Stage-specific effects of bone morphogenetic proteins on the oligodendrocyte lineage

Abstract

Oligodendrocyte maturation is regulated by multiple secreted factors present in the brain during critical stages of development. Whereas most of these factors promote oligodendrocyte proliferation and survival, members of the bone morphogenetic protein family (BMPs) recently have been shown to inhibit oligodendrocyte differentiation in vitro. Oligodendrocyte precursors treated with BMPs differentiate to the astrocyte lineage. Given that cells at various stages of the oligodendrocyte lineage have distinct responses to growth factors, we hypothesized that the response to BMP would be stage-specific. Using highly purified, stage-specific cultures, we found that BMP has distinct effects on cultured oligodendrocyte preprogenitors, precursors, and mature oligodendrocytes. Oligodendrocyte preprogenitors (PSA-NCAM+, A2B5-) treated with BMP2 or BMP4 developed a novel astrocyte phenotype characterized by a morphological change and expression of glial fibrillary acidic protein (GFAP) but little glutamine synthetase expression and no labeling with A2B5 antibody. In contrast, treating oligodendrocyte precursors with BMPs resulted in the accumulation of cells with the traditional type 2 astrocyte phenotype (GFAP+, A2B5+). However, many of the cells with an astrocytic morphology did not express GFAP or glutamine synthetase unless thyroid hormone was present in the medium. The addition of fibroblast growth factor along with BMP to either oligodendrocyte preprogenitor or the oligodendrocyte precursor cells inhibited the switch to the astrocyte lineage, whereas platelet-derived growth factor addition had no effect. Treatment of mature oligodendrocytes with BMP elicited no change in morphology or expression of GFAP. These data suggest that as cells progress through the oligodendrocyte lineage, they show developmentally restricted responses to the BMPs.

Pericyte‐derived bone morphogenetic protein 4 underlies white matter damage after chronic hypoperfusion

“…Furthermore, even when the OPCs were cultured in proliferation media which should maintain an OPC state, BMP4 treatment decreased Pdgfra mRNA expression in a dose‐dependent manner. This finding was inconsistent with other studies that demonstrated no effect 16, 57 or even a positive effect 43 of BMP4 on OPC proliferation. However, recent studies have suggested that the effects of BMP4 on stem cell proliferation are dose‐dependent; low dose BMP4 increases proliferation, but high dose BMP4 decreases proliferation of mesenchymal stem cells 53 or primordial germ cells 31.…”

Cortical Spreading Depression Shifts Cell Fate Determination of Progenitor Cells in the Adult Cortex

“…It has been known that BMPs are concerned with regulating the production of both oligodendrocytes and astrocytes. Application of BMPs to cultured cells inhibited the production of oligodendrocytes and facilitated the generation of new astrocytes in vitro (Grinspan et al, 2000;See et al, 2004). During development, overexpression of BMP4 showed both the decrease in oligodendrogenesis and the facilitation of astrogenesis in vivo (Gomes et al, 2003).…”

BMP signaling mutant mice exhibit glial cell maturation defects

“…Overexpression studies of BMPs include the addition of BMPs to in vitro culture systems which inhibits differentiation of OPCs and myelin protein expression but promotes astrocyte development (Grinspan et al, 2000;Gross et al, 1996;Mabie et al, 1997;See et al, 2004). In vivo experiments in which BMPs are overexpressed from neuron-specific promoters, or are over-expressed locally via bead implantation in Xenopus or implantation of BMPoverexpressing cells in chick indicate that BMPs promote astrogliogenesis while inhibiting oligodendrocyte development (Gomes et al, 2003;Mekki-Dauriac et al, 2002;Miller et al, 2004).…”

“…To further confirm that BMP signaling was completely disrupted in the oligodendrocyte lineage in double mutant animals, we investigated whether BMP4 was able to inhibit oligodendrocyte differentiation or induce type II astrogliogenesis of OPCs from double mutant animals, both well-known effects of BMPs on cultured OPCs (Grinspan et al, 2000;Mabie et al, 1997). Cultures from normal and Bmpr double knockout animals were placed in differentiation medium and treated with 50ng/ml BMP or left untreated for two days.…”

“…BMPs have also been hypothesized to regulate the development of both oligodendrocytes and astrocytes. In vitro, addition of BMPs to culture systems promotes astrogliogenesis and inhibits oligodendrogliogenesis (Grinspan et al, 2000;Mabie et al, 1997;See et al, 2004). In vivo, application of BMPs in developing spinal cord decreases the number of differentiated oligodendrocytes (Mekki-Dauriac et al, 2002;Miller et al, 2004).…”