Oligodendrocyte‐type 2 Astrocyte Progenitors Use a Metalloendoprotease to Spread and Migrate on CNS Myelin

Abstract

Oligodendrocyte-type 2 astrocyte (O-2A) progenitors are highly motile cells which migrate in the developing and adult central nervous system (CNS). Adult CNS myelin, however, contains inhibitory proteins, the neurite growth inhibitors NI 35/250, which block neurite outgrowth and spreading of many different cell types, such as astrocytes and fibroblasts. In the present study we investigated the spreading of dissociated cells and migration out of aggregates ('spheres') of primary O-2A cultures and of a glial precursor cell line (CG-4) on purified CNS myelin and on CNS tissue. Primary O-2A progenitors and CG-4 cells quickly attached to and spread on CNS myelin-coated culture dishes, showing no inhibition by the neurite growth inhibitors. CG-4 cells migrated with a velocity of 30 microns/h on a CNS myelin protein extract and at 5.7 microns/h on adult spinal cord tissue. Both cell spreading and migration on a CNS substrate could be specifically blocked by metalloprotease blockers like o-phenanthroline and the tetrapeptide carbobenzoxy-phe-ala-phe-tyr-amide, whereas blockers of the serine, aspartyl and cysteine proteases had no effect. On differentiation to astrocytes, the O-2A progenitors lost their ability to spread on CNS myelin. These results suggest the crucial involvement of a metalloprotease in the mechanism of migration on a CNS substrate. In vivo, migration of oligodendrocyte progenitors may be an important aspect of myelin repair following local traumatic, inflammatory or toxin-induced myelin loss.

The Expression of Matrix Metalloproteinase-12 by Oligodendrocytes Regulates Their Maturation and Morphological Differentiation

“…In recent years, metalloproteinase activity has been correlated with many aspects of development. Examples include the observations that angiogenesis (Canete Soler et al, 1995a;Vu et al, 1998;Werb et al, 1999) and the migration of neuronal precursor cells and OPCs (Amberger et al, 1997;Vaillant et al, 2003) seem to require metalloproteinase activity. A growing list has ascribed novel functions of metalloproteinases in normal development, such as in cytokine activation-inactivation and controlling apoptotic pathways (for review, see Sternlicht and Werb, 2001).…”

The origin and differentiation of microglial cells during development

“…In addition, microglia in culture produce and activate enzymes which degrade components of the extracellular matrix (Nakajima et al, 1992;Gottschall et al, 1995;Washington et al, 1996). These enzymes enhance neurite outgrowth Seeds et al, 1996), are involved in the spread and migration of glial precursors (Amberger et al, 1997), and probably also facilitate the migration of microglial cells through the nervous parenchyma, although their production by migrating ameboid cells during development has not yet been established.…”

Cell-Surface Glycoprotein of Oligodendrocyte Progenitors Involved in Migration

“…We established migration assays using modifications of the technique described by Amberger et al (1997) using CG4 cells and primary "oligospheres" (Avellana-Adalid et al, 1996). Aggregate cultures of the Oli-neu cell line were generated by suspending the cells at 1 ϫ 10 6 cells/ml in Sato/1% HS in glass flasks rotating at 70 rpm.…”