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

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 central nervous system (CNS), become activated and proliferative after demyelinating lesions. However, the extent of endogenous remyelination is limited because of the failure of adult OPCs to mature into myelinating oligodendrocytes (OLs) in the demyelinated CNS. Understanding the molecular mechanisms that 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 bone morphogenetic protein (BMP) type Ia, Ib, and 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. Overexpression of olig1 or olig2 blocked the astrocyte differentiation of adult OPCs induced by BMP2 and 4. Furthermore, overexpression of both olig1 and olig2, but not olig1 or olig2 alone, rescued OL differentiation from inhibition by BMP2 and 4. Our results demonstrated that downregulation 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 overexpression could be a useful therapeutic strategy to enhance endogenous remyelination and facilitate functional recovery in CNS demyelinated disorders.

BMP Signaling Mediates Astrocyte Differentiation of Oligodendrocyte Progenitor Cells

“…Thus, our results are completely consistent with earlier reports, indicating the validity of OPCs analyzed in the present study. It has been reported that several members of the BMP family, such as BMP-2 and 4, have been implicated as repressors of oligodendrocyte development in vitro by shifting oligodendrocyte precursors into the astrocyte lineage (Mabie et al 1997;Grinspan et al 2000;Cheng et al 2007). Thus, we speculated that BMPs in serum may be the key factors to induce astroglial differentiation of OPCs.…”

“…If BMPs induce OPCs to differentiate into astrocytes, the OPCs should express BMPR. Some previous reports indicated that OPCs derived from different sources all expressed BMPR (Mabie et al 1997;Kondo and Raff 2004;Cheng et al 2007). To verify whether the OPCs cultured in our system express BMP receptors, we collected the OPCs cultured in OPC-medium and then analyzed the mRNA expression of BMP receptors (BMPRIa, Ib and II) in OPCs using RT-PCR.…”

“…It has been reported that BMPs contributed to astrocyte differentiation from NPCs (Mabie et al 1997;Grinspan et al 2000;Cheng et al 2007). To explore the possibility whether the serum also contains BMPs that promote astrocyte differentiation of OPCs, we first examined content of BMP-2 and BMP-4 proteins in FBS, rat serum and human serum by ELISA.…”

Promoting remyelination for the treatment of multiple sclerosis: opportunities and challenges

“…BMP4 increases the levels of Wnt (Tbx3) and Notch target genes (Jag1, Hes1, Hes5, Hey1, and Hey2) [45] . BMP and Wnt-β-catenin also upregulate ID2 [42,46] , an inhibitory factor for oPC differentiation, thereby enhancing the crosstalk among signaling pathways that are known to inhibit myelination and repair.…”

Differential and cooperative actions of Olig1 and Olig2 transcription factors on immature proliferating cells after contusive spinal cord injury

“…Although glial progenitor cells (GPCs) which possess the potential to become OLs exist in the adult spinal cord and proliferate in response to SCI (McTigue et al, 2001;Zai and Wrathall, 2005), the extent of spontaneous remyelination is limited (Bunge et al, 1993;Karimi-Abdolrezaee et al, 2006). The failure of spontaneous remyelination may be due to inadequate signaling for the generation of mature OLs from proliferating GPCs (Cheng et al, 2007;Talbott et al, 2005).…”