Pericytes favor oligodendrocyte fate choice in adult neural stem cells

Maria Elena Silva; Simona Lange; Bryan Hinrichsen; Amber R. Philp; Carolina R. Reyes; Diego Halabi; Josselyne B. Mansilla; Peter Rotheneichner; Alerie Guzman de la Fuente; Sebastien Couillard-Despres; Luis F. Bátiz; Robin J.M. Franklin; Ludwig Aigner; Francisco J. Rivera

doi:10.3389/fncel.2019.00085

Pericytes favor oligodendrocyte fate choice in adult neural stem cells

Maria Elena Silva, Simona Lange, Bryan Hinrichsen, Amber R. Philp, Carolina R. Reyes, Diego Halabi, Josselyne B. Mansilla, Peter Rotheneichner, Alerie Guzman de la Fuente, Sebastien Couillard-Despres, Luis F. Bátiz, Robin J.M. Franklin, Ludwig Aigner, Francisco J. Rivera^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

20 Scopus citations

Abstract

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.

Original language	English
Article number	85
Pages (from-to)	1-7
Number of pages	7
Journal	Frontiers in Cellular Neuroscience
Volume	13
DOIs	https://doi.org/10.3389/fncel.2019.00085
State	Published - 29 Jan 2019

Bibliographical note

Funding 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).

Funding Information:
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;

Publisher Copyright:
© 2019 Silva, Lange, Hinrichsen, Philp, Reyes, Halabi, Mansilla, Rotheneichner, Guzman de la Fuente, Couillard-Despres, Bátiz, Franklin, Aigner and Rivera.

Keywords

Lama2
Neural stem cells
Oligodendrogenesis
Pericytes
Remyelination
Vascular niche

Access to Document

10.3389/fncel.2019.00085

Cite this

Silva, M. E., Lange, S., Hinrichsen, B., Philp, A. R., Reyes, C. R., Halabi, D., Mansilla, J. B., Rotheneichner, P., Guzman de la Fuente, A., Couillard-Despres, S., Bátiz, L. F., Franklin, R. J. M., Aigner, L., & Rivera, F. J. (2019). Pericytes favor oligodendrocyte fate choice in adult neural stem cells. Frontiers in Cellular Neuroscience, 13, 1-7. Article 85. https://doi.org/10.3389/fncel.2019.00085

@article{8b2eb351fdb642c7ae84386fb7eb74fd,

title = "Pericytes favor oligodendrocyte fate choice in adult neural stem cells",

abstract = "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.",

keywords = "Lama2, Neural stem cells, Oligodendrogenesis, Pericytes, Remyelination, Vascular niche, Lama2, Neural stem cells, Oligodendrogenesis, Pericytes, Remyelination, Vascular niche",

author = "Silva, {Maria Elena} and Simona Lange and Bryan Hinrichsen and Philp, {Amber R.} and Reyes, {Carolina R.} and Diego Halabi and Mansilla, {Josselyne B.} and Peter Rotheneichner and {Guzman de la Fuente}, Alerie and Sebastien Couillard-Despres and B{\'a}tiz, {Luis F.} and Franklin, {Robin J.M.} and Ludwig Aigner and Rivera, {Francisco J.}",

note = "Funding Information: We would like to thank to Dr. Carola Otth, Dr. Gonzalo Mardones, Dr. Alejandro Reyes, Dr. Mario Simirgiotis, Dr. Francisco Sep{\'u}lveda, Dr. Felipe Barros, the Institute of Biochemistry and Microbiology (UACh) and the Centro de Estudios Cient{\'i}ficos (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 Comisi{\'o}n Nacional de Investigaci{\'o}n Cient{\'i}fica y Tecnol{\'o}gica (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 f{\"u}r Bildung und Forschung, BMBF grants #0312134, #01GG0706 and #01GN0505); European Union{\textquoteright}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). Funding Information: The authors would like to thank the following funding agencies for their support: Chilean Comisi{\'o}n Nacional de Investigaci{\'o}n Cient{\'i}fica y Tecnol{\'o}gica (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; Publisher Copyright: {\textcopyright} 2019 Silva, Lange, Hinrichsen, Philp, Reyes, Halabi, Mansilla, Rotheneichner, Guzman de la Fuente, Couillard-Despres, B{\'a}tiz, Franklin, Aigner and Rivera.",

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doi = "10.3389/fncel.2019.00085",

language = "English",

volume = "13",

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journal = "Frontiers in Cellular Neuroscience",

issn = "1662-5102",

publisher = "Frontiers Media S.A.",

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Silva, ME, Lange, S, Hinrichsen, B, Philp, AR, Reyes, CR, Halabi, D, Mansilla, JB, Rotheneichner, P, Guzman de la Fuente, A, Couillard-Despres, S, Bátiz, LF, Franklin, RJM, Aigner, L & Rivera, FJ 2019, 'Pericytes favor oligodendrocyte fate choice in adult neural stem cells', Frontiers in Cellular Neuroscience, vol. 13, 85, pp. 1-7. https://doi.org/10.3389/fncel.2019.00085

TY - JOUR

T1 - Pericytes favor oligodendrocyte fate choice in adult neural stem cells

AU - Silva, Maria Elena

AU - Lange, Simona

AU - Hinrichsen, Bryan

AU - Philp, Amber R.

AU - Reyes, Carolina R.

AU - Halabi, Diego

AU - Mansilla, Josselyne B.

AU - Rotheneichner, Peter

AU - Guzman de la Fuente, Alerie

AU - Couillard-Despres, Sebastien

AU - Bátiz, Luis F.

AU - Franklin, Robin J.M.

AU - Aigner, Ludwig

AU - Rivera, Francisco J.

N1 - Funding 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). Funding Information: 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; Publisher Copyright: © 2019 Silva, Lange, Hinrichsen, Philp, Reyes, Halabi, Mansilla, Rotheneichner, Guzman de la Fuente, Couillard-Despres, Bátiz, Franklin, Aigner and Rivera.

PY - 2019/1/29

Y1 - 2019/1/29

N2 - 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.

AB - 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.

KW - Lama2

KW - Neural stem cells

KW - Oligodendrogenesis

KW - Pericytes

KW - Remyelination

KW - Vascular niche

KW - Lama2

KW - Neural stem cells

KW - Oligodendrogenesis

KW - Pericytes

KW - Remyelination

KW - Vascular niche

UR - http://www.scopus.com/inward/record.url?scp=85064215325&partnerID=8YFLogxK

U2 - 10.3389/fncel.2019.00085

DO - 10.3389/fncel.2019.00085

M3 - Article

AN - SCOPUS:85064215325

SN - 1662-5102

VL - 13

SP - 1

EP - 7

JO - Frontiers in Cellular Neuroscience

JF - Frontiers in Cellular Neuroscience

M1 - 85

ER -

Pericytes favor oligodendrocyte fate choice in adult neural stem cells

Abstract

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Keywords

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