Olig1 function is required for remyelination potential of transplanted neural progenitor cells in a model of viral-induced demyelination

Department of Molecular Biology and Biochemistry, University of California, Irvine 92697-3900, USA.
Experimental Neurology (Impact Factor: 4.7). 03/2012; 235(1):380-7. DOI: 10.1016/j.expneurol.2012.03.003
Source: PubMed


Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) resulting in cumulative neurologic deficits associated with progressive myelin loss. We have previously shown that transplantation of neural progenitor cells (NPCs) into mice persistently infected with the JHM strain of mouse hepatitis virus (JHMV) results in enhanced differentiation into oligodendrocyte progenitor cells (OPCs) that is associated with remyelination and axonal sparing. The current study examines the contributions of the transcription factor Olig1 on NPC differentiation and remyelination. Under defined conditions, NPCs preferentially differentiate into oligodendroglia whereas NPCs isolated from Olig1-deficient (Olig1-/-) mice exhibit enhanced differentiation into astrocytes. Transplantation of Olig1-/- and Olig1+/+ NPCs into JHMV-infected mice resulted in similar cell survival, proliferation, and selective migration to areas of demyelination. However, only recipients of wild type NPCs exhibited extensive remyelination compared to mice receiving Olig1-/- NPCs. In vivo characterization of NPCs revealed that Olig1+/+ NPCs preferentially differentiated into NG2-positive OPCs and formed processes expressing myelin basic protein that encircled axons. In contrast, the majority of transplanted Olig1-/- NPCs differentiated into GFAP-positive cells consistent with the astrocyte lineage. These results indicate that exogenous NPCs contribute to improved clinical and histological outcome and this is associated with remyelination by this donor population. Further, these findings reveal that Olig1function is required for the remyelination potential of NPCs after transplant, through specification and/or maintenance of oligodendroglial identity.

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    • "Finally, Olig1, which relocates to the nucleus in " activated " OPCs, and Ascl1/Mash1 are also required for remyelination (Arnett et al., 2004; Nakatani et al., 2013). Loss of Olig1 in transplanted NPCs results in astrocyte generation, rather than oligodendrocytes (Whitman et al., 2012), and selective deletion of Ascl1/Mash1 in OPCs prevents remyelination (Nakatani et al., 2013). In conclusion, it appears that expression of proliferation markers, as well as high levels of FGFR1, Shh, Sox17, Msi1, Myt1, Nkx2.2, Tcf4, and Ascl1/Mash1, together with nuclear Olig1/2 expression, may characterize " activated " OPCs engaged in the remyelination process. "
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    • "Transplanted cells can include NPCs, which, following injection into the brain of hypomyelinated mice, can result in differentiation into oligodendrocytes and myelin production [59]. In animal models of demyelination, rodent NPC injections also contribute to remyelination of axons [60–62]. Pluchino et al. [60] injected NPCs intracerebroventricularly or intravenously into chronic EAE mice and showed that NPCs differentiated into OPCs which made close contact with thinly myelinated axons. "
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    ABSTRACT: Transplantation of syngeneic neural progenitor cells (NPCs) into mice persistently infected with the JHM strain of mouse hepatitis virus (JHMV) results in enhanced differentiation into oligodendrocyte progenitor cells that is associated with remyelination, axonal sparing, and clinical improvement. Whether allogeneic NPCs are tolerated or induce immune-mediated rejection is controversial and poorly defined under neuroinflammatory demyelinating conditions. We have used the JHMV-induced demyelination model to evaluate the antigenicity of transplanted allogeneic NPCs within the central nervous system (CNS) of mice with established immune-mediated demyelination. Cultured NPCs constitutively expressed the costimulatory molecules CD80/CD86, and IFN-γ treatment induced expression of MHC class I and II antigens. Injection of allogeneic C57BL/6 NPCs (H-2(b) background) led to a delayed type hypersensitivity response in BALB/c (H-2(d) background) mice associated with T-cell proliferation and IFN-γ secretion following coculture with allogeneic NPCs. Transplantation of MHC-mismatched NPCs into JHMV-infected mice resulted in increased transcripts encoding the T-cell chemoattractant chemokines CXCL9 and CXCL10 that correlated with increased T-cell infiltration that was associated with NPC rejection. Treatment of MHC-mismatched mice with T-cell subset-specific depleting antibodies increased survival of allogeneic NPCs without affecting commitment to an oligodendrocyte lineage. Collectively, these results show that allogeneic NPCs are antigenic, and T-cells contribute to rejection following transplantation into an inflamed CNS suggesting that immunomodulatory treatments may be necessary to prolong survival of allogeneic cells. STEM CELLS2012;30:2584-2595.
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