Aging restricts the ability of mesenchymal stem cells to promote the generation of oligodendrocytes during remyelination

Francisco J. Rivera; Alerie G. de la Fuente; Chao Zhao; Maria E. Silva; Ginez A. Gonzalez; Roman Wodnar; Martina Feichtner; Simona Lange; Oihana Errea; Eleni Priglinger; Anna O'Sullivan; Pasquale Romanelli; Janusz J. Jadasz; Gabriele Brachtl; Richard Greil; Herbert Tempfer; Andreas Traweger; Luis F. Bátiz; Patrick Küry; Sebastien Couillard-Despres; Robin J.M. Franklin; Ludwig Aigner

doi:10.1002/glia.23624

Aging restricts the ability of mesenchymal stem cells to promote the generation of oligodendrocytes during remyelination

Francisco J. Rivera^*, Alerie G. de la Fuente, Chao Zhao, Maria E. Silva, Ginez A. Gonzalez, Roman Wodnar, Martina Feichtner, Simona Lange, Oihana Errea, Eleni Priglinger, Anna O'Sullivan, Pasquale Romanelli, Janusz J. Jadasz, Gabriele Brachtl, Richard Greil, Herbert Tempfer, Andreas Traweger, Luis F. Bátiz, Patrick Küry, Sebastien Couillard-DespresRobin J.M. Franklin, Ludwig Aigner

^*Corresponding author for this work

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

25 Scopus citations

Abstract

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) that leads to severe neurological deficits. Due to their immunomodulatory and neuroprotective activities and their ability to promote the generation of oligodendrocytes, mesenchymal stem cells (MSCs) are currently being developed for autologous cell therapy in MS. As aging reduces the regenerative capacity of all tissues, it is of relevance to investigate whether MSCs retain their pro-oligodendrogenic activity with increasing age. We demonstrate that MSCs derived from aged rats have a reduced capacity to induce oligodendrocyte differentiation of adult CNS stem/progenitor cells. Aging also abolished the ability of MSCs to enhance the generation of myelin-like sheaths in demyelinated cerebellar slice cultures. Finally, in a rat model for CNS demyelination, aging suppressed the capability of systemically transplanted MSCs to boost oligodendrocyte progenitor cell (OPC) differentiation during remyelination. Thus, aging restricts the ability of MSCs to support the generation of oligodendrocytes and consequently inhibits their capacity to enhance the generation of myelin-like sheaths. These findings may impact on the design of therapies using autologous MSCs in older MS patients.

Original language	English
Pages (from-to)	1510-1525
Number of pages	16
Journal	GLIA
Volume	67
Issue number	8
DOIs	https://doi.org/10.1002/glia.23624
State	Published - Aug 2019

Bibliographical note

Funding Information:
The authors would like to thank the following funding agencies for their support: Paracelsus Medical University PMU-FFF Long-Term Fellowship L-12/01/001-RIV and Stand-Alone Grant E-12/15/077-RIT [both to F.J.R.]; Chilean Comisión Nacional de Investigación Científica y Tecno-lógica [CONICYT] FONDECYT Program Regular Grant No. 1161787 [to F.J.R.], Regular Grant No. 1141015 [to L.F.B.]; Chilean CONICYT PCI Program Grant No. REDES170233 [to F.J.R.], Grant No. REDES180139 and Grant No. REDI170037; Chilean CONICYT FONDEF-IDeA Program Grant No. ID17AM0043 [to M.E.S. and F.J.R.]; European Union's Seventh Framework Programme [FP7/2007-2013] under grant agreements No. HEALTH-F2-2011-278850 [INMiND] and HEALTH-F2-2011-279288 [IDEA]). The work in the Küry laboratory was supported by the German Research Foundation (DFG; KU1934/2_1, KU1934/5-1) and the Christiane and Claudia Hempel Foundation for clinical and iBrain. The work in the Franklin laboratory was supported by grants from the UK Multiple Sclerosis Society and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, and a core support grant from the Wellcome Trust and MRC to the Wellcome-MRC Cambridge Stem Cell Institute. In addition, the present work was supported by the state of Salzburg (to L.A.). We thank Armin Schneider, Sygnis Pharma AG Heidelberg, Germany, for the MBP promoter construct. We disclose any conflict of interest.

