The dorsal root ganglion as a target for neurorestoration in neuropathic pain.

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.

High Dose Pharmaceutical Grade Biotin (MD1003) Accelerates Differentiation of Murine and Grafted Human Oligodendrocyte Progenitor Cells In Vivo.

Accumulating evidences suggest a strong correlation between metabolic changes and neurodegeneration in CNS demyelinating diseases such as multiple sclerosis (MS). Biotin, an essential cofactor for five carboxylases, is expressed by oligodendrocytes and involved in fatty acid synthesis and energy production. The metabolic effect of biotin or high-dose-biotin (MD1003) has been reported on rodent oligodendrocytes in vitro, and in neurodegenerative or demyelinating animal models.

Satellite glia of the adult dorsal root ganglia harbor stem cells that yield glia under physiological conditions and neurons in response to injury.

The presence of putative stem/progenitor cells has been suggested in adult peripheral nervous system (PNS) tissue, including the dorsal root ganglion (DRG). To date, their identification and fate in pathophysiological conditions have not been addressed. Combining multiple in vitro and in vivo approaches, we identified the presence of stem cells in the adult DRG satellite glial population, and progenitors were present in the DRGs and sciatic nerve.

Failed remyelination of the nonhuman primate optic nerve leads to axon degeneration, retinal damages, and visual dysfunction.

White matter disorders of the central nervous system (CNS), such as multiple sclerosis (MS), lead to failure of nerve conduction and long-lasting neurological disabilities affecting a variety of sensory and motor systems, including vision. While most disease-modifying therapies target the immune and inflammatory response, the promotion of remyelination has become a new therapeutic avenue to prevent neuronal degeneration and promote recovery. Most of these strategies have been developed in short-lived rodent models of demyelination, which spontaneously repair and do not reflect the size, organization, and biology of the human CNS.

One-step Reprogramming of Human Fibroblasts into Oligodendrocyte-like Cells by SOX10, OLIG2, and NKX6.2.

Limited access to human oligodendrocytes impairs better understanding of oligodendrocyte pathology in myelin diseases. Here, we describe a method to robustly convert human fibroblasts directly into oligodendrocyte-like cells (dc-hiOLs), which allows evaluation of remyelination-promoting compounds and disease modeling. Ectopic expression of SOX10, OLIG2, and NKX6.

Inflammation-driven glial alterations in the cuprizone mouse model probed with diffusion-weighted magnetic resonance spectroscopy at 11.7 T.

Inflammation of brain tissue is a complex response of the immune system to the presence of toxic compounds or to cell injury, leading to a cascade of pathological processes that include glial cell activation. Noninvasive MRI markers of glial reactivity would be very useful for in vivo detection and monitoring of inflammation processes in the brain, as well as for evaluating the efficacy of personalized treatments. Due to their specific location in glial cells, myo-inositol (mIns) and choline compounds (tCho) seem to be the best candidates for probing glial-specific intra-cellular compartments.

Beneficial contribution of induced pluripotent stem cell-progeny to Connexin 47 dynamics during demyelination-remyelination.

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.

Multiple sclerosis iPS-derived oligodendroglia conserve their properties to functionally interact with axons and glia in vivo.

Remyelination failure in multiple sclerosis (MS) is associated with a migration/differentiation block of oligodendroglia. The reason for this block is highly debated. It could result from disease-related extrinsic or intrinsic regulators in oligodendroglial biology.

Generation of oligodendrocytes and establishment of an all-human myelinating platform from human pluripotent stem cells.

Oligodendrocytes (OLs) are responsible for myelin production and metabolic support of neurons. Defects in OLs are crucial in several neurodegenerative diseases including multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). This protocol describes a method to generate oligodendrocyte precursor cells (OPCs) from human pluripotent stem cells (hPSCs) in only ~20 d, which can subsequently myelinate neurons, both in vitro and in vivo.

Human stem cell-derived oligodendrocytes: From humanized animal models to cell therapy in myelin diseases.

Oligodendrocytes are main targets in demyelinating and dysmyelinating diseases of the central nervous system (CNS), but are also involved in accidental, neurodegenerative and psychiatric disorders. The underlying pathology of these diseases is not fully understood and treatments are still lacking. The recent discovery of the induced pluripotent stem cell (iPSC) technology has open the possibility to address the biology of human oligodendroglial cells both in the dish and in vivo via engraftment in animal models, and paves the way for the development of treatment for myelin disorders.

Activation of Macrophages by Lysophosphatidic Acid through the Lysophosphatidic Acid Receptor 1 as a Novel Mechanism in Multiple Sclerosis Pathogenesis.

