Laura Reiche

Bio: Laura Reiche is an academic researcher from University of Düsseldorf. The author has contributed to research in topics: Myelin & Remyelination. The author has an hindex of 4, co-authored 6 publications receiving 42 citations.

Teriflunomide promotes oligodendroglial differentiation and myelination

Abstract: Multiple sclerosis (MS) is a neuroinflammatory autoimmune disease of the central nervous system (CNS) which in most cases initially presents with episodes of transient functional deficits (relapsing-remitting MS; RRMS) and eventually develops into a secondary progressive form (SPMS). Aside from neuroimmunological activities, MS is also characterized by neurodegenerative and regenerative processes. The latter involve the restoration of myelin sheaths—electrically insulating structures which are the primary targets of autoimmune attacks. Spontaneous endogenous remyelination takes place even in the adult CNS and is primarily mediated by activation, recruitment, and differentiation of resident oligodendroglial precursor cells (OPCs). However, the overall efficiency of remyelination is limited and further declines with disease duration and progression. From a therapeutic standpoint, it is therefore key to understand how oligodendroglial maturation can be modulated pharmacologically. Teriflunomide has been approved as a first-line treatment for RRMS in the USA and the European Union. As the active metabolite of leflunomide, an established disease-modifying anti-rheumatic drug, it mainly acts via an inhibition of de novo pyrimidine synthesis exerting a cytostatic effect on proliferating B and T cells. We investigated teriflunomide-dependent effects on primary rat oligodendroglial homeostasis, proliferation, and differentiation related to cellular processes important for myelin repair hence CNS regeneration in vitro. To this end, several cellular parameters, including specific oligodendroglial maturation markers, in vitro myelination, and p53 family member signaling, were examined by means of gene/protein expression analyses. The rate of myelination was determined using neuron-oligodendrocyte co-cultures. Low teriflunomide concentrations resulted in cell cycle exit while higher doses led to decreased cell survival. Short-term teriflunomide pulses can efficiently promote oligodendroglial cell differentiation suggesting that young, immature cells could benefit from such stimulation. In vitro myelination can be boosted by means of an early stimulation window with teriflunomide. p73 signaling is functionally involved in promoting OPC differentiation and myelination. Our findings indicate a critical window of opportunity during which regenerative oligodendroglial activities including myelination of CNS axons can be stimulated by teriflunomide.

Aberrant Oligodendrogenesis in Down Syndrome: Shift in Gliogenesis?

Abstract: Down syndrome (DS), or trisomy 21, is the most prevalent chromosomal anomaly accounting for cognitive impairment and intellectual disability (ID). Neuropathological changes of DS brains are characterized by a reduction in the number of neurons and oligodendrocytes, accompanied by hypomyelination and astrogliosis. Recent studies mainly focused on neuronal development in DS, but underestimated the role of glial cells as pathogenic players. Aberrant or impaired differentiation within the oligodendroglial lineage and altered white matter functionality are thought to contribute to central nervous system (CNS) malformations. Given that white matter, comprised of oligodendrocytes and their myelin sheaths, is vital for higher brain function, gathering knowledge about pathways and modulators challenging oligodendrogenesis and cell lineages within DS is essential. This review article discusses to what degree DS-related effects on oligodendroglial cells have been described and presents collected evidence regarding induced cell-fate switches, thereby resulting in an enhanced generation of astrocytes. Moreover, alterations in white matter formation observed in mouse and human post-mortem brains are described. Finally, the rationale for a better understanding of pathways and modulators responsible for the glial cell imbalance as a possible source for future therapeutic interventions is given based on current experience on pro-oligodendroglial treatment approaches developed for demyelinating diseases, such as multiple sclerosis.

C21orf91 Regulates Oligodendroglial Precursor Cell Fate-A Switch in the Glial Lineage?

Abstract: Neuropathological diseases of the central nervous system (CNS) are frequently associated with impaired differentiation of the oligodendroglial cell lineage and subsequent alterations in white matter structure and dynamics. Down syndrome (DS), or trisomy 21, is the most common genetic cause for cognitive impairments and intellectual disability (ID) and is associated with a reduction in the number of neurons and oligodendrocytes, as well as with hypomyelination and astrogliosis. Recent studies mainly focused on neuronal development in DS and underestimated the role of glial cells as pathogenic players. This also relates to C21ORF91, a protein considered a key modulator of aberrant CNS development in DS. We investigated the role of C21orf91 ortholog in terms of oligodendrogenesis and myelination using database information as well as through cultured primary oligodendroglial precursor cells (OPCs). Upon modulation of C21orf91 gene expression, we found this factor to be important for accurate oligodendroglial differentiation, influencing their capacity to mature and to myelinate axons. Interestingly, C21orf91 overexpression initiates a cell population coexpressing astroglial- and oligodendroglial markers indicating that elevated C21orf91 expression levels induce a gliogenic shift towards the astrocytic lineage reflecting non-equilibrated glial cell populations in DS brains.

Heterogeneous fate choice of genetically modulated adult neural stem cells in gray and white matter of the central nervous system.

