Date of Completion

2-4-2019

Embargo Period

2-1-2019

Keywords

primary progressive multiple sclerosis, induced pluripotent stem cells, neural progenitor cells, senescence, oligodendrocytes, myelin

Major Advisor

Stephen J. Crocker

Associate Advisor

Elisa Barbarese

Associate Advisor

Royce Mohan

Associate Advisor

Rosa Guzzo

Associate Advisor

Laura Haynes

Field of Study

Biomedical Science

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

Primary progressive multiple sclerosis (PPMS) is a chronic demyelinating disease of the central nervous system (CNS) currently lacking any effective treatment. Promoting endogenous brain repair offers a potential strategy to halt and possibly restore neurologic function in PPMS. To understand how the microenvironment within white matter lesions plays a role in repair I focused on neural progenitor cells (NPCs) since they have been found within lesions and influence oligodendrocyte progenitor cell (OPC) maturation. To better understand the cellular nature of NPCs in PPMS I developed induced pluripotent stem cells (iPSCs) from blood and skin samples of PPMS patients and age matched non-disease controls. Using these lines I determined that NPCs from PPMS cases provided no neuroprotection against active CNS demyelination and failed to promote OPC maturation whereas NPCs from age-matched control cell lines did so efficiently. I determined that NPCs from PPMS patients displayed hallmarks of cellular senescence, inhibiting their proper functioning. 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. Senescent NPCs were identified within white matter lesions of human progressive MS autopsy brain tissues. 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, I determined that NPCs are a source of elevated HMGB1 in human white matter lesions. Based on these data, cellular senescence contributes to altered NPC 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.

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