Sep 01 2014) ISSN: 1557-8534 [Electronic] United States
• PMID: 24749558 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Protein Kinase Inhibitors
• Receptors, Tumor Necrosis Factor
• Tnfrsf19 protein, mouse
• Protein Kinase C

Topics

• Animals
• Cell Differentiation
• Cells, Cultured
• Female
• Gene Knockdown Techniques
• Mice, Inbred C57BL
• Nerve Fibers, Myelinated (physiology)
• Neural Stem Cells (physiology, transplantation)
• Oligodendroglia (physiology)
• Protein Kinase C (antagonists & inhibitors, metabolism)
• Protein Kinase Inhibitors (pharmacology)
• Rats, Sprague-Dawley
• Receptors, Tumor Necrosis Factor (genetics, metabolism)
• Spinal Cord (metabolism, pathology)
• Spinal Cord Injuries (therapy)