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Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1990 Aug;87(16):6368–6372. doi: 10.1073/pnas.87.16.6368

Cooperation between two growth factors promotes extended self-renewal and inhibits differentiation of oligodendrocyte-type-2 astrocyte (O-2A) progenitor cells.

O Bögler 1, D Wren 1, S C Barnett 1, H Land 1, M Noble 1
PMCID: PMC54535  PMID: 2201028

Abstract

Bipotential oligodendrocyte-type-2 astrocyte (O-2A) progenitor cells, which give rise to oligodendrocytes and type-2 astrocytes in cultures of rat optic nerve, are one of the few cell types in which most aspects of proliferation and differentiation can be manipulated in a defined in vitro environment. Previous studies have shown that O-2A progenitors exposed to platelet-derived growth factor (PDGF) divide as migratory bipolar cells a limited number of times, with a cell cycle time of 18 hr, before clonally related progenitors differentiate into nondividing oligodendrocytes with a timing similar to that seen in vivo. In contrast, O-2A progenitors grown in the absence of mitogen do not divide but instead differentiate prematurely into oligodendrocytes, and progenitors exposed to appropriate inducing factors differentiate into type-2 astrocytes. We now have found that O-2A progenitors can be induced to undergo continuous self-renewal in the absence of oligodendrocytic differentiation by exposure to a combination of PDGF and basic fibroblast growth factor (bFGF). With the exception of the inhibition of differentiation, the O-2A progenitors exposed to PDGF and bFGF behaved similarly to those exposed to PDGF alone. In contrast, progenitors exposed to basic bFGF alone were multipolar, had a cell-cycle length of 45 hr, showed little migratory behavior, underwent premature oligodendrocytic differentiation, and did not cease division upon expression of oligodendrocyte marker antigens. Thus, inhibition of differentiation required the presence of both mitogens. Our results demonstrate that PDGF and bFGF act on O-2A progenitors as both inducers of division and as regulators of differentiation that modulate multiple aspects of O-2A progenitor development and, additionally, reveal a previously unrecognized means of regulating self-renewal processes, wherein cooperation between growth factors promotes continuous division in the absence of differentiation.