Funding Information:
information Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; Bavarian State Ministry of Sciences, Research and the Arts ForNeuroCell grant; Bundesministerium f?r Bildung und Forschung, Grant/Award Numbers: 01GG0706, 01GN0505, 0312134; Christiane and Claudia Hempel Foundation for Clinical and iBrain; Comisi?n Nacional de Investigaci?n Cient?fica y Tecnol?gica (CONICYT) ? Fondo Nacional de Desarrollo Cient?fico y Tecnol?gico (FONDECYT), Grant/Award Numbers: 1161787, 1141015; Comisi?n Nacional de Investigaci?n Cient?fica y Tecnol?gica (CONICYT) - Fondo de Fomento al Desarrollo Cient?fico y Tecnol?gico (FONDEF) - IDeA, Grant/Award Number: ID17AM0043; Comisi?n Nacional de Investigaci?n Cient?fica y Tecnol?gica (CONICYT) ? Programa de Cooperaci?n Internacional (PCI), Grant/Award Numbers: REDES170233, REDES180139, REDI170037; Deutsche Forschungsgemeinschaft, Grant/Award Numbers: KU1934/2_1, KU1934/5-1; European Union's Seventh Framework Programme (FP7/2007-2013; INMiND, IDEA), Grant/Award Numbers: HEALTH-F2-2011-278850, HEALTH-F2-2011-279288; Medical Research Council; PMU-FFF (Long-Term Fellowship, Stand-Alone Grant), Grant/Award Numbers: L-12/01/001-RIV, E-12/15/077-RIT; UK Multiple Sclerosis Society; Wellcome Trust; Wellcome-MRC Cambridge Stem Cell InstituteThe authors would like to thank the following funding agencies for their support: Paracelsus Medical University PMU-FFF Long-Term Fellowship L-12/01/001-RIV and Stand-Alone Grant E-12/15/077-RIT [both to F.J.R.]; Chilean Comisi?n Nacional de Investigaci?n Cient?fica y Tecnol?gica [CONICYT] FONDECYT Program Regular Grant No. 1161787 [to F.J.R.], Regular Grant No. 1141015 [to L.F.B.]; Chilean CONICYT PCI Program Grant No. REDES170233 [to F.J.R.], Grant No. REDES180139 and Grant No. REDI170037; Chilean CONICYT FONDEF-IDeA Program Grant No. ID17AM0043 [to M.E.S. and F.J.R.]; European Union's Seventh Framework Programme [FP7/2007-2013] under grant agreements No. HEALTH-F2-2011-278850 [INMiND] and HEALTH-F2-2011-279288 [IDEA]). The work in the K?ry laboratory was supported by the German Research Foundation (DFG; KU1934/2_1, KU1934/5-1) and the Christiane and Claudia Hempel Foundation for clinical and iBrain. The work in the Franklin laboratory was supported by grants from the UK Multiple Sclerosis Society and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, and a core support grant from the Wellcome Trust and MRC to the Wellcome-MRC Cambridge Stem Cell Institute. In addition, the present work was supported by the state of Salzburg (to L.A.). We thank Armin Schneider, Sygnis Pharma AG Heidelberg, Germany, for the MBP promoter construct. We disclose any conflict of interest.

Funding Information:
Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; Bavarian State Ministry of Sciences, Research and the Arts ForNeuroCell grant; Bundesministerium für Bildung und Forschung, Grant/Award Numbers: 01GG0706, 01GN0505, 0312134; Christiane and Claudia Hempel Foundation for Clinical and iBrain; Comisión Nacional de Investigación Científica y Tecnológica (CONICYT) – Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT), Grant/ Award Numbers: 1161787, 1141015; Comisión Nacional de Investigación Científica y Tecnológica (CONICYT) - Fondo de Fomento al Desarrollo Científico y Tecnológico (FONDEF) - IDeA, Grant/Award Number: ID17AM0043; Comisión Nacional de Investigación Científica y Tecnológica (CONICYT) – Programa de Cooperación Internacional (PCI), Grant/Award Numbers: REDES170233, REDES180139, REDI170037; Deutsche Forschungsgemeinschaft, Grant/ Award Numbers: KU1934/2_1, KU1934/5-1; European Union's Seventh Framework Programme (FP7/2007-2013; INMiND, IDEA), Grant/Award Numbers: HEALTH-F2-2011-278850, HEALTH-F2-2011-279288; Medical Research Council; PMU-FFF (Long-Term Fellowship, Stand-Alone Grant), Grant/Award Numbers: L-12/01/001-RIV, E-12/15/077-RIT; UK Multiple Sclerosis Society; Wellcome Trust; Wellcome-MRC Cambridge Stem Cell Institute

Publisher Copyright:
© 2019 The Authors. Glia published by Wiley Periodicals, Inc.

