PXD013060

PXD013060 is an original dataset announced via ProteomeXchange.

Title	Cellular Senescence in Progenitor Cells Contributes to Diminished Remyelination Potential in Progressive Multiple Sclerosis
Description	Cellular senescence is a form of adaptive cellular physiology associated with aging. Cellular senescence causes a pro-inflammatory 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 primary progressive multiple sclerosis (PPMS) patient induced pluripotent stem (iPS) cell lines 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 autopsy brain tissues and PPMS patient iPS-derived NPCs. 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 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 oligodendrocyte 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 progressive MS which may impact how this disease is modeled and inform development of future myelin regeneration strategies.
HostingRepository	PRIDE
AnnounceDate	2019-11-12
AnnouncementXML	Submission_2019-11-11_18:02:53.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Alexandra Nicaise
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	iodoacetamide derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2019-03-12 03:47:45	ID requested
⏵ 1	2019-11-11 18:02:55	announced

Nicaise AM, Wagstaff LJ, Willis CM, Paisie C, Chandok H, Robson P, Fossati V, Williams A, Crocker SJ, Cellular senescence in progenitor cells contributes to diminished remyelination potential in progressive multiple sclerosis. Proc Natl Acad Sci U S A, 116(18):9030-9039(2019) [pubmed]

submitter keyword: oligodendrocyte, neural progenitor cells, aging, rapamycin, proteomics

Stephen J. Crocker
contact affiliation	Department of Neuroscience University of Connecticut School of Medicine
contact email	crocker@uchc.edu
lab head
Alexandra Nicaise
contact affiliation	University of Connecticut School of Medicine
contact email	anicaise@uchc.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD013060
     1. Label: PRIDE project
     2. Name: Cellular Senescence in Progenitor Cells Contributes to Diminished Remyelination Potential in Progressive Multiple Sclerosis