title: Modulation of the Innate Immune Response by Human Neural Precursors Prevails over Oligodendrocyte Progenitor Remyelination to Rescue a Severe Model of Pelizaeus-Merzbacher Disease.
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.
authors.affiliation: INSERM, U1127, Institut du Cerveau et de la Moelle épinière, Paris Cedex 13, France.|Université Pierre et Marie Curie-Paris 6, UMR_S 1127, Paris, France.|CNRS, UMR 7225, Paris, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Marteyn
authors.affiliation: INSERM, U1127, Institut du Cerveau et de la Moelle épinière, Paris Cedex 13, France.|Université Pierre et Marie Curie-Paris 6, UMR_S 1127, Paris, France.|CNRS, UMR 7225, Paris, France.
authors.forename: Nadège
authors.initials: N
authors.lastname: Sarrazin
authors.affiliation: INSERM, U1141, F-75019, Paris, France.|Univerité Paris Diderot, Sorbonne Paris Cité, UMRS 1141, Paris, France.
authors.forename: Jun
authors.initials: J
authors.lastname: Yan
authors.affiliation: INSERM, U1127, Institut du Cerveau et de la Moelle épinière, Paris Cedex 13, France.|Université Pierre et Marie Curie-Paris 6, UMR_S 1127, Paris, France.|CNRS, UMR 7225, Paris, France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Bachelin
authors.affiliation: INSERM, U1127, Institut du Cerveau et de la Moelle épinière, Paris Cedex 13, France.|Université Pierre et Marie Curie-Paris 6, UMR_S 1127, Paris, France.|CNRS, UMR 7225, Paris, France.
authors.forename: Cyrille
authors.initials: C
authors.lastname: Deboux
authors.affiliation: INSERM, U1127, Institut du Cerveau et de la Moelle épinière, Paris Cedex 13, France.|Université Pierre et Marie Curie-Paris 6, UMR_S 1127, Paris, France.|CNRS, UMR 7225, Paris, France.|CENIR, Centre de NeuroImagerie de Recherche, ICM, Hôpital Pitié-Salpêtrière, Paris, France.
authors.forename: Mathieu D
authors.initials: MD
authors.lastname: Santin
authors.affiliation: INSERM, U1141, F-75019, Paris, France.|Univerité Paris Diderot, Sorbonne Paris Cité, UMRS 1141, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Gressens
authors.affiliation: INSERM, U1127, Institut du Cerveau et de la Moelle épinière, Paris Cedex 13, France.|Université Pierre et Marie Curie-Paris 6, UMR_S 1127, Paris, France.|CNRS, UMR 7225, Paris, France.
authors.forename: Violetta
authors.initials: V
authors.lastname: Zujovic
authors.affiliation: INSERM, U1127, Institut du Cerveau et de la Moelle épinière, Paris Cedex 13, France.|Université Pierre et Marie Curie-Paris 6, UMR_S 1127, Paris, France.|CNRS, UMR 7225, Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Baron-Van Evercooren
mesh_terms: D000818:Animals; D003711:Demyelinating Diseases / Q000276:immunology / Q000473:pathology; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007113:Immunity, Innate; D056747:Immunomodulation; D007249:Inflammation / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D051379:Mice; D017628:Microglia / Q000276:immunology / Q000473:pathology; D018991:Myelin Proteolipid Protein / Q000096:biosynthesis; D009186:Myelin Sheath / Q000378:metabolism; D058953:Neural Stem Cells / Q000276:immunology / Q000637:transplantation*; D009836:Oligodendroglia / Q000276:immunology / Q000637:transplantation*; D020371:Pelizaeus-Merzbacher Disease / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D012038:Regeneration
chemical_list: D018991:Myelin Proteolipid Protein; C472930:PLP1 protein, human
keywords: Cell-based therapy; Human neural precursor cells; Modulation of inflammation; Pelizaeus-Merzbacher disease; Remyelination