Keywords

CNS stem and progenitor cells
aging
cell therapy
mesenchymal stem cells
multiple sclerosis
oligodendrocytes
remyelination

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10.1002/glia.23624

Cite this

Rivera, F. J., de la Fuente, A. G., Zhao, C., Silva, M. E., Gonzalez, G. A., Wodnar, R., Feichtner, M., Lange, S., Errea, O., Priglinger, E., O'Sullivan, A., Romanelli, P., Jadasz, J. J., Brachtl, G., Greil, R., Tempfer, H., Traweger, A., Bátiz, L. F., Küry, P., ... Aigner, L. (2019). Aging restricts the ability of mesenchymal stem cells to promote the generation of oligodendrocytes during remyelination. GLIA, 67(8), 1510-1525. https://doi.org/10.1002/glia.23624

@article{81e186c5324c44c3895eb80f52f3f904,

title = "Aging restricts the ability of mesenchymal stem cells to promote the generation of oligodendrocytes during remyelination",

abstract = "Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) that leads to severe neurological deficits. Due to their immunomodulatory and neuroprotective activities and their ability to promote the generation of oligodendrocytes, mesenchymal stem cells (MSCs) are currently being developed for autologous cell therapy in MS. As aging reduces the regenerative capacity of all tissues, it is of relevance to investigate whether MSCs retain their pro-oligodendrogenic activity with increasing age. We demonstrate that MSCs derived from aged rats have a reduced capacity to induce oligodendrocyte differentiation of adult CNS stem/progenitor cells. Aging also abolished the ability of MSCs to enhance the generation of myelin-like sheaths in demyelinated cerebellar slice cultures. Finally, in a rat model for CNS demyelination, aging suppressed the capability of systemically transplanted MSCs to boost oligodendrocyte progenitor cell (OPC) differentiation during remyelination. Thus, aging restricts the ability of MSCs to support the generation of oligodendrocytes and consequently inhibits their capacity to enhance the generation of myelin-like sheaths. These findings may impact on the design of therapies using autologous MSCs in older MS patients.",

keywords = "CNS stem and progenitor cells, aging, cell therapy, mesenchymal stem cells, multiple sclerosis, oligodendrocytes, remyelination",

author = "Rivera, {Francisco J.} and {de la Fuente}, {Alerie G.} and Chao Zhao and Silva, {Maria E.} and Gonzalez, {Ginez A.} and Roman Wodnar and Martina Feichtner and Simona Lange and Oihana Errea and Eleni Priglinger and Anna O'Sullivan and Pasquale Romanelli and Jadasz, {Janusz J.} and Gabriele Brachtl and Richard Greil and Herbert Tempfer and Andreas Traweger and B{\'a}tiz, {Luis F.} and Patrick K{\"u}ry and Sebastien Couillard-Despres and Franklin, {Robin J.M.} and Ludwig Aigner",

