Circulating platelets modulate oligodendrocyte progenitor cell differentiation during remyelination.

Revealing unknown cues that regulate oligodendrocyte progenitor cell (OPC) function in remyelination is important to optimise the development of regenerative therapies for multiple sclerosis (MS). Platelets are present in chronic non-remyelinated lesions of MS and an increase in circulating platelets has been described in experimental autoimmune encephalomyelitis (EAE) mice, an animal model for MS. However, the contribution of platelets to remyelination remains unexplored. Here we show platelet aggregation in proximity to OPCs in areas of experimental demyelination. Partial depletion of circulating platelets impaired OPC differentiation and remyelination, without altering blood-brain barrier stability and neuroinflammation. Transient exposure to platelets enhanced OPC differentiation in vitro, whereas sustained exposure suppressed this effect. In a mouse model of thrombocytosis (Calr+/-), there was a sustained increase in platelet aggregation together with a reduction of newly-generated oligodendrocytes following toxin-induced demyelination. These findings reveal a complex bimodal contribution of platelet to remyelination and provide insights into remyelination failure in MS.

Progesterone through Progesterone Receptor B Isoform Promotes Rodent Embryonic Oligodendrogenesis.

Oligodendrocytes are the myelinating cells of the central nervous system (CNS). These cells arise during the embryonic development by the specification of the neural stem cells to oligodendroglial progenitor cells (OPC); newly formed OPC proliferate, migrate, differentiate, and mature to myelinating oligodendrocytes in the perinatal period. It is known that progesterone promotes the proliferation and differentiation of OPC in early postnatal life through the activation of the intracellular progesterone receptor (PR). Progesterone supports nerve myelination after spinal cord injury in adults. However, the role of progesterone in embryonic OPC differentiation as well as the specific PR isoform involved in progesterone actions in these cells is unknown. By using primary cultures obtained from the embryonic mouse spinal cord, we showed that embryonic OPC expresses both PR-A and PR-B isoforms. We found that progesterone increases the proliferation, differentiation, and myelination potential of embryonic OPC through its PR by upregulating the expression of oligodendroglial genes such as neuron/glia antigen 2 (NG2), sex determining region Y-box9 (SOX9), myelin basic protein (MBP), 2',3'-cyclic-nucleotide 3'-phosphodiesterase (CNP1), and NK6 homeobox 1 (NKX 6.1). These effects are likely mediated by PR-B, as they are blocked by the silencing of this isoform. The results suggest that progesterone contributes to the process of oligodendrogenesis during prenatal life through specific activation of PR-B.

Pericytes in Multiple Sclerosis.

Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating disease that affects the central nervous system (CNS), particularly, in young adults. Current MS treatments aim to reduce demyelination; however, these have limited efficacy, display side effects and lack of regenerative activities. Oligodendrocyte progenitor cells (OPCs) represents the major source for new myelin. Upon demyelination, OPCs get activated, proliferate, migrate towards the lesion, and differentiate into remyelinating oligodendrocytes. Although myelin repair (remyelination) represents a robust response to myelin damage, during MS, this regenerative phenomenon decays in efficiency or even fails. CNS-resident pericytes (CNS-PCs) are essential for vascular homeostasis regulating blood-brain barrier (BBB) permeability and stability as well as endothelial cells (ECs) function during angiogenesis and neovascularization. Recent studies indicate that CNS-PCs also play a crucial role regulating OPC function during remyelination, and very importantly, these cells are substantially affected in MS. This chapter summarizes important aspects of MS and CNS remyelination as well as it provides new insights supporting the contribution of CNS-PCs to myelin regeneration and to MS pathology. Currently, there is evidence arguing in favor of CNS-PCs as novel therapeutic targets for the development of future treatments for MS.

Glioprotective Effect of Resveratrol: an Emerging Therapeutic Role for Oligodendroglial Cells.

Resveratrol is a natural polyphenol compound highly found in red wine that displays several beneficial effects on the central nervous system (CNS), preventing or slowing the progression of a wide variety of neurological diseases. Its neuroprotective role is particularly associated to modulation of antioxidant and anti-inflammatory responses in glial cells in a mechanism dependent of heme oxygenase 1 (HO-1) signaling pathway. Oligodendrocyte progenitor cells (OPC), primarily known for giving rise to mature oligodendrocytes, have emerged as dynamic cells that are also important to maintain the CNS homeostasis. In this sense, we have demonstrated that resveratrol has a protective effect on oligodendroglial functionality against lipopolysaccharide (LPS)-mediated cytotoxicity and that its glioprotective mechanism involves the nuclear factor erythroid 2-related factor 2 (Nrf2) and HO-1 pathways. LPS, through toll-like receptor 4 (TLR4), affected the release of trophic factors by OPC, including transforming growth factor beta (TGF-ß), brain-derived neurotrophic factor (BDNF), and glial cell-derived neurotrophic factor (GDNF), and resveratrol reestablished the trophic factor release to control levels. Additionally, resveratrol prevented the LPS-induced increase in the intracellular reactive oxygen species (ROS) as well as the decrease in glutathione (GSH) levels and in glutamate cysteine ligase (GCL) activity, through Nrf2/HO-1 signaling pathways. Resveratrol also prevented the increase of the transcriptional activities of nuclear factor κB (NFκB) and hypoxia-inducible factor 1 alpha (HIF-1α) after LPS challenge. In summary, this is the first study showing the glioprotective effect of resveratrol on oligodendroglial cells.

Adult mesenchymal stem cell therapy for myelin repair in Multiple Sclerosis

Multiple sclerosis (MS) is a demyelinating immune-mediated disease of the central nervous system (CNS). It is the most frequent neurological disease in young adults and affects over 2 million people worldwide. Current treatments reduce the relapse rate and the formation of inflammatory lesions in the CNS, but with only temporary and limited success. Despite the presence of endogenous oligodendroglial progenitors (OPCs) and of spontaneous remyelination, at least in early MS its levels and its qualities are apparently insufficient for a sustained endogenous functional repair. Therefore, novel MS therapies should consider not only immunemodulatory but also myelin repair activities. Mesenchymal stem cells (MSCs) represent an attractive alternative to develop a cell-based therapy for MS. MSCs display stromal features and exert bystander immunemodulatory and neuroprotective activities. Importantly, MSCs induce oligodendrocyte fate decision and differentiation/maturation of adult neural progenitors, suggesting the existence of MSC-derived remyelination activity. Moreover, transplanted MSCs promote functional recovery and myelin repair in different MS animal models. Here, we summarize the current knowledge on endogenous mechanisms for remyelination and proposed autologous MSC therapy as a promising strategy for MS treatment.