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Cellular senescence in progenitor cells contributes to diminished remyelination potential in progressive multiple sclerosis.
Nicaise, Alexandra M; Wagstaff, Laura J; Willis, Cory M; Paisie, Carolyn; Chandok, Harshpreet; Robson, Paul; Fossati, Valentina; Williams, Anna; Crocker, Stephen J.
Afiliación
  • Nicaise AM; Department of Neuroscience, University of Connecticut School of Medicine, Farmington, CT 06030.
  • Wagstaff LJ; The MRC Centre for Regenerative Medicine and MS Society Edinburgh Centre, Edinburgh bioQuarter, The University of Edinburgh, Edinburgh EH16 4UU, United Kingdom.
  • Willis CM; Department of Neuroscience, University of Connecticut School of Medicine, Farmington, CT 06030.
  • Paisie C; The Jackson Laboratory for Genomic Medicine, Farmington, CT 06030.
  • Chandok H; The Jackson Laboratory for Genomic Medicine, Farmington, CT 06030.
  • Robson P; The Jackson Laboratory for Genomic Medicine, Farmington, CT 06030.
  • Fossati V; Department of Genetics and Genome Sciences, University of Connecticut School of Medicine, Farmington, CT 06032.
  • Williams A; The New York Stem Cell Foundation Research Institute, New York, NY 10019.
  • Crocker SJ; The MRC Centre for Regenerative Medicine and MS Society Edinburgh Centre, Edinburgh bioQuarter, The University of Edinburgh, Edinburgh EH16 4UU, United Kingdom.
Proc Natl Acad Sci U S A ; 116(18): 9030-9039, 2019 04 30.
Article en En | MEDLINE | ID: mdl-30910981
Cellular senescence is a form of adaptive cellular physiology associated with aging. Cellular senescence causes a proinflammatory cellular phenotype that impairs tissue regeneration, has been linked to stress, and is implicated in several human neurodegenerative diseases. We had previously determined that neural progenitor cells (NPCs) derived from induced pluripotent stem cell (iPSC) lines from patients with primary progressive multiple sclerosis (PPMS) failed to promote oligodendrocyte progenitor cell (OPC) maturation, whereas NPCs from age-matched control cell lines did so efficiently. Herein, we report that expression of hallmarks of cellular senescence were identified in SOX2+ progenitor cells within white matter lesions of human progressive MS (PMS) autopsy brain tissues and iPS-derived NPCs from patients with PPMS. Expression of cellular senescence genes in PPMS NPCs was found to be reversible by treatment with rapamycin, which then enhanced PPMS NPC support for oligodendrocyte (OL) differentiation. A proteomic analysis of the PPMS NPC secretome identified high-mobility group box-1 (HMGB1), which was found to be a senescence-associated inhibitor of OL differentiation. Transcriptome analysis of OPCs revealed that senescent NPCs induced expression of epigenetic regulators mediated by extracellular HMGB1. Lastly, we determined that progenitor cells are a source of elevated HMGB1 in human white matter lesions. Based on these data, we conclude that cellular senescence contributes to altered progenitor cell functions in demyelinated lesions in MS. Moreover, these data implicate cellular aging and senescence as a process that contributes to remyelination failure in PMS, which may impact how this disease is modeled and inform development of future myelin regeneration strategies.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Senescencia Celular / Esclerosis Múltiple Crónica Progresiva / Células-Madre Neurales Límite: Animals / Humans Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2019 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Senescencia Celular / Esclerosis Múltiple Crónica Progresiva / Células-Madre Neurales Límite: Animals / Humans Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2019 Tipo del documento: Article Pais de publicación: Estados Unidos