Platelet-derived growth factor from astrocytes drives the clock that times oligodendrocyte development in culture

Abstract

The various cell types in a multicellular animal differentiate on a predictable schedule but the mechanisms responsible for timing cell differentiation are largely unknown. We have studied a population of bipotential glial (O-2A) progenitor cells in the developing rat optic nerve that gives rise to oligodendrocytes beginning at birth and to type-2 astrocytes beginning in the second postnatal week. Whereas, in vivo, these O-2A progenitor cells proliferate and give rise to postimitotic oligodendrocytes over several weeks, in serum-free (or low-serum) culture they stop dividing prematurely and differentiate into oligodendrocytes within two or three days. The normal timing of oligodendrocyte development can be restored if embryonic optic-nerve cells are cultured in medium conditioned by type-1 astrocytes, the first glial cells to differentiate in the nerve: in this case the progenitor cells continue to proliferate, the first oligodendrocytes appear on the equivalent of the day of birth, and new oligodendrocytes continue to develop over several weeks, just as in vivo. Here we show that platelet-derived growth factor (PDGF) can replace type-1-astrocyte-conditioned medium in restoring the normal timing of oligodendrocyte differentiation in vitro and that anti-PDGF antibodies inhibit this property of the appropriately conditioned medium. We also show that PDGF is present in the developing optic nerve. These findings suggest that type-1-astrocyte-derived PDGF drives the clock that times oligodendrocyte development.

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

“…The most widely used in vitro model is primary culture of oPCs, as isolated oligodendrocytes in culture follow a developmental program that is very similar to that in vivo [9] , suggesting that intrinsic regulation exists to instruct oPCs to differentiate into mature oligodendrocytes and produce process [10] . Slice cultures can, to some extent, maintain the 3D architecture of the cerebellar white and grey matter and provide a valuable ex vivo model to study demyelination/ remyelination.…”

Oligodendrocyte progenitor cells can act as cell of origin for experimental glioma

“…The O2-A glial progenitor cell that can give rise to oligodendrocytes and type-2 astrocytes in vitro has been shown to proliferate in response to PDGF and differentiate on withdrawal of PDGF Raff et al, 1988). Also in vivo O2-A cells have been shown to respond to PDGF signaling by proliferation (Calver et al, 1998).…”

Cell Therapy for Multiple Sclerosis

“…One approach is to increase the recruitment and number of cycling OPCs by growth factor treatment. Candidates include platelet-derived growth factor [88][89][90], neuregulin-1, which is not essential for myelination in the CNS but can induce hypermyelination when overexpressed [91], and epidermal growth factor [59]. In addition, sonic hedgehog signaling stimulates the maintenance and renewal of neural precursors in the neurogenic niches of the adult brain [92,93].…”