Chu, Yu-Hsuan
[Author]
;
Schachtrup, Christian
[Degree supervisor]Albert-Ludwigs-Universität Freiburg Institut für Anatomie und Zellbiologie,
Albert-Ludwigs-Universität Freiburg Fakultät für Biologie,
Albert-Ludwigs-Universität Freiburg Fakultät für Biologie
The regulatory role of Id2 / Id3 in adult subventricular zone neural stem / progenitor cells affecting multiple sclerosis disease progression
University thesis:
Dissertation, Universität Freiburg, 2021
Footnote:
Description:
Abstract: Multiple sclerosis (MS) is an autoinflammatory disease of the central nervous system (CNS) characterized by blood-brain barrier (BBB) opening, leukocyte infiltration, demyelination and axonal degeneration (1, 2). Although the detailed cause is still unknown, the pathogenesis of MS is believed to involve a complex multicellular interaction between peripheral autoreactive immune cells and activated CNS myeloid cells (3, 4), which lead to the great difficulties developing specific and efficacious therapeutic treatment to halt the disease. Recently, neural stem / progenitor cell (NSPC)-based therapy has emerged as an attractive strategy to treat various neurodegenerative diseases, including MS (5, 6). Although the evidence of physically replacing the lost tissue is scarce, transplanted NSPCs secrete variable trophic factors supporting repairing processes and show notable effects targeting myeloid cell reprogramming thus ameliorating inflammatory burden in MS (7, 8). While adult CNS-resident NSPCs in the subventricular zone (SVZ) of the lateral ventricle, which represent the largest germinal niche in the adult brain, can generate new neurons and glia contributing to the repair processes during CNS injury and neurological diseases (9-11), a potential immunoregulatory role of endogenous NSPCs in MS disease initiation and progression remains unclear. Here, we uncovered a immunomodulatory function of endogenous NSPCs that reduce the pro-inflammatory properties of CNS-resident myeloid cells, thereby preventing the initiation of experimental autoimmune encephalomyelitis (EAE), a mouse model for MS. NSPC-targeted depletion of inhibitor of DNA binding (Id) 2/3 proteins, which are known as central regulator of SVZ NSPC behavior by translating various environmental stimuli into cellular transcriptional activity (9, 10, 12), alters the cellular composition and secretory profile of the SVZ stem cell niche after EAE induction. Id gene-depleted NSPCs increased vascular barrier properties and reduce microglial activation in the stem cell niche. Thus, Id-depleted NSPCs successfully alleviated the vulnerability of the niche to peripheral inflammation and prevented the early activation of CNS resident myeloid cells (parenchymal microglia/subarachnoidal myeloid cells). This in turn resulted in a reduced accumulation of chemotactic cues in the cerebrospinal fluid, suppressing autoreactive T cell infiltration, demyelination, and relapsing paralysis. Our results highlight the functional significance of endogenous NSPCs as signal mediators between the CNS and peripheral immune system, and indicate their potential as therapeutic targets for CNS inflammatory diseases