The transcription factor peroxisome proliferator-activated receptor (PPAR)-delta promotes oligodendrocyte differentiation and myelin formation in vitro and is prevalent throughout the brain and spinal cord. Its expression after injury, however, has not been examined. Thus, we used a spinal contusion model to examine the spatiotemporal expression of PPAR-delta in naïve and injured spinal cords from adult rats. As previously reported, PPAR-delta was expressed by neurons and oligodendrocytes in uninjured spinal cords; PPAR-delta was also detected in NG2 cells (potential oligodendrocyte progenitors) within the white matter and gray matter. After spinal cord injury (SCI), PPAR-delta mRNA and protein were present early and increased over time. Overall PPAR-delta+ cell numbers declined at 1 day post injury (dpi), likely reflecting neuron loss, and then rose through 14 dpi. A large proportion of NG2 cells expressed PPAR-delta after SCI, especially along lesion borders. PPAR-delta+ NG2 cell numbers were significantly higher than naive by 7 dpi and remained elevated through at least 28 dpi. PPAR-delta+ oligodendrocyte numbers declined at 1 dpi and then increased over time such that >20% of oligodendrocytes expressed PPAR-delta after SCI compared with approximately 10% in uninjured tissue. The most prominent increase in PPAR-delta+ oligodendrocytes was along lesion borders where at least a portion of newly generated oligodendrocytes (bromodeoxyuridine+) were PPAR-delta+. Consistent with its role in cellular differentiation, the early rise in PPAR-delta+ NG2 cells followed by an increase in new PPAR-delta+ oligodendrocytes suggests that this transcription factor may be involved in the robust oligodendrogenesis detected previously along SCI lesion borders.

Mutations in Adenosine deaminase acting on RNA 1 (ADAR1) gene encoding RNA editing enzyme ADAR1 results in the neuroinflammatory leukodystrophy Aicardi Goutières Syndrome (AGS). AGS is an early onset leukoencephalopathy with an exacerbated interferon response leading to neurological regression with intellectual disability, spasticity, and motor deficits. We have generated three induced pluripotent stem cell (iPSC) lines from peripheral blood mononuclear cells (PBMCs) of individuals with ADAR1G1007R mutation. The generated iPSCs were investigated to confirm a normal karyotype, pluripotency, and trilineage differentiation potential. The reprogrammed iPSCs will allow us to model AGS, dissect the cellular mechanisms and testing different treatment targets.

Peroxisome Proliferator Activated Receptor (PPAR)-α is a key regulator of lipid metabolism and recent studies reveal it also regulates inflammation in several different disease models. Gemfibrozil, an agonist of PPAR-α, is a FDA approved drug for hyperlipidemia and has been shown to inhibit clinical signs in a rodent model of multiple sclerosis. Since many studies have shown improved outcome from spinal cord injury (SCI) by anti-inflammatory and neuroprotective agents, we tested the efficacy of oral gemfibrozil given before or after SCI for promoting tissue preservation and behavioral recovery after spinal contusion injury in mice. Unfortunately, the results were contrary to our hypothesis; in our first attempt, gemfibrozil treatment exacerbated locomotor deficits and increased tissue pathology after SCI. In subsequent experiments, the behavioral effects were not replicated but histological outcomes again were worse. We also tested the efficacy of a different PPAR-α agonist, fenofibrate, which also modulates immune responses and is beneficial in several neurodegenerative disease models. Fenofibrate treatment did not improve recovery, although there was a slight trend for a modest increase in histological tissue sparing. Based on our results, we conclude that PPAR-α agonists yield either no effect or worsen recovery from spinal cord injury, at least at the doses and the time points of drug delivery tested here. Further, patients sustaining spinal cord injury while taking gemfibrozil might be prone to exacerbated tissue damage.

In multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), relapses are markedly reduced during pregnancy. Exosomes are lipid-bound vesicles and are more abundant in the serum during pregnancy. Using murine EAE, we demonstrate that serum exosomes suppress T cell activation, promote the maturation of oligodendrocyte precursor cells (OPC), and pregnancy exosomes facilitate OPC migration into active CNS lesions. However, exosomes derived from both pregnant and non-pregnant mice reduced the severity of established EAE. Thus, during pregnancy, serum exosomes modulate the immune and central nervous systems and contribute to pregnancy-associated suppression of EAE.

One of the fundamental limitations in assessing potential efficacy in Central Nervous System (CNS) transplantation of stem cells is the capacity for monitoring cell survival and migration noninvasively and longitudinally. Human glial-restricted progenitor (hGRP) cells (Q-Cells) have been investigated for their utility in providing neuroprotection following transplantation into models of amyotrophic lateral sclerosis (ALS) and have been granted a Food and Drug Administration (FDA) Investigational New Drug (IND) for intraspinal transplantation in ALS patients. Furthermore, clinical development of these cells for therapeutic use will rely on the ability to track the cells using noninvasive imaging methodologies as well as the verification that the transplanted GRPs have disease-relevant activity. As a first step in development, we investigated the use of a perfluorocarbon (PFC) dual-modal (19 F magnetic resonance imaging [MRI] and fluorescence) tracer agent to label Q-Cells in culture and following spinal cord transplantation. PFCs have a number of potential benefits that make them appealing for clinical use. They are quantitative, noninvasive, biologically inert, and highly specific. In this study, we developed optimized PFC labeling protocols for Q-Cells and demonstrate that PFCs do not significantly alter the glial identity of Q-Cells. We also show that PFCs do not interfere with the capacity for differentiation into astrocytes either in vitro or following transplantation into the ventral horn of the mouse spinal cord, and can be visualized in vivo by hot spot 19 F MRI. These studies provide a foundation for further preclinical development of PFCs within the context of evaluating Q-Cell transplantation in the brain and spinal cord of future ALS patients using 19 F MRI. Stem Cells Translational Medicine 2019;8:355-365.