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Selected References

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  1. Bottenstein J. E., Sato G. H. Growth of a rat neuroblastoma cell line in serum-free supplemented medium. Proc Natl Acad Sci U S A. 1979 Jan;76(1):514–517. doi: 10.1073/pnas.76.1.514. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Eccleston P. A., Silberberg D. H. Fibroblast growth factor is a mitogen for oligodendrocytes in vitro. Brain Res. 1985 Aug;353(2):315–318. doi: 10.1016/0165-3806(85)90221-4. [DOI] [PubMed] [Google Scholar]
  3. Eisenbarth G. S., Walsh F. S., Nirenberg M. Monoclonal antibody to a plasma membrane antigen of neurons. Proc Natl Acad Sci U S A. 1979 Oct;76(10):4913–4917. doi: 10.1073/pnas.76.10.4913. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Gearing D. P., Gough N. M., King J. A., Hilton D. J., Nicola N. A., Simpson R. J., Nice E. C., Kelso A., Metcalf D. Molecular cloning and expression of cDNA encoding a murine myeloid leukaemia inhibitory factor (LIF). EMBO J. 1987 Dec 20;6(13):3995–4002. doi: 10.1002/j.1460-2075.1987.tb02742.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Gonzalez A. M., Buscaglia M., Ong M., Baird A. Distribution of basic fibroblast growth factor in the 18-day rat fetus: localization in the basement membranes of diverse tissues. J Cell Biol. 1990 Mar;110(3):753–765. doi: 10.1083/jcb.110.3.753. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Hughes S. M., Lillien L. E., Raff M. C., Rohrer H., Sendtner M. Ciliary neurotrophic factor induces type-2 astrocyte differentiation in culture. Nature. 1988 Sep 1;335(6185):70–73. doi: 10.1038/335070a0. [DOI] [PubMed] [Google Scholar]
  7. Johnson G. D., Davidson R. S., McNamee K. C., Russell G., Goodwin D., Holborow E. J. Fading of immunofluorescence during microscopy: a study of the phenomenon and its remedy. J Immunol Methods. 1982 Dec 17;55(2):231–242. doi: 10.1016/0022-1759(82)90035-7. [DOI] [PubMed] [Google Scholar]
  8. Lillien L. E., Sendtner M., Rohrer H., Hughes S. M., Raff M. C. Type-2 astrocyte development in rat brain cultures is initiated by a CNTF-like protein produced by type-1 astrocytes. Neuron. 1988 Aug;1(6):485–494. doi: 10.1016/0896-6273(88)90179-1. [DOI] [PubMed] [Google Scholar]
  9. Logan A., Logan S. D. Distribution of fibroblast growth factor in the central and peripheral nervous systems of various mammals. Neurosci Lett. 1986 Aug 29;69(2):162–165. doi: 10.1016/0304-3940(86)90596-3. [DOI] [PubMed] [Google Scholar]
  10. Miller R. H., David S., Patel R., Abney E. R., Raff M. C. A quantitative immunohistochemical study of macroglial cell development in the rat optic nerve: in vivo evidence for two distinct astrocyte lineages. Dev Biol. 1985 Sep;111(1):35–41. doi: 10.1016/0012-1606(85)90432-4. [DOI] [PubMed] [Google Scholar]
  11. Noble M., Murray K. Purified astrocytes promote the in vitro division of a bipotential glial progenitor cell. EMBO J. 1984 Oct;3(10):2243–2247. doi: 10.1002/j.1460-2075.1984.tb02122.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Noble M., Murray K., Stroobant P., Waterfield M. D., Riddle P. Platelet-derived growth factor promotes division and motility and inhibits premature differentiation of the oligodendrocyte/type-2 astrocyte progenitor cell. Nature. 1988 Jun 9;333(6173):560–562. doi: 10.1038/333560a0. [DOI] [PubMed] [Google Scholar]
  13. Pruss R. M. Thy-1 antigen on astrocytes in long-term cultures of rat central nervous system. Nature. 1979 Aug 23;280(5724):688–690. doi: 10.1038/280688a0. [DOI] [PubMed] [Google Scholar]
  14. Raff M. C., Abney E. R., Fok-Seang J. Reconstitution of a developmental clock in vitro: a critical role for astrocytes in the timing of oligodendrocyte differentiation. Cell. 1985 Aug;42(1):61–69. doi: 10.1016/s0092-8674(85)80101-x. [DOI] [PubMed] [Google Scholar]
  15. Raff M. C., Lillien L. E., Richardson W. D., Burne J. F., Noble M. D. Platelet-derived growth factor from astrocytes drives the clock that times oligodendrocyte development in culture. Nature. 1988 Jun 9;333(6173):562–565. doi: 10.1038/333562a0. [DOI] [PubMed] [Google Scholar]
  16. Raff M. C., Miller R. H., Noble M. A glial progenitor cell that develops in vitro into an astrocyte or an oligodendrocyte depending on culture medium. Nature. 1983 Jun 2;303(5916):390–396. doi: 10.1038/303390a0. [DOI] [PubMed] [Google Scholar]
  17. Raff M. C., Mirsky R., Fields K. L., Lisak R. P., Dorfman S. H., Silberberg D. H., Gregson N. A., Leibowitz S., Kennedy M. C. Galactocerebroside is a specific cell-surface antigenic marker for oligodendrocytes in culture. Nature. 1978 Aug 24;274(5673):813–816. [PubMed] [Google Scholar]
  18. Ranscht B., Clapshaw P. A., Price J., Noble M., Seifert W. Development of oligodendrocytes and Schwann cells studied with a monoclonal antibody against galactocerebroside. Proc Natl Acad Sci U S A. 1982 Apr;79(8):2709–2713. doi: 10.1073/pnas.79.8.2709. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Richardson W. D., Pringle N., Mosley M. J., Westermark B., Dubois-Dalcq M. A role for platelet-derived growth factor in normal gliogenesis in the central nervous system. Cell. 1988 Apr 22;53(2):309–319. doi: 10.1016/0092-8674(88)90392-3. [DOI] [PubMed] [Google Scholar]
  20. Saneto R. P., de Vellis J. Characterization of cultured rat oligodendrocytes proliferating in a serum-free, chemically defined medium. Proc Natl Acad Sci U S A. 1985 May;82(10):3509–3513. doi: 10.1073/pnas.82.10.3509. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Small R. K., Riddle P., Noble M. Evidence for migration of oligodendrocyte--type-2 astrocyte progenitor cells into the developing rat optic nerve. Nature. 1987 Jul 9;328(6126):155–157. doi: 10.1038/328155a0. [DOI] [PubMed] [Google Scholar]
  22. Smith A. G., Heath J. K., Donaldson D. D., Wong G. G., Moreau J., Stahl M., Rogers D. Inhibition of pluripotential embryonic stem cell differentiation by purified polypeptides. Nature. 1988 Dec 15;336(6200):688–690. doi: 10.1038/336688a0. [DOI] [PubMed] [Google Scholar]
  23. Temple S., Raff M. C. Clonal analysis of oligodendrocyte development in culture: evidence for a developmental clock that counts cell divisions. Cell. 1986 Mar 14;44(5):773–779. doi: 10.1016/0092-8674(86)90843-3. [DOI] [PubMed] [Google Scholar]
  24. Williams R. L., Hilton D. J., Pease S., Willson T. A., Stewart C. L., Gearing D. P., Wagner E. F., Metcalf D., Nicola N. A., Gough N. M. Myeloid leukaemia inhibitory factor maintains the developmental potential of embryonic stem cells. Nature. 1988 Dec 15;336(6200):684–687. doi: 10.1038/336684a0. [DOI] [PubMed] [Google Scholar]
  25. Yamamori T., Fukada K., Aebersold R., Korsching S., Fann M. J., Patterson P. H. The cholinergic neuronal differentiation factor from heart cells is identical to leukemia inhibitory factor. Science. 1989 Dec 15;246(4936):1412–1416. doi: 10.1126/science.2512641. [DOI] [PubMed] [Google Scholar]

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