Matrix metalloproteinases shape the oligodendrocyte (niche) during development and upon demyelination

Abstract

The oligodendrocyte lineage cell is crucial to proper brain function. During central nervous system development, oligodendrocyte progenitor cells (OPCs) migrate and proliferate to populate the entire brain and spinal cord, and subsequently differentiate into mature oligodendrocytes that wrap neuronal axons in an insulating myelin layer. When damage occurs to the myelin sheath, OPCs are activated and recruited to the demyelinated site, where they differentiate into oligodendrocytes that remyelinate the denuded axons. The process of OPC attraction and differentiation is influenced by a multitude of factors from the cell's niche. Matrix metalloproteinases (MMPs) are powerful and versatile enzymes that do not only degrade extracellular matrix proteins, but also cleave cell surface receptors, growth factors, signaling molecules, proteases and other precursor proteins, leading to their activation or degradation. MMPs are markedly upregulated during brain development and upon demyelinating injury, where their broad functions influence the behavior of neural progenitor cells (NPCs), OPCs and oligodendrocytes. In this review, we focus on the role of MMPs in (re)myelination. We will start out in the developing brain with describing the effects of MMPs on NPCs, OPCs and eventually oligodendrocytes. Then, we will outline their functions in oligodendrocyte process extension and developmental myelination. Finally, we will review their potential role in demyelination, describe their significance in remyelination and discuss the evidence for a role of MMPs in remyelination failure, focusing on multiple sclerosis. In conclusion, MMPs shape the oligodendrocyte (niche) both during development and upon demyelination, and thus are important players in directing the fate and behavior of oligodendrocyte lineage cells throughout their life cycle.

Keywords: Demyelination; Extracellular matrix; Matrix metalloproteinase; Multiple sclerosis; Oligodendrocyte progenitor cell; Remyelination.