note = "Funding Information: The authors would like to thank the following funding agencies for their support: Paracelsus Medical University PMU-FFF Long-Term Fellowship L-12/01/001-RIV and Stand-Alone Grant E-12/15/077-RIT [both to F.J.R.]; Chilean Comisi{\'o}n Nacional de Investigaci{\'o}n Cient{\'i}fica y Tecno-l{\'o}gica [CONICYT] FONDECYT Program Regular Grant No. 1161787 [to F.J.R.], Regular Grant No. 1141015 [to L.F.B.]; Chilean CONICYT PCI Program Grant No. REDES170233 [to F.J.R.], Grant No. REDES180139 and Grant No. REDI170037; Chilean CONICYT FONDEF-IDeA Program Grant No. ID17AM0043 [to M.E.S. and F.J.R.]; European Union's Seventh Framework Programme [FP7/2007-2013] under grant agreements No. HEALTH-F2-2011-278850 [INMiND] and HEALTH-F2-2011-279288 [IDEA]). The work in the K{\"u}ry laboratory was supported by the German Research Foundation (DFG; KU1934/2_1, KU1934/5-1) and the Christiane and Claudia Hempel Foundation for clinical and iBrain. The work in the Franklin laboratory was supported by grants from the UK Multiple Sclerosis Society and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, and a core support grant from the Wellcome Trust and MRC to the Wellcome-MRC Cambridge Stem Cell Institute. In addition, the present work was supported by the state of Salzburg (to L.A.). We thank Armin Schneider, Sygnis Pharma AG Heidelberg, Germany, for the MBP promoter construct. We disclose any conflict of interest. Funding Information: information Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; Bavarian State Ministry of Sciences, Research and the Arts ForNeuroCell grant; Bundesministerium f?r Bildung und Forschung, Grant/Award Numbers: 01GG0706, 01GN0505, 0312134; Christiane and Claudia Hempel Foundation for Clinical and iBrain; Comisi?n Nacional de Investigaci?n Cient?fica y Tecnol?gica (CONICYT) ? Fondo Nacional de Desarrollo Cient?fico y Tecnol?gico (FONDECYT), Grant/Award Numbers: 1161787, 1141015; Comisi?n Nacional de Investigaci?n Cient?fica y Tecnol?gica (CONICYT) - Fondo de Fomento al Desarrollo Cient?fico y Tecnol?gico (FONDEF) - IDeA, Grant/Award Number: ID17AM0043; Comisi?n Nacional de Investigaci?n Cient?fica y Tecnol?gica (CONICYT) ? Programa de Cooperaci?n Internacional (PCI), Grant/Award Numbers: REDES170233, REDES180139, REDI170037; Deutsche Forschungsgemeinschaft, Grant/Award Numbers: KU1934/2_1, KU1934/5-1; European Union's Seventh Framework Programme (FP7/2007-2013; INMiND, IDEA), Grant/Award Numbers: HEALTH-F2-2011-278850, HEALTH-F2-2011-279288; Medical Research Council; PMU-FFF (Long-Term Fellowship, Stand-Alone Grant), Grant/Award Numbers: L-12/01/001-RIV, E-12/15/077-RIT; UK Multiple Sclerosis Society; Wellcome Trust; Wellcome-MRC Cambridge Stem Cell InstituteThe authors would like to thank the following funding agencies for their support: Paracelsus Medical University PMU-FFF Long-Term Fellowship L-12/01/001-RIV and Stand-Alone Grant E-12/15/077-RIT [both to F.J.R.]; Chilean Comisi?n Nacional de Investigaci?n Cient?fica y Tecnol?gica [CONICYT] FONDECYT Program Regular Grant No. 1161787 [to F.J.R.], Regular Grant No. 1141015 [to L.F.B.]; Chilean CONICYT PCI Program Grant No. REDES170233 [to F.J.R.], Grant No. REDES180139 and Grant No. REDI170037; Chilean CONICYT FONDEF-IDeA Program Grant No. ID17AM0043 [to M.E.S. and F.J.R.]; European Union's Seventh Framework Programme [FP7/2007-2013] under grant agreements No. HEALTH-F2-2011-278850 [INMiND] and HEALTH-F2-2011-279288 [IDEA]). The work in the K?ry laboratory was supported by the German Research Foundation (DFG; KU1934/2_1, KU1934/5-1) and the Christiane and Claudia Hempel Foundation for clinical and iBrain. The work in the Franklin laboratory was supported by grants from the UK Multiple Sclerosis Society and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, and a core support grant from the Wellcome Trust and MRC to the Wellcome-MRC Cambridge Stem Cell Institute. In addition, the present work was supported by the state of Salzburg (to L.A.). We thank Armin Schneider, Sygnis Pharma AG Heidelberg, Germany, for the MBP promoter construct. We disclose any conflict of interest. Funding Information: Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; Bavarian State Ministry of Sciences, Research and the Arts ForNeuroCell grant; Bundesministerium f{\"u}r Bildung und Forschung, Grant/Award Numbers: 01GG0706, 01GN0505, 0312134; Christiane and Claudia Hempel Foundation for Clinical and iBrain; Comisi{\'o}n Nacional de Investigaci{\'o}n Cient{\'i}fica y Tecnol{\'o}gica (CONICYT) – Fondo Nacional de Desarrollo Cient{\'i}fico y Tecnol{\'o}gico (FONDECYT), Grant/ Award Numbers: 1161787, 1141015; Comisi{\'o}n Nacional de Investigaci{\'o}n Cient{\'i}fica y Tecnol{\'o}gica (CONICYT) - Fondo de Fomento al Desarrollo Cient{\'i}fico y Tecnol{\'o}gico (FONDEF) - IDeA, Grant/Award Number: ID17AM0043; Comisi{\'o}n Nacional de Investigaci{\'o}n Cient{\'i}fica y Tecnol{\'o}gica (CONICYT) – Programa de Cooperaci{\'o}n Internacional (PCI), Grant/Award Numbers: REDES170233, REDES180139, REDI170037; Deutsche Forschungsgemeinschaft, Grant/ Award Numbers: KU1934/2_1, KU1934/5-1; European Union's Seventh Framework Programme (FP7/2007-2013; INMiND, IDEA), Grant/Award Numbers: HEALTH-F2-2011-278850, HEALTH-F2-2011-279288; Medical Research Council; PMU-FFF (Long-Term Fellowship, Stand-Alone Grant), Grant/Award Numbers: L-12/01/001-RIV, E-12/15/077-RIT; UK Multiple Sclerosis Society; Wellcome Trust; Wellcome-MRC Cambridge Stem Cell Institute Publisher Copyright: {\textcopyright} 2019 The Authors. Glia published by Wiley Periodicals, Inc.",

