BMP Signaling and Olig1/2 Interact to Regulate the Differentiation and Maturation of Adult Oligodendrocyte Precursor Cells

¹ Kentucky Spinal Cord Injury Research Center, and Departments of Neurological Surgery
² Kentucky Spinal Cord Injury Research Center, and Departments of Neurological Surgery and Department of Anesthesiology, the Second Xian-Ya Hospital of South Central University, Changsha, Hunan 410011, P.R. China
³ Kentucky Spinal Cord Injury Research Center, and Departments of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, Kentucky, 40202
⁴ Kentucky Spinal Cord Injury Research Center, and Departments of Neurological Surgery and Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, Kentucky, 40202

^* To whom correspondence should be addressed. E-mail: q0cao001{at}gwise.louisville.edu.

	Abstract

Promotion of remyelination is an important therapeutic strategy for the treatment of the demyelinating neurological disorders. Adult oligodendrocyte precursor cells (OPCs), which normally reside quiescently in the adult CNS, become activated and proliferative after demyelinating lesions. However, the extent of endogenous remyelination is limited due to the failure of adult OPCs to mature into myelinating OLs in the demyelinated CNS. Understanding the molecular mechanisms which regulate the differentiation of adult OPCs could lead to new therapeutic strategies to treat these disorders. In this study, we established a stable culture of adult spinal cord OPCs and developed a reliable in vitro protocol to induce their sequential differentiation. Adult OPCs expressed BMP type Ia, Ib and type II receptor subunits, which are required for BMP signal transduction. BMP2 and 4 promoted dose-dependent astrocyte differentiation of adult OPCs with concurrent suppression of OL differentiation. Treatment of OPCs with BMP2 and 4 increased ID4 expression and decreased the expression of olig1 and olig2. Over-expression of olig1 or olig2 blocked the astrocyte differentiation of adult OPCs induced by BMP2 and 4. Furthermore, over-expression of both olig1 and olig2, but not olig1 or olig2 alone, rescued OL differentiation from inhibition by BMP2 and 4. Our results demonstrated that down-regulation of olig1 and olig2 is an important mechanism by which BMP2 and 4 inhibit OL differentiation of adult OPCs. These data suggest that blocking BMP signaling combined with olig1/2 over-expression could be a useful therapeutic strategy to enhance endogenous remyelination and facilitate functional recovery in CNS demyelinated disorders.