The transplantation of well defined populations of precursor cells offers a means of repairing damaged tissue and of delivering therapeutic compounds to sites of injury or degeneration. For example, a functional immune system can be reconstituted by transplantation of purified haematopoietic stem cells, and transplanted skeletal myoblasts and keratinocytes can participate in the formation of normal tissue in host animals. Cell transplantation in the central nervous system (CNS) has been proposed as a means of correcting neuronal dysfunction in diseases associated with neuronal loss; it might also rectify glial cell dysfunction, with transplanted oligodendrocyte precursor cells eventually allowing repair of demyelinating damage in the CNS. Here we use co-operating growth factors to expand purified populations of oligodendrocyte type-2 astrocyte (O-2A) progenitor cells for several weeks in vitro. When injected into demyelinating lesions in spinal cords of adult rats, created in such a way as to preclude host-mediated remyelination, these expanded populations are capable of producing extensive remyelination. In addition, transplantation of O-2A progenitor cells genetically modified to express the bacterial beta-galactosidase gene gives rise to beta-galactosidase-positive oligodendrocytes which remyelinate demyelinated axons within the lesion. These results offer a viable strategy for the manipulation of neural precursor cells which is compatible with attempts to repair damaged CNS tissue by precursor transplantation.
"Pre-existing mature oligodendrocytes are unlikely to contribute to remyelination, either directly or by de- and re-differentiating (similarly to Schwann cells in the peripheral nervous system [PNS] ), as previous studies have reported a lack of remyelination capacity of post-mitotic oligodendrocytes, even if they survive within a demyelinated lesion or are transplanted from a normally myelinating area into a lesion site [46, 47]. Conversely, rat OPCs transplanted into demyelinated areas can differentiate into myelinating oligodendrocytes and produce robust myelin . Furthermore, dividing endogenous progenitor cells in the adult rat brain have been shown to respond to demyelination by differentiating into myelin-forming oligodendrocytes . "
[Show abstract][Hide abstract] ABSTRACT: We review the current state of knowledge of remyelination in multiple sclerosis (MS), concentrating on advances in the understanding of the pathology and the regenerative response, and we summarise progress on the development of new therapies to enhance remyelination aimed at reducing progressive accumulation of disability in MS. We discuss key target pathways identified in experimental models, as although most identified targets have not yet progressed to the stage of being tested in human clinical trials, they may provide treatment strategies for demyelinating diseases in the future. Finally, we discuss some of the problems associated with testing this class of drugs, where they might fit into the therapeutic arsenal and the gaps in our knowledge.
"Early cell-culture studies showed that OPCs purified from rat optic nerves differentiate not only into oligodendrocytes but also into process-bearing “type-2 astrocytes” in the presence of serum factors, which led to the concept of bipotential oligodendrocyte type-2-astrocyte (O-2A) progenitor cells . There are now controversial observations suggesting that bipotentiality of polydendrocytes might be real or an in vitro artifact [126, 128, 129], and most likely these cells are inherently capable of differentiating into astrocytes but are prevented from fulfilling their astroglial fate in the normal in vivo environment . "
[Show abstract][Hide abstract] ABSTRACT: During the last two decades basic research in neuroscience has remarkably expanded due to the discovery of neural stem cells (NSCs) and adult neurogenesis in the mammalian central nervous system (CNS). The existence of such unexpected plasticity triggered hopes for alternative approaches to brain repair, yet deeper investigation showed that constitutive mammalian neurogenesis is restricted to two small “neurogenic sites” hosting NSCs as remnants of embryonic germinal layers and subserving homeostatic roles in specific neural systems. The fact that in other classes of vertebrates adult neurogenesis is widespread in the CNS and useful for brain repair sometimes creates misunderstandings about the real reparative potential in mammals. Nevertheless, in the mammalian CNS parenchyma, which is commonly considered as “nonneurogenic,” some processes of gliogenesis and, to a lesser extent, neurogenesis also occur. This “parenchymal” cell genesis is highly heterogeneous as to the position, identity, and fate of the progenitors. In addition, even the regional outcomes are different. In this paper the heterogeneity of mammalian parenchymal neurogliogenesis will be addressed, also discussing the most common pitfalls and misunderstandings of this growing and promising research field.
"Glial cell death via apoptosis, particularly loss of myelinating OLGs, may result in consequent axonal demyelination (Jensen et al. 1999; Tamura et al. 2005; Warden et al. 2001). In support this hypothesis, remyelination of the spinal cord axons via cell transplantation (Akiyama et al. 2002; Groves et al. 1993; Keirstead et al. 2005) or transplants combined with cAMP elevation or neurotrophic factors (Cao et al. 2005; Pearse et al. 2004) have been shown to improve functional recovery in SCI rodents significantly. In addition, RhoA might negatively regulate myelin formation in the CNS because RhoA activation by Lingo1, a protein present in OLGs, appears to suppress myelination of CNS axons (Mi et al. 2005; Mi et al. 2009). "
[Show abstract][Hide abstract] ABSTRACT: Nonsteroidal anti-inflammatory drugs (NSAIDs) are extensively used to relieve pain and inflammation in humans via cyclooxygenase inhibition. Our recent research suggests that certain NSAIDs including ibuprofen suppress intracellular RhoA signal and improve significant axonal growth and functional recovery following axonal injury in the CNS. Several NSAIDs have been shown to reduce generation of amyloid-beta42 peptide via inactivation of RhoA signal, supporting potent RhoA-repressing function of selected NSAIDs. In this report, we demonstrate that RhoA-inhibiting NSAIDs ibuprofen and indomethacin dramatically reduce cell death of oligodendrocytes in cultures or along the white matter tracts in rats with a spinal cord injury. More importantly, we demonstrate that treatments with the RhoA-inhibiting NSAIDs significantly increase axonal myelination along the white matter tracts following a traumatic contusion spinal cord injury. In contrast, non-RhoA-inhibiting NSAID naproxen does not have such an effect. Thus, our results suggest that RhoA inactivation with certain NSAIDs benefits recovery of injured CNS axons not only by promoting axonal elongation, but by enhancing glial survival and axonal myelination along the disrupted axonal tracts. This study, together with previous reports, supports that RhoA signal is an important therapeutic target for promoting recovery of injured CNS and that RhoA-inhibiting NSAIDs provide great therapeutic potential for CNS axonal injuries in adult mammals.
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