Injury-induced perivascular niche supports alternative differentiation of adult rodent CNS progenitor cells.

Following CNS demyelination, oligodendrocyte progenitor cells (OPCs) are able to differentiate into either remyelinating oligodendrocytes (OLs) or remyelinating Schwann cells (SCs). However, the signals that determine which type of remyelinating cell is generated and the underlying mechanisms involved have not been identified. Here, we show that distinctive microenvironments created in discrete niches within demyelinated white matter determine fate decisions of adult OPCs. By comparative transcriptome profiling we demonstrate that an ectopic, injury-induced perivascular niche is enriched with secreted ligands of the BMP and Wnt signalling pathways, produced by activated OPCs and endothelium, whereas reactive astrocyte within non-vascular area express the dual BMP/Wnt antagonist Sostdc1. The balance of BMP/Wnt signalling network is instructive for OPCs to undertake fate decision shortly after their activation: disruption of the OPCs homeostasis during demyelination results in BMP4 upregulation, which, in the absence of Socstdc1, favours SCs differentiation.

De novo fatty acid synthesis by Schwann cells is essential for peripheral nervous system myelination.

Myelination calls for a remarkable surge in cell metabolism to facilitate lipid and membrane production. Endogenous fatty acid (FA) synthesis represents a potentially critical process in myelinating glia. Using genetically modified mice, we show that Schwann cell (SC) intrinsic activity of the enzyme essential for de novo FA synthesis, fatty acid synthase (FASN), is crucial for precise lipid composition of peripheral nerves and fundamental for the correct onset of myelination and proper myelin growth. Upon FASN depletion in SCs, epineurial adipocytes undergo lipolysis, suggestive of a compensatory role. Mechanistically, we found that a lack of FASN in SCs leads to an impairment of the peroxisome proliferator-activated receptor (PPAR) γ-regulated transcriptional program. In agreement, defects in myelination of FASN-deficient SCs could be ameliorated by treatment with the PPARγ agonist rosiglitazone ex vivo and in vivo. Our results reveal that FASN-driven de novo FA synthesis in SCs is mandatory for myelination and identify lipogenic activation of the PPARγ transcriptional network as a putative downstream functional mediator.

MRI signature in a novel mouse model of genetically induced adult oligodendrocyte cell death.

Two general pathological processes contribute to multiple sclerosis (MS): acute inflammation and degeneration. While magnetic resonance imaging (MRI) is highly sensitive in detecting abnormalities related to acute inflammation both clinically and in animal models of experimental autoimmune encephalomyelitis (EAE), the correlation of these readouts with acute and future disabilities has been found rather weak. This illustrates the need for imaging techniques addressing neurodegenerative processes associated with MS. In the present work we evaluated the sensitivity of different MRI techniques (T(2) mapping, macrophage tracking based on labeling cells in vivo by ultrasmall particles of iron oxide (USPIO), diffusion tensor imaging (DTI) and magnetization transfer imaging (MTI)) to detect histopathological changes in a novel animal model making use of intrinsic, temporally and spatially controlled triggering of oligodendrocyte cell death. This mouse model allows studying the MRI signature associated to neurodegenerative processes of MS in the absence of adaptive inflammatory components that appear to be foremost in the EAE models. Our results revealed pronounced T(2) hyperintensities in brain stem and cerebellar structures, which we attribute to structural alteration of white matter by pronounced vacuolation. Brain areas were found devoid of significant macrophage infiltration in line with the absence of a peripheral inflammatory response. The significant decrease in diffusion anisotropy derived from DTI measures in these structures is mainly caused by a pronounced decrease in diffusivity parallel to the fiber indicative of axonal damage. Triggering of oligodendrocyte ablation did not translate into a significant increase in radial diffusivity. Only minor decreases in MT ratio have been observed, which is attributed to inefficient removal of myelin debris.

Genetically induced adult oligodendrocyte cell death is associated with poor myelin clearance, reduced remyelination, and axonal damage.