year = "2019",

month = aug,

doi = "10.1002/glia.23624",

language = "English",

volume = "67",

pages = "1510--1525",

journal = "GLIA",

issn = "0894-1491",

publisher = "John Wiley and Sons Inc.",

number = "8",

}

Rivera, FJ, de la Fuente, AG, Zhao, C, Silva, ME, Gonzalez, GA, Wodnar, R, Feichtner, M, Lange, S, Errea, O, Priglinger, E, O'Sullivan, A, Romanelli, P, Jadasz, JJ, Brachtl, G, Greil, R, Tempfer, H, Traweger, A, Bátiz, LF, Küry, P, Couillard-Despres, S, Franklin, RJM & Aigner, L 2019, 'Aging restricts the ability of mesenchymal stem cells to promote the generation of oligodendrocytes during remyelination', GLIA, vol. 67, no. 8, pp. 1510-1525. https://doi.org/10.1002/glia.23624

TY - JOUR

T1 - Aging restricts the ability of mesenchymal stem cells to promote the generation of oligodendrocytes during remyelination

AU - Rivera, Francisco J.

AU - de la Fuente, Alerie G.

AU - Zhao, Chao

AU - Silva, Maria E.

AU - Gonzalez, Ginez A.

AU - Wodnar, Roman

AU - Feichtner, Martina

AU - Lange, Simona

AU - Errea, Oihana

AU - Priglinger, Eleni

AU - O'Sullivan, Anna

AU - Romanelli, Pasquale

AU - Jadasz, Janusz J.

AU - Brachtl, Gabriele

AU - Greil, Richard

AU - Tempfer, Herbert

AU - Traweger, Andreas

AU - Bátiz, Luis F.

AU - Küry, Patrick

AU - Couillard-Despres, Sebastien

AU - Franklin, Robin J.M.

