PLASTICITY IN THE ADULT HUMAN OLIGODENDROCYTE LINEAGE

Preoligodendrocytes have been described in cultures and tissue prints of adult human white matter (Armstrong et al., 1992). To characterize further these precursors of human oligodendrocytes, we have investigat ed whether they express genes playing a critical role in oligodendrocy te development. In the intact human brain, platelet-derived growth fac tor receptor alpha (PDGF alpha R) and myelin transcription factor 1 (M yTI) transcripts are expressed in 1-2% of cells of the oligodendrocyte lineage (OL), and clusters of such cells can be found in the perivent ricular region. Myelin basic protein transcripts containing exon 2 inf ormation (exon 2+ MBP), which are characteristic of the premyelinating stage, are detected in 15-20% of OL cells in vivo. When OL cells are separated from human white matter and allowed to regenerate in vitro, a much larger proportion of these cells express developmentally regula ted genes, while exon 2- MBP and proteolipid protein (PLP) transcripts characteristic of mature OL cells appear transiently downregulated. B asic fibroblast growth factor (bFGF), even in the presence of PDGF, do es not promote DNA synthesis in these cultured OL cells. Yet bFGF indu ces human oligodendrocytes to regenerate their processes rapidly in vi tro and to express O4 antigens as well as exon 2+ MBP, MyTI, and PLP t ranscripts. While bFGF accelerates early regenerative processes, it al so maintains high expression of exon 2+ MBP transcripts in OL cells fo r up to 2 weeks in vitro. In contrast, high levels of insulin in the a bsence of bFGF allow accumulation of exon 2- MBP and PLP transcripts i n most OL cells at 2-3 weeks in vitro. We propose that the myelinated human brain harbors a small pool of precursors of oligodendrocytes and that growth factor-regulated phenotypic plasticity rather than mitoge nic potential accounts for the regeneration of oligodendrocytes in the initial stages of demyelinating diseases such as multiple sclerosis.