Loss of oligodendrocytes is a feature of many demyelinating diseases including multiple sclerosis. Here, we have established and characterized a novel model of genetically induced adult oligodendrocyte death. Specific primary loss of adult oligodendrocytes leads to a well defined and highly reproducible course of disease development that can be followed longitudinally by magnetic resonance imaging. Histological and ultrastructural analyses revealed progressive myelin vacuolation, in parallel to disease development that includes motor deficits, tremor, and ataxia. Myelin damage and clearance were associated with induction of oligodendrocyte precursor cell proliferation, albeit with some regional differences. Remyelination was present in the mildly affected corpus callosum. Consequences of acutely induced cell death of adult oligodendrocytes included secondary axonal damage. Microglia were activated in affected areas but without significant influx of B-cells, T-helper cells, or T-cytotoxic cells. Analysis of the model on a RAG-1 (recombination activating gene-1)-deficient background, lacking functional lymphocytes, did not change the observed disease and pathology compared with immune-competent mice. We conclude that this model provides the opportunity to study the consequences of adult oligodendrocyte death in the absence of primary axonal injury and reactive cells of the adaptive immune system. Our results indicate that if the blood-brain barrier is not disrupted, myelin debris is not removed efficiently, remyelination is impaired, and axonal integrity is compromised, likely as the result of myelin detachment. This model will allow the evaluation of strategies aimed at improving remyelination to foster axon protection.

CNS-resident glial progenitor/stem cells produce Schwann cells as well as oligodendrocytes during repair of CNS demyelination.

After central nervous system (CNS) demyelination-such as occurs during multiple sclerosis-there is often spontaneous regeneration of myelin sheaths, mainly by oligodendrocytes but also by Schwann cells. The origins of the remyelinating cells have not previously been established. We have used Cre-lox fate mapping in transgenic mice to show that PDGFRA/NG2-expressing glia, a distributed population of stem/progenitor cells in the adult CNS, produce the remyelinating oligodendrocytes and almost all of the Schwann cells in chemically induced demyelinated lesions. In contrast, the great majority of reactive astrocytes in the vicinity of the lesions are derived from preexisting FGFR3-expressing cells, likely to be astrocytes. These data resolve a long-running debate about the origins of the main players in CNS remyelination and reveal a surprising capacity of CNS precursors to generate Schwann cells, which normally develop from the embryonic neural crest and are restricted to the peripheral nervous system.

Postnatal Schwann cell proliferation but not myelination is strictly and uniquely dependent on cyclin-dependent kinase 4 (cdk4).

Peripheral myelin formation depends on axonal signals that tightly control proliferation and differentiation of the associated Schwann cells. Here we demonstrate that the molecular program controlling proliferation of Schwann cells switches at birth. We have analyzed the requirements for three members of the cyclin-dependent kinase (cdk) family in Schwann cells using cdk-deficient mice. Mice lacking cdk4 showed a drastic decrease in the proliferation rate of Schwann cells at postnatal days 2 and 5, but proliferation was unaffected at embryonic day 18. In contrast, ablation of cdk2 and cdk6 had no significant influence on postnatal Schwann cell proliferation. Taken together, these findings indicate that postnatal Schwann cell proliferation is uniquely controlled by cdk4. Despite the lack of the postnatal wave of Schwann cell proliferation, axons were normally myelinated in adult cdk4-deficient sciatic nerves. Following nerve injury, Schwann cells lacking cdk4 were unable to re-enter the cell cycle, while Schwann cells deficient in cdk2 or cdk6 displayed proliferation rates comparable to controls. We did not observe compensatory effects such as elevated cdk4 levels in uninjured or injured nerves of cdk2 or cdk6-deficient mice. Our data demonstrate that prenatal and postnatal Schwann cell proliferation are driven by distinct molecular cues, and that postnatal proliferation is not a prerequisite for the generation of Schwann cell numbers adequate for correct myelination.