Abstract: Apart from dedicated oligodendroglial progenitor cells, adult neural stem cells (aNSCs) can also give rise to new oligodendrocytes in the adult central nervous system (CNS). This process mainly confers myelinating glial cell replacement in pathological situations and can hence contribute to glial heterogeneity. Our previous studies demonstrated that the p57kip2 gene encodes an intrinsic regulator of glial fate acquisition and we here investigated to what degree its modulation can affect stem cell-dependent oligodendrogenesis in different CNS environments. We therefore transplanted p57kip2 knockdown aNSCs into white and gray matter (WM and GM) regions of the mouse brain, into uninjured spinal cords as well as in the vicinity of spinal cord injuries and evaluated integration and differentiation in vivo. Our experiments revealed that under healthy conditions intrinsic suppression of p57kip2 as well as WM localization promote differentiation toward myelinating oligodendrocytes at the expense of astrocyte generation. Moreover, p57kip2 knockdown conferred a strong benefit on cell survival augmenting net oligodendrocyte generation. In the vicinity of hemisectioned spinal cords, the gene knockdown led to a similar induction of oligodendroglial features; however, newly generated oligodendrocytes appeared to suffer more from the hostile environment. This study contributes to our understanding of mechanisms of adult oligodendrogenesis and glial heterogeneity and further reveals critical factors when considering aNSC mediated cell replacement in injury and disease.

Immunological Aspects of Approved MS Therapeutics.

Abstract: Multiple sclerosis (MS) is the most common neurological immune-mediated disease leading to disability in young adults. The outcome of the disease is unpredictable, and over time, neurological disabilities accumulate. Interferon beta-1b was the first drug to be approved in the 1990s for relapsing-remitting MS to modulate the course of the disease. Over the past two decades, the treatment landscape has changed tremendously. Currently, more than a dozen drugs representing 1 substances with different mechanisms of action have been approved (interferon beta preparations, glatiramer acetate, fingolimod, siponimod, mitoxantrone, teriflunomide, dimethyl fumarate, cladribine, alemtuzumab, ocrelizumab, and natalizumab). Ocrelizumab was the first medication to be approved for primary progressive MS. The objective of this review is to present the modes of action of these drugs and their effects on the immunopathogenesis of MS. Each agent's clinical development and potential side effects are discussed.

Curcumin Ameliorates White Matter Injury after Ischemic Stroke by Inhibiting Microglia/Macrophage Pyroptosis through NF-κB Suppression and NLRP3 Inflammasome Inhibition.

Abstract: NLRP3 inflammasome-mediated pyroptosis is a proinflammatory programmed cell death pathway, which plays a vital role in functional outcomes after stroke. We previously described the beneficial effects of curcumin against stroke-induced neuronal damage through modulating microglial polarization. However, the impact of curcumin on microglial pyroptosis remains unknown. Here, stroke was modeled in mice by middle cerebral artery occlusion (MCAO) for 60 minutes and treated with curcumin (150 mg/kg) intraperitoneally immediately after reperfusion, followed by daily administrations for 7 days. Curcumin ameliorated white matter (WM) lesions and brain tissue loss 21 days poststroke and improved sensorimotor function 3, 10, and 21 days after stroke. Furthermore, curcumin significantly reduced the number of gasdermin D+ (GSDMD+) Iba1+ and caspase-1+Iba1+ microglia/macrophage 21 days after stroke. In vitro, lipopolysaccharide (LPS) with ATP treatment was used to induce pyroptosis in primary microglia. Western blot revealed a decrease in pyroptosis-related proteins, e.g., GSDMD-N, cleaved caspase-1, NLRP3, IL-1β, and IL-18, following in vitro or in vivo curcumin treatment. Mechanistically, both in vivo and in vitro studies confirmed that curcumin inhibited the activation of the NF-κB pathway. NLRP3 knocked down by siRNA transfection markedly increased the inhibitory effects of curcumin on microglial pyroptosis and proinflammatory responses, both in vitro and in vivo. Furthermore, stereotaxic microinjection of AAV-based NLRP3 shRNA significantly improved sensorimotor function and reduced WM lesion following curcumin treatment in MCAO mice. Our study suggested that curcumin reduced stroke-induced WM damage, improved functional outcomes, and attenuated microglial pyroptosis, at least partially, through suppression of the NF-κB/NLRP3 signaling pathway, further supporting curcumin as a potential therapeutic drug for stroke.

