Oligodendroglial pathology is central to de‐ and dysmyelinating, but also contributes to neurodegenerative and psychiatric diseases as well as brain injury. The understanding of oligodendroglial ...biology in health and disease has been significantly increased during recent years by experimental in vitro and in vivo preclinical studies as well as histological analyses of human tissue samples. However, for many of these diseases the underlying pathology is still not fully understood and treatment options are frequently lacking. This is at least partly caused by the limited access to human oligodendrocytes from patients to perform functional studies and drug screens. The induced pluripotent stem cell technology (iPSC) represents a possibility to circumvent this obstacle and paves new ways to study human disease and to develop new treatment options for so far incurable central nervous system (CNS) diseases. In this review, we summarize the differences between human and rodent oligodendrocytes, provide an overview of the different techniques to generate oligodendrocytes from human progenitor or stem cells and describe the results from studies using iPSC derived oligodendroglial lineage cells. Furthermore, we discuss future perspectives and challenges of the iPSC technology with respect to disease modeling, drug screen, and cell transplantation approaches.
Main Points
Oligodendrocytes are functionally involved in many CNS diseases.
iPSC derived oligodendrocytes represent a promising tool for disease modeling, compound screenings, and potentially cell replacement therapies.
The molecular basis of CNS myelin regeneration (remyelination) is poorly understood. We generated a comprehensive transcriptional profile of the separate stages of spontaneous remyelination that ...follow focal demyelination in the rat CNS and found that transcripts that encode the retinoid acid receptor RXR-γ were differentially expressed during remyelination. Cells of the oligodendrocyte lineage expressed RXR-γ in rat tissues that were undergoing remyelination and in active and remyelinated multiple sclerosis lesions. Knockdown of RXR-γ by RNA interference or RXR-specific antagonists severely inhibited oligodendrocyte differentiation in culture. In mice that lacked RXR-γ, adult oligodendrocyte precursor cells efficiently repopulated lesions after demyelination, but showed delayed differentiation into mature oligodendrocytes. Administration of the RXR agonist 9-cis-retinoic acid to demyelinated cerebellar slice cultures and to aged rats after demyelination caused an increase in remyelinated axons. Our results indicate that RXR-γ is a positive regulator of endogenous oligodendrocyte precursor cell differentiation and remyelination and might be a pharmacological target for regenerative therapy in the CNS.
The presence of peripheral myelinating cells in the central nervous system (CNS) has gained the neurobiologist attention over the years. Despite the confirmed presence of Schwann cells in the CNS in ...pathological conditions, and the long list of their beneficial effects on central remyelination, the cues that impede or allow Schwann cells to successfully conquer and remyelinate central axons remain partially undiscovered. A better knowledge of these factors stands out as crucial to foresee a rational therapeutic approach for the use of Schwann cells in CNS repair. Here, we review the diverse origins of Schwann cells into the CNS, both peripheral and central, as well as the CNS components that inhibit Schwann survival and migration into the central parenchyma. Namely, we analyze the astrocyte‐ and the myelin‐derived components that restrict Schwann cells into the CNS. Finally, we highlight the unveiled mode of invasion of these peripheral cells through the central environment, using blood vessels as scaffolds to pave their ways toward demyelinated lesions. In short, this review presents the so far uncovered knowledge of this complex CNS‐peripheral nervous system (PNS) relationship.
Schwann cells, from PNS and CNS origin, are able myelinate demyelinated CNS.
Schwann cells need to overcome inhibitory signals from astrocytes and CNS myelin to invade CNS.
Blood vessels provide routes for their migration guided within CNS.