Multiple sclerosis (MS) is a neuroinflammatory disease whose pathogenesis remains unclear. Lysophosphatidic acid (LPA) is an endogenous phospholipid involved in multiple immune cell functions and dysregulated in MS. Its receptor LPA is expressed in macrophages and regulates their activation, which is of interest due to the role of macrophage activation in MS in both destruction and repair.

Schwann cells: Rescuers of central demyelination.

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.

Stem cell derived oligodendrocytes to study myelin diseases.

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.

Blood vessels guide Schwann cell migration in the adult demyelinated CNS through Eph/ephrin signaling.

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.

Myelin-Associated Glycoprotein Inhibits Schwann Cell Migration and Induces Their Death.

Remyelination of CNS axons by Schwann cells (SCs) is not efficient, in part due to the poor migration of SCs into the adult CNS. Although it is known that migrating SCs avoid white matter tracts, the molecular mechanisms underlying this exclusion have never been elucidated. We now demonstrate that myelin-associated glycoprotein (MAG), a well known inhibitor of neurite outgrowth, inhibits rat SC migration and induces their death via γ-secretase-dependent regulated intramembrane proteolysis of the p75 neurotrophin receptor (also known as p75 cleavage).

Rapid and efficient generation of oligodendrocytes from human induced pluripotent stem cells using transcription factors.

Rapid and efficient protocols to generate oligodendrocytes (OL) from human induced pluripotent stem cells (iPSC) are currently lacking, but may be a key technology to understand the biology of myelin diseases and to develop treatments for such disorders. Here, we demonstrate that the induction of three transcription factors (SOX10, OLIG2, NKX6.2) in iPSC-derived neural progenitor cells is sufficient to rapidly generate O4 OL with an efficiency of up to 70% in 28 d and a global gene-expression profile comparable to primary human OL.

Inflammatory demyelination induces ependymal modifications concomitant to activation of adult (SVZ) stem cell proliferation.

Ependymal cells (E1/E2) and ciliated B1cells confer a unique pinwheel architecture to the ventricular surface of the subventricular zone (SVZ), and their cilia act as sensors to ventricular changes during development and aging. While several studies showed that forebrain demyelination reactivates the SVZ triggering proliferation, ectopic migration, and oligodendrogenesis for myelin repair, the potential role of ciliated cells in this process was not investigated. Using conventional and lateral wall whole mount preparation immunohistochemistry in addition to electron microscopy in a forebrain-targeted model of experimental autoimmune encephalomyelitis (tEAE), we show an early decrease in numbers of pinwheels, B1 cells, and E2 cells.

Is involvement of inflammation underestimated in Pelizaeus-Merzbacher disease?

Pelizaeus-Merzbacher disease (PMD) is a severe hypomyelinating leukodystrophy resulting from proteolipid protein 1 gene (PLP1) mutations leading to oligodendrocyte loss. While neuroinflammation has recently become a common feature and actor in neurodegenerative diseases, the involvement of inflammation in PMD physiopathology is still highly debated despite evidence for strong astrogliosis and microglial cell activation. Activation of the innate immune system, and more particularly, of microglia and astrocytes, is mostly associated with the deleterious role of neuroinflammation.

Modulation of the Innate Immune Response by Human Neural Precursors Prevails over Oligodendrocyte Progenitor Remyelination to Rescue a Severe Model of Pelizaeus-Merzbacher Disease.

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.

Skin-derived neural precursors competitively generate functional myelin in adult demyelinated mice.

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.

Adult DRG Stem/Progenitor Cells Generate Pericytes in the Presence of Central Nervous System (CNS) Developmental Cues, and Schwann Cells in Response to CNS Demyelination.

It has been proposed that the adult dorsal root ganglia (DRG) harbor neural stem/progenitor cells (NPCs) derived from the neural crest. However, the thorough characterization of their stemness and differentiation plasticity was not addressed. In this study, we investigated adult DRG-NPC stem cell properties overtime, and their fate when ectopically grafted in the central nervous system.

Tocopherol derivative TFA-12 promotes myelin repair in experimental models of multiple sclerosis.

Multiple sclerosis (MS) is an inflammatory disease of the CNS that is associated with demyelination and axonal loss, resulting in severe neurological handicap. Current MS therapies mostly target neuroinflammation but have only a little impact on CNS myelin repair. Progress toward treatments that enhance remyelination would therefore represent major advances in MS treatment.

Overexpression of CD44 in neural precursor cells improves trans-endothelial migration and facilitates their invasion of perivascular tissues in vivo.

Neural precursor (NPC) based therapies are used to restore neurons or oligodendrocytes and/or provide neuroprotection in a large variety of neurological diseases. In multiple sclerosis models, intravenously (i.v) -delivered NPCs reduced clinical signs via immunomodulation.