Oligodendrocyte progenitors are present in the normal adult human CNS and in the lesions of multiple sclerosis

Abstract

In multiple sclerosis, partial remyelination is conspicuous in many lesions, but widespread and lasting myelin repair ultimately fails as disability and handicap accumulate. Thus far, the precise identity of the cell responsible for limited spontaneous myelin repair has remained obscure. In the rodent, the proliferative oligodendrocyte progenitor is the most efficient remyelinating cell; this has now been identified in cultures prepared from normal human brain, but has proved difficult to demonstrate in situ. We adapted techniques using antibodies against the human platelet-derived growth factor-alpha receptor to identify oligodendrocyte progenitors in human tissue sections. Small numbers of oligodendrocyte progenitors were found in normal adult human white matter. Progenitors were also demonstrable in acute and chronic lesions from patients dying with multiple sclerosis, but with no evidence of any marked reactive increase in cell numbers. Understanding the biology of the remyelinating cell, and in particular the reason for its apparent failure to repopulate demyelinated lesions, is important for the development of remyelination treatments.

Cell Therapy for Multiple Sclerosis

“…Multi-potential precursors are abundant in many regions of the adult brain parenchyma [31][32][33][34]. In particular, oligodendrocyte progenitor cells (OPCs) were isolated from various regions of the adult rodent CNS [35][36][37], and were identified also in the adult human brain [38][39][40][41][42] and spinal cord [43]. OPCs are identified by expression of chondroitin-sulfate proteoglycan NG2+ and of platelet-derived growth factor receptor-α are highly abundant in the adult CNS, comprising up to 5% of its cells [37].…”

“…Some studies showed a depletion of progenitor cells after focal demyelination in experimental animals [52,74], whereas others showed that repeated episodes of demyelination did not slow down remyelination [75]. In pathological specimens of chronic MS lesions in human patients, neither decrease nor reactive increase was observed relative to normal white matter [39,[76][77][78]. This suggests that the response of the progenitor cell population to the demyelinating process in the human brain is deficient.…”

“…Alternatively, if reversible cell autonomous factors or inhibitory factors that are expressed in the demyelinated tissue limit OPC differentiation into remyelinating oligodendrocytes, then the rationale treatment would be to target them directly. Active inhibition of resident OPCs is suggested by the sharp border of demyelinated plaque, surrounded by OPCs [39,76,77]. It was suggested, for example, that re-expression of Notch1, a regulator of oligodendrocyte progenitor differentiation, inhibits remyelination in MS [85].…”

Myelin Regeneration in Multiple Sclerosis: Targeting Endogenous Stem Cells

“…As with all regenerative processes the efficiency of remyelination decreases with age primarily due to a decrease in the ability of recruited cells to differentiate [32][33][34][35]. This age-associated decline in remyelination resembles and may be in part a determinant of a now well-recognized feature of many chronically demyelinated MS lesions, which are replete with oligodendrocyte lineage cells that are unable to differentiate into myelinating oligodendrocytes [36][37][38][39].…”

Distinctive Properties of Human Adult Brain-Derived Myelin Progenitor Cells

“…6 -12 Cells bearing specific surface markers [O4, galactocerebroside (GalC), chondroitin sulfate proteoglycan (NG2), proteolipid protein (PLP), platelet-derived growth factor receptor-␣ (PDGF-R␣)] or morphological features characteristic of myelin progenitor cells, are described in MS lesions. Phenotypic profiles of such cells include: O4 ϩ GalC Ϫ NG2 Ϫ , 13 PDGF-R␣ ϩ GalC Ϫ , 14,15 PDGF-R␣ ϩ , NG2 ϩ , 16 and PLP ϩ pre-OLGs. 17 These cells do not however appear to be overrepresented nor are they consistently proliferating in the lesions.…”