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 Federico Batiz, Patrick Küry, Sebastien Couillard-DespresRobin J.M. Franklin, Ludwig Aigner

Research output: Contribution to journalArticlepeer-review

14 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 languageEnglish
Pages (from-to)1510-1525
Number of pages16
JournalGLIA
Volume67
Issue number8
DOIs
StatePublished - 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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