This article provides an overview of the current knowledge relating to the potential use of transplanted stem cells in the treatment of patients with multiple sclerosis (MS). Two types of stem cells, ...CNS-derived neural stem/precursor cells (NPCs) and bone marrow-derived mesenchymal stem cells (MSCs) are considered to provide reproducible and robust therapeutic effects when intravenously or intrathecally injected into both rodents and primates with experimental autoimmune encephalomyelitis. Furthermore, preliminary safety data concerning the use of intrathecally injected autologous MSCs in patients with progressive MS are available. We discuss how the data gathered to date challenge the narrow view that the therapeutic effects of NPCs and MSCs observed in the treatment of MS are accomplished solely by cell replacement. Both types of stem cell, when transplanted systemically, might instead influence disease outcome by releasing a plethora of factors that are immunomodulatory or neuroprotective, thereby directly or indirectly influencing the regenerative properties of intrinsic CNS stem/precursor cells.
Neuropathic pain is a severe and chronic condition widely found in the general population. The reason for this is the extensive variety of damage or diseases that can spark this unpleasant constant ...feeling in patients. During the processing of pain, the dorsal root ganglia constitute an important region where dorsal root ganglion neurons play a crucial role in the transmission and propagation of sensory electrical stimulation. Furthermore, the dorsal root ganglia have recently exhibited a regenerative capacity that should not be neglected in the understanding of the development and resolution of neuropathic pain and in the elucidation of innovative therapies. Here, we will review the complex interplay between cells (satellite glial cells and inflammatory cells) and factors (cytokines, neurotrophic factors and genetic factors) that takes place within the dorsal root ganglia and accounts for the generation of the aberrant excitation of primary sensory neurons occurring in neuropathic pain. More importantly, we will summarize an updated view of the current pharmacologic and nonpharmacologic therapies targeting the dorsal root ganglia for the treatment of neuropathic pain.
Neural stem cells (NSCs) persist in defined brain niches, including the subventricular zone (SVZ), throughout adulthood and generate new neurons destined to support specific neurological functions. ...Whether brain diseases such as multiple sclerosis (MS) are associated with changes in adult NSCs and whether this might contribute to the development and/or persistence of neurological deficits remains poorly investigated. We examined SVZ function in mice in which we targeted an MS-like pathology to the forebrain. In these mice, which we refer to herein as targeted EAE (tEAE) mice, there was a reduction in the number of neuroblasts compared with control mice. Altered expression of the transcription factors Olig2 and Dlx2 in the tEAE SVZ niche was associated with amplification of pro-oligodendrogenic transit-amplifying cells and decreased neuroblast generation, which resulted in persistent reduction in olfactory bulb neurogenesis. Altered SVZ neurogenesis led to impaired long-term olfactory memory, mimicking the olfactory dysfunction observed in MS patients. Importantly, we also found that neurogenesis was reduced in the SVZ of MS patients compared with controls. Thus, our findings suggest that neuroinflammation induces functional alteration of adult NSCs that may contribute to olfactory dysfunction in MS patients.
Oligodendrocytes are extensively coupled to astrocytes, a phenomenon ensuring glial homeostasis and maintenance of central nervous system myelin. Molecular disruption of this communication occurs in ...demyelinating diseases such as multiple sclerosis. Less is known about the vulnerability and reconstruction of the panglial network during adult demyelination‐remyelination. Here, we took advantage of lysolcithin‐induced demyelination to investigate the expression dynamics of the oligodendrocyte specific connexin 47 (Cx47) and to some extent that of astrocyte Cx43, and whether this dynamic could be modulated by grafted induced pluripotent stem cell (iPSC)‐neural progeny. Our data show that disruption of Cx43‐Cx47 mediated hetero‐cellular gap‐junction intercellular communication following demyelination is larger in size than demyelination. Loss of Cx47 expression is timely rescued during remyelination and accelerated by the grafted neural precursors. Moreover, mouse and human iPSC‐derived oligodendrocytes express Cx47, which co‐labels with astrocyte Cx43, indicating their integration into the panglial network. These data suggest that in rodents, full lesion repair following transplantation occurs by panglial reconstruction in addition to remyelination. Targeting panglial elements by cell therapy or pharmacological compounds may help accelerating or stabilizing re/myelination in myelin disorders.
