دورية أكاديمية
Cellular senescence in progenitor cells contributes to diminished remyelination potential in progressive multiple sclerosis.
| العنوان: | Cellular senescence in progenitor cells contributes to diminished remyelination potential in progressive multiple sclerosis. |
|---|---|
| المؤلفون: | Nicaise, Alexandra M, Wagstaff, Laura J, Willis, Cory M, Paisie, Carolyn, Chandok, Harshpreet, Robson, Paul, Fossati, Valentina, Williams, Anna, Crocker, Stephen J |
| المصدر: | Faculty Research 2019 |
| بيانات النشر: | The Mouseion at the JAXlibrary |
| سنة النشر: | 2019 |
| المجموعة: | The Jackson Laboratory: The Mouseion at the JAXlibrary |
| مصطلحات موضوعية: | JGM, Aminohydrolases, Cystathionine beta-Synthase, Fibroblasts, Folic Acid, Formate-Tetrahydrofolate Ligase, Glycine Hydroxymethyltransferase, Humans, Kinetics, Methenyltetrahydrofolate Cyclohydrolase, Methylenetetrahydrofolate Dehydrogenase (NADP), Psychoses, Substance-Induced, Serine, Life Sciences, Medicine and Health Sciences |
| الوصف: | 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. |
| نوع الوثيقة: | text |
| وصف الملف: | application/pdf |
| اللغة: | unknown |
| العلاقة: | https://mouseion.jax.org/stfb2019/100Test; https://mouseion.jax.org/context/stfb2019/article/1104/viewcontent/9030.full.pdfTest |
| DOI: | 10.1073/pnas.1818348116 |
| الإتاحة: | https://doi.org/10.1073/pnas.1818348116Test https://mouseion.jax.org/stfb2019/100Test https://mouseion.jax.org/context/stfb2019/article/1104/viewcontent/9030.full.pdfTest |
| رقم الانضمام: | edsbas.3C36190E |
| قاعدة البيانات: | BASE |
| DOI: | 10.1073/pnas.1818348116 |
|---|