p57kip2 is dynamically regulated in experimental autoimmune encephalomyelitis

Abstract: Die vorliegende Dissertationsarbeit befasst sich mit den Mechanismen glialer Differenzierung und der Frage, inwieweit diese im Rahmen inflammatorischer Erkrankungen des Zentralen Nerversystems (ZNS) wie der Multiplen Sklerose (MS) von Bedeutung sind. Multiple Sklerose ist eine autoimmune inflammatorische ZNS Erkrankung, die eine Zerstorung der axon-isolierenden Myelinscheiden zur Folge hat. Hierdurch kommt es zunachst zu einer Herabsetzung der elektrischen Uberleitungsgeschwindigkeit in den neuronalen Axonen und schlieslich zum direkten axonalen Schaden. Die myelinbildenden Zellen des ZNS, die Oligodendrozyten, konnen die zerstorten Myelinscheiden in der Folge nur unvollstandig erneuern, wobei dies nicht zuletzt mit der eingeschrankten Fahigkeit von residenten Oligodendrozytenvorlauferzellen zu differenzieren in Verbindung gebracht wird. In der vorgelegten Arbeit konnte nun gezeigt werden, dass eine anhaltende Reduzierung der Genexpression von p57kip2, eines Zyklin abhangigen Kinaseinhibitors, in oligodendroglialen Vorlauferzellen zu einer erleichterten und verstarkten Differenzierung dieser myelinisierenden Zellen fuhrt. Zu diesem Zweck wurden primare Rattenoligodendrozyten aus dem neugeborenen Rattenhirn mit einem Gensuppressionsvektor fur p57kip2 transfiziert und anschliesend immunzytochemisch und morphologisch analysiert. Neben diesen in vitro Studien wurde gezeigt, dass p57kip2 im Rahmen der MOG-EAE (Myelin-Oligodendrozyten- Glykoprotein induzierte experimentelle autoimmune Enzephalomyelitis), einer Modellerkrankung der MS in der Ratte, fast ausschlieslich von Oligodendrozyten und ihren Vorlauferzellen exprimiert und schubabhangig reguliert wird. Hierfur wurde Material aus dem gesunden und dem EAE-Rattenhirn mittels qRT-PCR und Immunhistochemie aufgearbeitet und miteinander verglichen. Gemeinsam legen die in dieser Arbeit vorgestellten Ergebnisse nahe, dass es sich bei p57kip2 um einen neuartigen negativen Regulator der (Re-) Myelinisierung handelt, der sich an der Schnittstelle zwischen Genexpression und Zellmorphogenese befindet. Insbesondere in Hinblick auf das immer noch begrenzte Verstandnis der zerebralen (Re-) Myelinisierungsmechanismen kann die vorgelegte Arbeit neue Wege in Richtung auf alternative Therapiestrategien, wie der Stimulierung hirneigener Regenerationsprozesse weisen. Die im Rahmen dieser Doktorarbeit generierten Daten konnten in einem Fachjournal publiziert werden (Kremer et al., PNAS 2009 106:9087-9092).

Current advancements in promoting remyelination in multiple sclerosis.

Abstract: Current multiple sclerosis (MS) therapies are effective in reducing relapse rate, short-term measures of disability, and magnetic resonance imaging (MRI) measures of inflammation in relapsing remitting MS (RRMS), whereas in progressive/degenerative disease phases these medications are of little or no benefit. Therefore, the development of new therapies aimed at reversing neurodegeneration is of great interest. Remyelination, which is usually a spontaneous endogenous process, is achieved when myelin-producing oligodendrocytes are generated from oligodendrocyte precursor cells (OPCs). Even though these precursor cells are abundant in MS brains, their regeneration capacity is limited. Enhancing the generation of myelin-producing cells is therefore a major focus of MS research. Here we present an overview of the different advancements in the field of remyelination, including suitable animal models for testing remyelination therapies, approved medications with a proposed role in regeneration, myelin repair treatments under investigation in clinical trials, as well as future therapeutics aimed at facilitating myelin repair.

Mechanism-based criteria to improve therapeutic outcomes in progressive multiple sclerosis.

Abstract: In contrast to the multiple disease-modifying therapies that are available for relapsing–remitting multiple sclerosis (MS), the therapeutic options for progressive MS (PMS) are limited. Recent advances in our understanding of the neuroimmunology of PMS, including the mechanisms that drive slowly expanding lesions, have fuelled optimism for improved treatment of this condition. In this Review, we highlight the commonly observed neuropathology of PMS and discuss the associated mechanisms of CNS injury. We then apply this knowledge to formulate criteria for therapeutic efficacy in PMS, beginning with the need for early treatment owing to the substantial neuropathology that is already present at the initial clinical presentation. Other requirements include: antagonism of neuroaxonal injury mediators such as pro-inflammatory microglia and lymphocytes; remediation of oxidative stress resulting from iron deposition and mitochondrial dysfunction; and promotion of neuroprotection through remyelination. We consider whether current disease-modifying therapies for relapsing–remitting MS meet the criteria for successful therapeutics in PMS and suggest that the evidence favours the early introduction of sphingosine 1-phosphate receptor modulators. Finally, we weigh up emerging medications, including repurposed generic medications and Bruton’s tyrosine kinase inhibitors, against these fundamental criteria. In this new therapeutic era in PMS, success depends collectively on understanding disease mechanisms, drug characteristics (including brain penetration) and rational use. Despite substantial progress in the development of disease-modifying therapies for multiple sclerosis (MS), the therapeutic options for progressive MS (PMS) remain limited. The authors present criteria for therapeutic success in PMS and consider the extent to which current drugs meet these criteria.