AU - Aigner, Ludwig

N1 - Funding Information: The authors would like to thank the following funding agencies for their support: Paracelsus Medical University PMU-FFF Long-Term Fellowship L-12/01/001-RIV and Stand-Alone Grant E-12/15/077-RIT [both to F.J.R.]; Chilean Comisión Nacional de Investigación Científica y Tecno-lógica [CONICYT] FONDECYT Program Regular Grant No. 1161787 [to F.J.R.], Regular Grant No. 1141015 [to L.F.B.]; Chilean CONICYT PCI Program Grant No. REDES170233 [to F.J.R.], Grant No. REDES180139 and Grant No. REDI170037; Chilean CONICYT FONDEF-IDeA Program Grant No. ID17AM0043 [to M.E.S. and F.J.R.]; European Union's Seventh Framework Programme [FP7/2007-2013] under grant agreements No. HEALTH-F2-2011-278850 [INMiND] and HEALTH-F2-2011-279288 [IDEA]). The work in the Küry laboratory was supported by the German Research Foundation (DFG; KU1934/2_1, KU1934/5-1) and the Christiane and Claudia Hempel Foundation for clinical and iBrain. The work in the Franklin laboratory was supported by grants from the UK Multiple Sclerosis Society and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, and a core support grant from the Wellcome Trust and MRC to the Wellcome-MRC Cambridge Stem Cell Institute. In addition, the present work was supported by the state of Salzburg (to L.A.). We thank Armin Schneider, Sygnis Pharma AG Heidelberg, Germany, for the MBP promoter construct. We disclose any conflict of interest. Funding Information: information Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; Bavarian State Ministry of Sciences, Research and the Arts ForNeuroCell grant; Bundesministerium f?r Bildung und Forschung, Grant/Award Numbers: 01GG0706, 01GN0505, 0312134; Christiane and Claudia Hempel Foundation for Clinical and iBrain; Comisi?n Nacional de Investigaci?n Cient?fica y Tecnol?gica (CONICYT) ? Fondo Nacional de Desarrollo Cient?fico y Tecnol?gico (FONDECYT), Grant/Award Numbers: 1161787, 1141015; Comisi?n Nacional de Investigaci?n Cient?fica y Tecnol?gica (CONICYT) - Fondo de Fomento al Desarrollo Cient?fico y Tecnol?gico (FONDEF) - IDeA, Grant/Award Number: ID17AM0043; Comisi?n Nacional de Investigaci?n Cient?fica y Tecnol?gica (CONICYT) ? Programa de Cooperaci?n Internacional (PCI), Grant/Award Numbers: REDES170233, REDES180139, REDI170037; Deutsche Forschungsgemeinschaft, Grant/Award Numbers: KU1934/2_1, KU1934/5-1; European Union's Seventh Framework Programme (FP7/2007-2013; INMiND, IDEA), Grant/Award Numbers: HEALTH-F2-2011-278850, HEALTH-F2-2011-279288; Medical Research Council; PMU-FFF (Long-Term Fellowship, Stand-Alone Grant), Grant/Award Numbers: L-12/01/001-RIV, E-12/15/077-RIT; UK Multiple Sclerosis Society; Wellcome Trust; Wellcome-MRC Cambridge Stem Cell InstituteThe authors would like to thank the following funding agencies for their support: Paracelsus Medical University PMU-FFF Long-Term Fellowship L-12/01/001-RIV and Stand-Alone Grant E-12/15/077-RIT [both to F.J.R.]; Chilean Comisi?n Nacional de Investigaci?n Cient?fica y Tecnol?gica [CONICYT] FONDECYT Program Regular Grant No. 1161787 [to F.J.R.], Regular Grant No. 1141015 [to L.F.B.]; Chilean CONICYT PCI Program Grant No. REDES170233 [to F.J.R.], Grant No. REDES180139 and Grant No. REDI170037; Chilean CONICYT FONDEF-IDeA Program Grant No. ID17AM0043 [to M.E.S. and F.J.R.]; European Union's Seventh Framework Programme [FP7/2007-2013] under grant agreements No. HEALTH-F2-2011-278850 [INMiND] and HEALTH-F2-2011-279288 [IDEA]). The work in the K?ry laboratory was supported by the German Research Foundation (DFG; KU1934/2_1, KU1934/5-1) and the Christiane and Claudia Hempel Foundation for clinical and iBrain. The work in the Franklin laboratory was supported by grants from the UK Multiple Sclerosis Society and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, and a core support grant from the Wellcome Trust and MRC to the Wellcome-MRC Cambridge Stem Cell Institute. In addition, the present work was supported by the state of Salzburg (to L.A.). We thank Armin Schneider, Sygnis Pharma AG Heidelberg, Germany, for the MBP promoter construct. We disclose any conflict of interest. Funding Information: Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; Bavarian State Ministry of Sciences, Research and the Arts ForNeuroCell grant; Bundesministerium für Bildung und Forschung, Grant/Award Numbers: 01GG0706, 01GN0505, 0312134; Christiane and Claudia Hempel Foundation for Clinical and iBrain; Comisión Nacional de Investigación Científica y Tecnológica (CONICYT) – Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT), Grant/ Award Numbers: 1161787, 1141015; Comisión Nacional de Investigación Científica y Tecnológica (CONICYT) - Fondo de Fomento al Desarrollo Científico y Tecnológico (FONDEF) - IDeA, Grant/Award Number: ID17AM0043; Comisión Nacional de Investigación Científica y Tecnológica (CONICYT) – Programa de Cooperación Internacional (PCI), Grant/Award Numbers: REDES170233, REDES180139, REDI170037; Deutsche Forschungsgemeinschaft, Grant/ Award Numbers: KU1934/2_1, KU1934/5-1; European Union's Seventh Framework Programme (FP7/2007-2013; INMiND, IDEA), Grant/Award Numbers: HEALTH-F2-2011-278850, HEALTH-F2-2011-279288; Medical Research Council; PMU-FFF (Long-Term Fellowship, Stand-Alone Grant), Grant/Award Numbers: L-12/01/001-RIV, E-12/15/077-RIT; UK Multiple Sclerosis Society; Wellcome Trust; Wellcome-MRC Cambridge Stem Cell Institute Publisher Copyright: © 2019 The Authors. Glia published by Wiley Periodicals, Inc.

