Pericytes Stimulate Oligodendrocyte Progenitor Cell Differentiation during CNS Remyelination

Abstract

SummaryThe role of the neurovascular niche in CNS myelin regeneration is incompletely understood. Here, we show that, upon demyelination, CNS-resident pericytes (PCs) proliferate, and parenchymal non-vessel-associated PC-like cells (PLCs) rapidly develop. During remyelination, mature oligodendrocytes were found in close proximity to PCs. In Pdgfbret/ret mice, which have reduced PC numbers, oligodendrocyte progenitor cell (OPC) differentiation was delayed, although remyelination proceeded to completion. PC-conditioned medium accelerated and enhanced OPC differentiation in vitro and increased the rate of remyelination in an ex vivo cerebellar slice model of demyelination. We identified Lama2 as a PC-derived factor that promotes OPC differentiation. Thus, the functional role of PCs is not restricted to vascular homeostasis but includes the modulation of adult CNS progenitor cells involved in regeneration.

RETRACTED ARTICLE: Pericyte degeneration causes white matter dysfunction in the mouse central nervous system

“…S19i). The present data are consistent, however, with previous findings in pericyte-deficient mice showing no changes in astrocyte, microglia and macrophage responses after white matter injury, or changes in pro-inflammatory and anti-inflammatory cell profiles 59 , and/or numbers of astrocytes and microglia at the resting state 17 . Pericytes can also interact with different cell types, as for example supporting OPCs differentiation into oligodendrocytes as shown in cultures in vitro , but do not influence remyelination from OPCs in vivo , as shown in pericyte-deficient mice with diminished PDGF-BB bioavailability after spinal cord white matter injury 59 .…”

Emerging links between cerebrovascular and neurodegenerative diseases—a special role for pericytes

“…Similarly, OPC migrate along the vasculature during CNS development in response to endothelial cell-derived CXCL12, which acts on CXCR4 on the oligodendrocyte progenitors [142]. Direct interactions between pericytes and oligodendrocyte progenitors [143], as well as a role for pericytes in oligodendrocyte differentiation [144], have also been proposed, and a putative perivascular source of oligodendrocyte progenitors has been identified that can be activated following oligodendrocyte progenitor ablation [145]. To what extent these mechanisms are altered in SVD will be an interesting avenue for future research.…”

Pericytes modulate myelination in the central nervous system

“…The findings from De La Fuente et al () are based on the data obtained from Pdgfβ ret/ret mice, which have altered tissue distribution of PDGFβ protein due to loss of a proteoglycan binding motif, as a genetic model for pericyte deficiency to study toxin‐induced demyelination (Armulik et al, ; De La Fuente et al, ). However, some abnormalities were previously described in those mice not necessarily pericyte absence‐related, such as retarded growth (Lindblom et al, ), and progressive brain calcification (Keller et al, ).…”

“…The authors used a mouse model of central nervous system demyelination combined with genetic depletion of pericytes to study the role of pericytes during remyelination. Strikingly, their results demonstrated that oligodendrocyte progenitors differentiation and myelin formation are delayed during remyelination in pericytes‐deficient mice (De La Fuente et al, ). Furthermore, pericytes‐derived conditioned medium promotes oligodendrocyte progenitors differentiation in vitro.…”

“…Now, in a recent article in Cell Reports , De La Fuente and colleagues show that pericytes modulate oligodendrocyte progenitors involved in central nervous system regeneration (De La Fuente et al, ). Interestingly, following white matter demyelination, pericytes activate and reside near differentiating oligodendrocyte progenitors.…”