Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Upon demyelination, oligodendrocyte progenitor cells (OPCs) are activated and they proliferate, migrate and differentiate into myelin-producing oligodendrocytes. Besides OPCs, neural stem cells (NSCs) may respond to demyelination and generate oligodendrocytes. We have recently shown that CNS-resident pericytes (PCs) respond to demyelination, proliferate and secrete Laminin alpha2 (Lama2) that, in turn, enhances OPC differentiation. Here, we aimed to evaluate whether PCs influence the fate choice of NSCs in vitro, towards the production of new myelin-producing cells. Indeed, upon exposure to conditioned medium derived from PCs (PC-CM), the majority of NSCs gave rise to GalC- and myelin basic protein (MBP)-expressing oligodendrocytes at the expense of the generation of GFAP-positive astrocytes. Consistent with these findings, PC-CM induces an increase in the expression of the oligodendrocyte fate determinant Olig2, while the expression level of the astrocyte determinant ID2 is decreased. Finally, pre-incubation of PC-CM with an anti-Lama2 antibody prevented the generation of oligodendrocytes. Our findings indicate that PCs-derived Lama2 instructs NSCs to an oligodendrocyte fate choice favoring the generation of myelin-producing cells at the expense of astrocytes in vitro. Further studies aiming to reveal the role of PCs during remyelination may pave the way for the development of new therapies for the treatment of MS.
Bibliographical noteFunding Information:
We would like to thank to Dr. Carola Otth, Dr. Gonzalo Mardones, Dr. Alejandro Reyes, Dr. Mario Simirgiotis, Dr. Francisco Sepúlveda, Dr. Felipe Barros, the Institute of Biochemistry and Microbiology (UACh) and the Centro de Estudios Científicos (CECs) for providing with the necessary equipment to carry experiments and for the data analysis. Funding. The authors would like to thank the following funding agencies for their support: Chilean Comisión Nacional de Investigación Científica y Tecnológica (CONICYT) FONDECYT Program Regular Grant N° 1161787 (FR), Regular Grant N° 1141015 (LB); Chilean CONICYT PCI Program Grant N° REDES170233 (to FR), Grant N° REDES180139 and Grant N° REDI170037; Chilean CONICYT FONDEF-IDeA Program Grant N° ID17AM0043 (MS and FR); Paracelsus Medical University PMU-FFF Long-Term Fellowship L-12/01/001-RIV and Stand- Alone Grant E-12/15/077-RIT (both to FR); the Bavarian State Ministry of Sciences, Research and the Arts (ForNeuroCell grant; LA); the Germany Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung, BMBF grants #0312134, #01GG0706 and #01GN0505); European Union’s Seventh Framework Programme (FP7/2007-2013) under grant agreements n° HEALTH-F2-2011-278850 (INMiND) and HEALTH-F2-2011-279288 (IDEA). The work in the Franklin laboratory was supported by a programme grant from the UK MS Society and Adelson Medical Research Foundation and a core support grant from the Wellcome Trust and MRC to the Wellcome Trust-MRC Cambridge Stem Cell Institute. In addition, the present work was supported by the state of Salzburg (to LA).
The authors would like to thank the following funding agencies for their support: Chilean Comisión Nacional de Investigación Científica y Tecnológica (CONICYT) FONDECYT Program Regular Grant N◦ 1161787 (FR), Regular Grant N◦ 1141015 (LB); Chilean CONICYT PCI Program Grant N◦ REDES170233 (to FR), Grant N◦ REDES180139 and Grant N◦ REDI170037; Chilean CONICYT FONDEF-IDeA Program Grant N◦ ID17AM0043 (MS and FR); Paracelsus Medical University PMU-FFF Long-Term Fellowship L-12/01/001-RIV and Stand-Alone Grant E-12/15/077-RIT (both to FR); the Bavarian State Ministry of Sciences, Research and the Arts (ForNeuroCell grant;
© 2019 Silva, Lange, Hinrichsen, Philp, Reyes, Halabi, Mansilla, Rotheneichner, Guzman de la Fuente, Couillard-Despres, Bátiz, Franklin, Aigner and Rivera.
- Neural stem cells
- Vascular niche