The effect of glia-glia interactions on oligodendrocyte precursor cell biology during development and in demyelinating diseases

Abstract

Oligodendrocyte precursor cells (OPCs) originate in specific areas of the developing central nervous system (CNS). Once generated, they migrate towards their destinations where they differentiate into mature oligodendrocytes. In the adult, 5–8% of all cells in the CNS are OPCs, cells that retain the capacity to proliferate, migrate, and differentiate into oligodendrocytes. Indeed, these endogenous OPCs react to damage in demyelinating diseases, like multiple sclerosis (MS), representing a key element in spontaneous remyelination. In the present work, we review the specific interactions between OPCs and other glial cells (astrocytes, microglia) during CNS development and in the pathological scenario of MS. We focus on: (i) the role of astrocytes in maintaining the homeostasis and spatial distribution of different secreted cues that determine OPC proliferation, migration, and differentiation during CNS development; (ii) the role of microglia and astrocytes in the redistribution of iron, which is crucial for myelin synthesis during CNS development and for myelin repair in MS; (iii) how microglia secrete different molecules, e.g., growth factors, that favor the recruitment of OPCs in acute phases of MS lesions; and (iv) how astrocytes modify the extracellular matrix in MS lesions, affecting the ability of OPCs to attempt spontaneous remyelination. Together, these issues demonstrate how both astroglia and microglia influence OPCs in physiological and pathological situations, reinforcing the concept that both development and neural repair are complex and global phenomena. Understanding the molecular and cellular mechanisms that control OPC survival, proliferation, migration, and differentiation during development, as well as in the mature CNS, may open new opportunities in the search for reparative therapies in demyelinating diseases like MS.

Peripherally derived FGF21 promotes remyelination in the central nervous system

“…OPC proliferation and subsequent remyelination processes (e.g., migration, differentiation into mature oligodendrocytes) ensure the restoration of saltatory conduction (7), provision of trophic support for axons (8), and promotion of functional recovery (9); therefore, the mechanism of remyelination has attracted considerable attention in regard to its potential applications in regenerative medicine aimed at treating CNS demyelinating diseases. Remyelination is thought to be dependent on factors derived from the CNS microenvironment (10,11). For example, plateletderived growth factor (PDGF) and basic fibroblast growth factor (FGF), which are expressed by astrocytes (10), are both important for OPC proliferation (12).…”

Robust increase of microglia proliferation in the fornix of hippocampal axonal pathway after a single LPS stimulation

“…Classically, microglia have been presumed to be quiescent under physiological conditions and activated upon severe inflammatory stimulation or brain damage (Schwartz et al, 2006;Hanisch and Kettenmann, 2007). Microglia are activated and increased in number as a consequence of both the proliferation of resident microglia and recruitment of circulating hematopoietic cells that infiltrate the brains after the autoimmune disease multiple sclerosis (Odoardi et al, 2012;Clemente et al, 2013) and brain damages (Lambertsen et al, 2011). Proinflammatory M1 microglia, activated via toll-like receptors and interferon-γ (IFN-γ), mediate clearance of pathogens, toxic factors, and tissue debris of apoptotic cells (Gordon, 2003;Kigerl et al 2009;Huizinga et al, 2012;Suzumura, 2013).…”

The melanocortin ACTH 1-39 promotes protection of oligodendrocytes by astroglia

“…AS can promote OPC differentiation and myelination, enhancing the potential for remyelination ( [14,32], reviews). An early study showed that over several days in culture, unstimulated AS decreased apoptosis of OL prepared from mature mouse brain.…”