Pericytes Stimulate Oligodendrocyte Progenitor Cell Differentiation during CNS Remyelination

Alerie Guzman De La Fuente; Simona Lange; Maria Elena Silva; Ginez A. Gonzalez; Herbert Tempfer; Peter van Wijngaarden; Chao Zhao; Ludovica Di Canio; Andrea Trost; Lara Bieler; Pia Zaunmair; Peter Rotheneichner; Anna O'Sullivan; Sebastien Couillard-Despres; Oihana Errea; Maarja A. Mäe; Johanna Andrae; Liqun He; Annika Keller; Luis F. Bátiz; Christer Betsholtz; Ludwig Aigner; Robin J.M. Franklin; Francisco J. Rivera

doi:10.1016/j.celrep.2017.08.007

Pericytes Stimulate Oligodendrocyte Progenitor Cell Differentiation during CNS Remyelination

Alerie Guzman De La Fuente, Simona Lange, Maria Elena Silva, Ginez A. Gonzalez, Herbert Tempfer, Peter van Wijngaarden, Chao Zhao, Ludovica Di Canio, Andrea Trost, Lara Bieler, Pia Zaunmair, Peter Rotheneichner, Anna O'Sullivan, Sebastien Couillard-Despres, Oihana Errea, Maarja A. Mäe, Johanna Andrae, Liqun He, Annika Keller, Luis F. BátizChrister Betsholtz, Ludwig Aigner, Robin J.M. Franklin, Francisco J. Rivera^*

^*Corresponding author for this work

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

92 Scopus citations

Abstract

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 Pdgfb^ret/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.

Translated title of the contribution	Los pericitos estimulan la diferenciación de las células progenitoras de oligodendrocitos durante la remielinización del SNC
Original language	English
Pages (from-to)	1755-1764
Number of pages	10
Journal	Cell Reports
Volume	20
Issue number	8
DOIs	https://doi.org/10.1016/j.celrep.2017.08.007
State	Published - 22 Aug 2017

Bibliographical note

Funding Information:
We thank Hannelore Bauer, Peter Hammerl, and Andreas Traweger for technical advice and support. 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 ).

Publisher Copyright:
© 2017 The Authors

Keywords

Lama2
neurovascular niche
oligodendrocyte progenitor cell
pericytes
remyelination

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10.1016/j.celrep.2017.08.007

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De La Fuente, A. G., Lange, S., Silva, M. E., Gonzalez, G. A., Tempfer, H., van Wijngaarden, P., Zhao, C., Di Canio, L., Trost, A., Bieler, L., Zaunmair, P., Rotheneichner, P., O'Sullivan, A., Couillard-Despres, S., Errea, O., Mäe, M. A., Andrae, J., He, L., Keller, A., ... Rivera, F. J. (2017). Pericytes Stimulate Oligodendrocyte Progenitor Cell Differentiation during CNS Remyelination. Cell Reports, 20(8), 1755-1764. https://doi.org/10.1016/j.celrep.2017.08.007

@article{f4b9fa0089ff4956bf60e13caa172cf7,

title = "Pericytes Stimulate Oligodendrocyte Progenitor Cell Differentiation during CNS Remyelination",

abstract = "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.",

keywords = "Lama2, neurovascular niche, oligodendrocyte progenitor cell, pericytes, remyelination, Lama2, Nicho neurovascular, C{\'e}lula progenitora de oligodendrocitos, Remielinizaci{\'o}n",

author = "{De La Fuente}, {Alerie Guzman} and Simona Lange and Silva, {Maria Elena} and Gonzalez, {Ginez A.} and Herbert Tempfer and {van Wijngaarden}, Peter and Chao Zhao and {Di Canio}, Ludovica and Andrea Trost and Lara Bieler and Pia Zaunmair and Peter Rotheneichner and Anna O'Sullivan and Sebastien Couillard-Despres and Oihana Errea and M{\"a}e, {Maarja A.} and Johanna Andrae and Liqun He and Annika Keller and B{\'a}tiz, {Luis F.} and Christer Betsholtz and Ludwig Aigner and Franklin, {Robin J.M.} and Rivera, {Francisco J.}",

note = "Funding Information: We thank Hannelore Bauer, Peter Hammerl, and Andreas Traweger for technical advice and support. 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 Investigaci{\'o}n 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{\textquoteright}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.{\textquoteright}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 ). Publisher Copyright: {\textcopyright} 2017 The Authors",

year = "2017",

month = aug,

day = "22",

doi = "10.1016/j.celrep.2017.08.007",

language = "English",

volume = "20",

pages = "1755--1764",

journal = "Cell Reports",

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De La Fuente, AG, Lange, S, Silva, ME, Gonzalez, GA, Tempfer, H, van Wijngaarden, P, Zhao, C, Di Canio, L, Trost, A, Bieler, L, Zaunmair, P, Rotheneichner, P, O'Sullivan, A, Couillard-Despres, S, Errea, O, Mäe, MA, Andrae, J, He, L, Keller, A, Bátiz, LF, Betsholtz, C, Aigner, L, Franklin, RJM & Rivera, FJ 2017, 'Pericytes Stimulate Oligodendrocyte Progenitor Cell Differentiation during CNS Remyelination', Cell Reports, vol. 20, no. 8, pp. 1755-1764. https://doi.org/10.1016/j.celrep.2017.08.007

TY - JOUR

T1 - Pericytes Stimulate Oligodendrocyte Progenitor Cell Differentiation during CNS Remyelination

AU - De La Fuente, Alerie Guzman

AU - Lange, Simona

AU - Silva, Maria Elena

AU - Gonzalez, Ginez A.

AU - Tempfer, Herbert

AU - van Wijngaarden, Peter

AU - Zhao, Chao

AU - Di Canio, Ludovica

AU - Trost, Andrea

AU - Bieler, Lara

AU - Zaunmair, Pia

AU - Rotheneichner, Peter

AU - O'Sullivan, Anna

AU - Couillard-Despres, Sebastien

AU - Errea, Oihana

AU - Mäe, Maarja A.

AU - Andrae, Johanna

AU - He, Liqun

AU - Keller, Annika

AU - Bátiz, Luis F.

AU - Betsholtz, Christer

AU - Aigner, Ludwig

AU - Franklin, Robin J.M.

AU - Rivera, Francisco J.

N1 - Funding Information: We thank Hannelore Bauer, Peter Hammerl, and Andreas Traweger for technical advice and support. 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 ). Publisher Copyright: © 2017 The Authors

PY - 2017/8/22

Y1 - 2017/8/22

N2 - 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.

AB - 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.

KW - Lama2

KW - neurovascular niche

KW - oligodendrocyte progenitor cell

KW - pericytes

KW - remyelination

KW - Lama2

KW - Nicho neurovascular

KW - Célula progenitora de oligodendrocitos

KW - Remielinización

UR - http://www.scopus.com/inward/record.url?scp=85028296852&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2017.08.007

DO - 10.1016/j.celrep.2017.08.007

M3 - Article

C2 - 28834740

AN - SCOPUS:85028296852

SN - 2211-1247

VL - 20

SP - 1755

EP - 1764

JO - Cell Reports

JF - Cell Reports

IS - 8

ER -

Pericytes Stimulate Oligodendrocyte Progenitor Cell Differentiation during CNS Remyelination

Abstract

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Keywords

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