Main Points
Loss of oligodendrocyte Cx47 expression caused by lysolecithin‐induced demyelination is timely rescued during remyelination.
Panglial repair correlates with remyelination and is accelerated by the grafted iPSC‐neural precursor cells.
Pelizaeus-Merzbacher disease (PMD) results from an X-linked misexpression of proteolipid protein 1 (PLP1). This leukodystrophy causes severe hypomyelination with progressive inflammation, leading to ...neurological dysfunctions and shortened life expectancy. While no cure exists for PMD, experimental cell-based therapy in the dysmyelinated shiverer model suggested that human oligodendrocyte progenitor cells (hOPCs) or human neural precursor cells (hNPCs) are promising candidates to treat myelinopathies. However, the fate and restorative advantages of human NPCs/OPCs in a relevant model of PMD has not yet been addressed. Using a model of Plp1 overexpression, resulting in demyelination with progressive inflammation, we compared side-by-side the therapeutic benefits of intracerebrally grafted hNPCs and hOPCs. Our findings reveal equal integration of the donor cells within presumptive white matter tracks. While the onset of exogenous remyelination was earlier in hOPCs-grafted mice than in hNPC-grafted mice, extended lifespan occurred only in hNPCs-grafted animals. This improved survival was correlated with reduced neuroinflammation (microglial and astrocytosis loads) and microglia polarization toward M2-like phenotype followed by remyelination. Thus modulation of neuroinflammation combined with myelin restoration is crucial to prevent PMD pathology progression and ensure successful rescue of PMD mice. These findings should help to design novel therapeutic strategies combining immunomodulation and stem/progenitor cell-based therapy for disorders associating hypomyelination with inflammation as observed in PMD.
Schwann cells (SC) enter the central nervous system (CNS) in pathophysiological conditions. However, how SC invade the CNS to remyelinate central axons remains undetermined. We studied SC migratory ...behavior ex vivo and in vivo after exogenous transplantation in the demyelinated spinal cord. The data highlight for the first time that SC migrate preferentially along blood vessels in perivascular extracellular matrix (ECM), avoiding CNS myelin. We demonstrate in vitro and in vivo that this migration route occurs by virtue of a dual mode of action of Eph/ephrin signaling. Indeed, EphrinB3, enriched in myelin, interacts with SC Eph receptors, to drive SC away from CNS myelin, and triggers their preferential adhesion to ECM components, such as fibronectin via integrinβ1 interactions. This complex interplay enhances SC migration along the blood vessel network and together with lesion-induced vascular remodeling facilitates their timely invasion of the lesion site. These novel findings elucidate the mechanism by which SC invade and contribute to spinal cord repair.
Induced pluripotent stem cell-derived (iPS-derived) neural precursor cells may represent the ideal autologous cell source for cell-based therapy to promote remyelination and neuroprotection in myelin ...diseases. So far, the therapeutic potential of reprogrammed cells has been evaluated in neonatal demyelinating models. However, the repair efficacy and safety of these cells has not been well addressed in the demyelinated adult CNS, which has decreased cell plasticity and scarring. Moreover, it is not clear if these induced pluripotent-derived cells have the same reparative capacity as physiologically committed CNS-derived precursors. Here, we performed a side-by-side comparison of CNS-derived and skin-derived neural precursors in culture and following engraftment in murine models of adult spinal cord demyelination. Grafted induced neural precursors exhibited a high capacity for survival, safe integration, migration, and timely differentiation into mature bona fide oligodendrocytes. Moreover, grafted skin-derived neural precursors generated compact myelin around host axons and restored nodes of Ranvier and conduction velocity as efficiently as CNS-derived precursors while outcompeting endogenous cells. Together, these results provide important insights into the biology of reprogrammed cells in adult demyelinating conditions and support use of these cells for regenerative biomedicine of myelin diseases that affect the adult CNS.
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