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Cellular senescence in progenitor cells contributes to diminished remyelination potential in progressive multiple sclerosis
- Source :
- Nicaise, A M, Wagstaff, L J, Willis, C M, Paisie, C, Chandok, H, Robson, P, Fossati, V, Williams, A & Crocker, S J 2019, ' Cellular senescence in progenitor cells contributes to diminished remyelination potential in progressive multiple sclerosis ', Proceedings of the National Academy of Sciences, vol. 116, no. 18, pp. 9030-9039 . https://doi.org/10.1073/pnas.1818348116, Proceedings of the National Academy of Sciences of the United States of America
- Publication Year :
- 2019
- Publisher :
- Proceedings of the National Academy of Sciences, 2019.
-
Abstract
- Significance We identify cellular senescence occurring in neural progenitor cells (NPCs) from primary progressive multiple sclerosis (PPMS). In this study, senescent progenitor cells were identified within demyelinated white matter lesions in progressive MS (PMS) autopsy tissue, and induced pluripotent stem-derived NPCs from patients with PPMS were found to express cellular senescence markers compared with age-matched control NPCs. Reversal of this cellular senescence phenotype, by treatment with rapamycin, restored PPMS NPC-mediated support for oligodendrocyte (OL) maturation. Proteomic and histological analyses identify senescent progenitor cells in PMS as a source of high-mobility group box-1, which limits maturation and promotes transcriptomic changes in OLs. These findings provide evidence that cellular senescence is an active process in PMS that may contribute to limited remyelination in disease.<br />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.
- Subjects :
- Senescence
Medical Sciences
Multiple Sclerosis
Biology
Transcriptome
03 medical and health sciences
proteomics
0302 clinical medicine
medicine
Humans
neural progenitor cell
Progenitor cell
Remyelination
Induced pluripotent stem cell
Cellular Senescence
030304 developmental biology
0303 health sciences
Multidisciplinary
rapamycin
Stem Cells
Regeneration (biology)
aging
Biological Sciences
Multiple Sclerosis, Chronic Progressive
Oligodendrocyte
Neural stem cell
Cell biology
stomatognathic diseases
medicine.anatomical_structure
PNAS Plus
oligodendrocyte
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 10916490 and 00278424
- Volume :
- 116
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences
- Accession number :
- edsair.doi.dedup.....1fc51a712af2cd01caf914fc199b390b