Modulation of the Innate Immune Response by Human Neural Precursors Prevails over Oligodendrocyte Progenitor Remyelination to Rescue a Severe Model of Pelizaeus-Merzbacher Disease

Author:

Marteyn Antoine123,Sarrazin Nadège123,Yan Jun45,Bachelin Corinne123,Deboux Cyrille123,Santin Mathieu D.1236,Gressens Pierre45,Zujovic Violetta123,Baron-Van Evercooren Anne123

Affiliation:

1. INSERM, U1127, Institut du Cerveau et de la Moelle épinière, Paris Cedex 13, France

2. Université Pierre et Marie Curie-Paris 6, UMR_S 1127, Paris, France

3. CNRS, UMR 7225, Paris, France

4. INSERM, U1141, F-75019, Paris, France

5. Univerité Paris Diderot, Sorbonne Paris Cité, UMRS 1141, Paris, France

6. CENIR, Centre de NeuroImagerie de Recherche, ICM, Hôpital Pitié-Salpêtrière, Paris, France

Abstract

Abstract Pelizaeus-Merzbacher disease (PMD) results from an X-linked misexpression of proteolipid protein 1 (PLP1). This leukodystrophy causes severe hypomyelination with progressive inflammation, leading to neurological dysfunctions and shortened life expectancy. While no cure exists for PMD, experimental cell-based therapy in the dysmyelinated shiverer model suggested that human oligodendrocyte progenitor cells (hOPCs) or human neural precursor cells (hNPCs) are promising candidates to treat myelinopathies. However, the fate and restorative advantages of human NPCs/OPCs in a relevant model of PMD has not yet been addressed. Using a model of Plp1 overexpression, resulting in demyelination with progressive inflammation, we compared side-by-side the therapeutic benefits of intracerebrally grafted hNPCs and hOPCs. Our findings reveal equal integration of the donor cells within presumptive white matter tracks. While the onset of exogenous remyelination was earlier in hOPCs-grafted mice than in hNPC-grafted mice, extended lifespan occurred only in hNPCs-grafted animals. This improved survival was correlated with reduced neuroinflammation (microglial and astrocytosis loads) and microglia polarization toward M2-like phenotype followed by remyelination. Thus modulation of neuroinflammation combined with myelin restoration is crucial to prevent PMD pathology progression and ensure successful rescue of PMD mice. These findings should help to design novel therapeutic strategies combining immunomodulation and stem/progenitor cell-based therapy for disorders associating hypomyelination with inflammation as observed in PMD.

Funder

European Leukotreat project

European Foundation for Leukodystrophies (ELA)

“Institut pour la Recherche sur la Moelle épinière et l'Encéphale” (IRME)

“ICM Carnot Institut”

“Investissements d'Avenir”

“Translational Research Infrastructure for Biotherapies in Neurosciences”

Publisher

Oxford University Press (OUP)

Subject

Cell Biology,Developmental Biology,Molecular Medicine

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