Pericytes Stimulate Oligodendrocyte Progenitor Cell Differentiation during CNS Remyelination
The 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. ; This work was supported by research funds from Chilean FONDECYT Program CONICYT Grants 1161787 (to F.J.R.) and 1141015 (to L.F.B); Direccion de Investigación y Desarrollo-Universidad Austral de Chile (DID-UACh); Paracelsus Medical University PMU-FFF Long-Term Fellowship L-12/01/001-RIV (to F.J.R.) and Stand-Alone Grant E-12/15/077-RIT (to F.J.R. and A.T.); the European Union Seventh Framework Program (FP7/2007-2013) under Grant Agreements HEALTH-F2-2011-278850 (INMiND), HEALTH-F2-2011-279288 (IDEA), and FP7-REGPOT-316120 (GlowBrain); Austrian Science Fund FWF Special Research Program (SFB) F44 (F4413-B23) "Cell Signaling in Chronic CNS Disorders"; and State Government of Salzburg, Austria (Stiftungsprofessur and 20204-WISS/80/199-2014). In addition, this study was supported by grants from a core support grant from the Wellcome Trust (203151/Z/16/Z) and MRC to the Wellcome Trust–Medical Research Council Cambridge Stem Cell Institute, the UK Multiple Sclerosis Society (941/11), the David and Isobel Walker Trust, "Investissements d'avenir" IHU-A-ICM and Obra Social La Caixa, the Swedish Science Council (2015-00550), the Swedish Cancer Foundation (15 0735), the Knut and Alice Wallenberg Foundation (2015.0030), the European Research Council (AdG 294556 BBBARRIER), and the Leducq Foundation (Sphingonet; 14CVD02). P.v.W. was supported by National Health & Medical Research Council of Australia Early Career Fellowship 628928. Work in A.K.'s group was funded by the Swiss National Science Foundation (31003A_159514/1; http://www.snf.ch/en) and The Synapsis Foundation (http://www.alzheimer-synapsis.ch).