PY - 2019/8

Y1 - 2019/8

N2 - Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) that leads to severe neurological deficits. Due to their immunomodulatory and neuroprotective activities and their ability to promote the generation of oligodendrocytes, mesenchymal stem cells (MSCs) are currently being developed for autologous cell therapy in MS. As aging reduces the regenerative capacity of all tissues, it is of relevance to investigate whether MSCs retain their pro-oligodendrogenic activity with increasing age. We demonstrate that MSCs derived from aged rats have a reduced capacity to induce oligodendrocyte differentiation of adult CNS stem/progenitor cells. Aging also abolished the ability of MSCs to enhance the generation of myelin-like sheaths in demyelinated cerebellar slice cultures. Finally, in a rat model for CNS demyelination, aging suppressed the capability of systemically transplanted MSCs to boost oligodendrocyte progenitor cell (OPC) differentiation during remyelination. Thus, aging restricts the ability of MSCs to support the generation of oligodendrocytes and consequently inhibits their capacity to enhance the generation of myelin-like sheaths. These findings may impact on the design of therapies using autologous MSCs in older MS patients.

AB - Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) that leads to severe neurological deficits. Due to their immunomodulatory and neuroprotective activities and their ability to promote the generation of oligodendrocytes, mesenchymal stem cells (MSCs) are currently being developed for autologous cell therapy in MS. As aging reduces the regenerative capacity of all tissues, it is of relevance to investigate whether MSCs retain their pro-oligodendrogenic activity with increasing age. We demonstrate that MSCs derived from aged rats have a reduced capacity to induce oligodendrocyte differentiation of adult CNS stem/progenitor cells. Aging also abolished the ability of MSCs to enhance the generation of myelin-like sheaths in demyelinated cerebellar slice cultures. Finally, in a rat model for CNS demyelination, aging suppressed the capability of systemically transplanted MSCs to boost oligodendrocyte progenitor cell (OPC) differentiation during remyelination. Thus, aging restricts the ability of MSCs to support the generation of oligodendrocytes and consequently inhibits their capacity to enhance the generation of myelin-like sheaths. These findings may impact on the design of therapies using autologous MSCs in older MS patients.

KW - CNS stem and progenitor cells

KW - aging

KW - cell therapy

KW - mesenchymal stem cells

KW - multiple sclerosis

KW - oligodendrocytes

KW - remyelination

UR - http://www.scopus.com/inward/record.url?scp=85065097226&partnerID=8YFLogxK

U2 - 10.1002/glia.23624

DO - 10.1002/glia.23624

M3 - Article

C2 - 31038798

AN - SCOPUS:85065097226

SN - 0894-1491

VL - 67

SP - 1510

EP - 1525

JO - GLIA

JF - GLIA

IS - 8

ER -

Aging restricts the ability of mesenchymal stem cells to promote the generation of oligodendrocytes during remyelination

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