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. STEM CELLS 2016;34:984-996 SIGNIFICANCE STATEMENTCell-based therapy emerged as a promising approach to treat white matter diseases. Although evidences of myelin repair were provided both with neural stem/precursor cells and oligodendrocyte progenitor cells in dysmyelinating conditions, the benefit of one cell type over the other is a matter of debate, especially in severe diseases associating demyelination and inflammation such as Pleizeaus Merzbacher Disease (PMD). We provide evidence that human neural stem/precursor cells are the best cellular source to rescue the PMD phenotye providing modulation of the innate immune response and remyelination. Moreover, our data highlight the major implication of neuroinflammation in PMD disease severity and the necessity to modulate it in priority to promote survival and motor recovery.

Stem cell derived oligodendrocytes to study myelin diseases

“…When compared to rodent iPSC‐derived progenies, human iPSC derived progenies generated similarly functional oligodendrocytes (Figure ). Although already committed to the oligodendroglial lineage and the O4+ stage, the transplanted iPSC‐O4+ cells migrated as extensively rostrocaudally and dorsoventrally as hfNPC in the immunodeficient shiverer host, differentiated 3–4 fold more into CC1+ oligodendrocytes and contributed 1.5 fold more to myelination of the dorsal column lesion compared to hfNPC, suggesting as previously demonstrated with fetal cells (Marteyn et al, ), improved (re)myelination when cells are grafted as OPC rather than NPC. Altogether, these data demonstrate that irrespective of their source (fetal or pluripotent), human stem cells/OPCs respond dynamically and interact specifically with the host environment.…”

“…These in vitro and in vivo differences between rodent and human cells highlight the necessity to further study the biology of human oligodendroglia to improve our understanding of myelin diseases and the development of therapeutic treatments. Human OPC have been successfully isolated from fetal as well adult brain tissue upon immunoselection for OPC markers such as A2B5 and PDGFRα (Ruffini, Arbour, Blain, Olivier, & Antel, 2004;Sim et al, 2011;Windrem et al, 2002;Windrem et al, 2004), or have been differentiated from fetal brain derived NPC (Marteyn et al, 2016). However, ethical concerns and the scarce access to human brain tissue is a restrictive factor for the isolation and study of primary human OL.…”

Genetic dissection of oligodendroglial and neuronalPlp1function in a novel mouse model of spastic paraplegia type 2

“…The remarkable variety of the cellular pathogenesis indicates that no single therapy concept may work for all patients with SPG2 or PMD. Consequently, the therapeutic approaches to SPG2/PMD vary widely, including downregulating the toxic PLP/Plp overexpression (Prukop et al, ), cholesterol‐dependent modulation of intracellular PLP trafficking (Saher et al, ), neuroprotective dietary supplementation with Turmeric (Epplen et al, ; Yu et al, ), stem cell therapy (Gupta et al, ; Marteyn et al, ; Osorio et al, ), manipulating the unfolded protein response (Southwood, Garbern, Jiang, & Gow, ) or microglial proteases and protease inhibitors (Shimizu et al, ), and ablating the activation of T‐lymphocytes (Groh et al, ; Ip et al, ; Ip et al, ). Considering the presence of cytotoxic T‐lymphocytes in the CNS of a wide range of SPG2/PMD models, T‐lymphocytes are probably involved in the progression of axonal pathology in all or most SPG2/PMD spectrum disorders; yet they probably do not explain the axonal pathology to its full extent.…”

Electroacupuncture Promotes Remyelination after Cuprizone Treatment by Enhancing Myelin Debris Clearance

“…Accumulating evidence suggests that microglia is associated with the clearance and phagocytosis of degraded and collapsed myelin debris, existence of which is detrimental to OPC proliferation and remyelination (Kotter et al, 2005, 2006; Ruckh et al, 2012; Kocur et al, 2015). Studies also found that microglia, especially M2 phenotype, are positively related to the recruitment of OPCs and their differentiation into mature oligodendrocytes, as well as myelin formation (Miron et al, 2013; Wang et al, 2015; Marteyn et al, 2016). Although EA shows a therapeutic effect on various neurodegenerative diseases achieved by its ability to alleviate existing neuroinflammation and glial dysfunction, it is unclear whether EA could modulate microglia function during the process of demyelination and remyelination.…”