Publications by authors named "Leda Dimou"

42 Publications

NG2-Glia Transiently Overcome Their Homeostatic Network and Contribute to Wound Closure After Brain Injury.

Front Cell Dev Biol 2021 27;9:662056. Epub 2021 Apr 27.

Physiological Genomics, Biomedical Center, Ludwig-Maximilians-University Munich, Munich, Germany.

In the adult brain, NG2-glia represent a cell population that responds to injury. To further investigate if, how and why NG2-glia are recruited to the injury site, we analyzed in detail the long-term reaction of NG2-glia after a lesion by time-lapse two-photon microscopy. Live imaging over several weeks of GFP-labeled NG2-glia in the stab wounded cerebral cortex revealed their fast and heterogeneous reaction, including proliferation, migration, polarization, hypertrophy, or a mixed response, while a small subset of cells remained unresponsive. At the peak of the reaction, 2-4 days after the injury, NG2-glia accumulated around and within the lesion core, overcoming the homeostatic control of their density, which normalized back to physiological conditions only 4 weeks after the insult. Genetic ablation of proliferating NG2-glia demonstrated that this accumulation contributed beneficially to wound closure. Thus, NG2-glia show a fast response to traumatic brain injury (TBI) and participate in tissue repair.
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http://dx.doi.org/10.3389/fcell.2021.662056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128074PMC
April 2021

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

Glia 2020 02 21;68(2):393-406. Epub 2019 Oct 21.

Department of Neurology, Medical Faculty, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.

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.
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http://dx.doi.org/10.1002/glia.23724DOI Listing
February 2020

Recent Advances in Live Imaging of Cells of the Oligodendrocyte Lineage.

Methods Mol Biol 2019 ;1936:275-294

Molecular and Translational Neuroscience, Department of Neurology, Ulm University, Ulm, Germany.

Myelination is an important process that takes place also in the periphery during development and in the adulthood. Myelin serves as an electric isolator for axons, leading to a fast conduction of the action potential, and provides trophic support for the axon, both aspects highly important for the proper function of the nervous system. In the central nervous system, myelination starts shortly after birth and cells from the oligodendrocyte lineage tightly regulate this process during the whole life span. Initially, it was thought that under physiological conditions myelin generation only occurs in early postnatal development and that myelination stops at early adult ages. Historically, the process of myelination has mainly been studied in fixed tissue, and predominantly analyzed by electron microscopy, bringing valuable insights in the structure and distribution of myelin in the central nervous system. Nevertheless, the outdated notion of the static nature of myelin during adulthood was challenged in the past decades by the development of new techniques bringing in a new picture of a lively structure that is in constant remodeling under physiological and disease conditions. As fixed tissue can only provide information at a specific timepoint, the necessity of new techniques to study this process in vivo has become clear. In this chapter, we will review some of the latest techniques developed in order to study myelin and the oligodendrocyte lineage, as these cells are important for the formation and restructuration of the myelin. We will also introduce a protocol to prepare a cranial window to study NG2-glia (also known as oligodendrocyte progenitor cells) of the cerebral cortex in vivo, by 2-photon laser scanning microscopy. However, this technique can also be performed to study other cell populations or structures such as myelin, which will be discussed in this chapter as well. Despite being simple, this protocol has shown to be powerful to study the oligodendrocyte lineage and potentially is applicable to study myelin in vivo, which could turn into a key technique in the understanding of myelination and other functions that the oligodendrocyte lineage might have under physiological and disease conditions.
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http://dx.doi.org/10.1007/978-1-4939-9072-6_16DOI Listing
July 2019

Differential local tissue permissiveness influences the final fate of GPR17-expressing oligodendrocyte precursors in two distinct models of demyelination.

Glia 2018 05 9;66(5):1118-1130. Epub 2018 Feb 9.

Laboratory of Molecular and Cellular Pharmacology of the Purinergic Transmission, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, Milan, 20133, Italy.

Promoting remyelination is recognized as a novel strategy to foster repair in neurodegenerative demyelinating diseases, such as multiple sclerosis. In this respect, the receptor GPR17, recently emerged as a new target for remyelination, is expressed by early oligodendrocyte precursors (OPCs) and after a certain differentiation stage it has to be downregulated to allow progression to mature myelinating oligodendrocytes. Here, we took advantage of the first inducible GPR17 reporter mouse line (GPR17-iCreER xCAG-eGFP mice) allowing to follow the final fate of GPR17 cells by tamoxifen-induced GFP-labeling to unveil the destiny of these cells in two demyelination models: experimental autoimmune encephalomyelitis (EAE), characterized by marked immune cell activation and inflammation, and cuprizone induced demyelination, where myelin dysfunction is achieved by a toxic insult. In both models, demyelination induced a strong increase of fluorescent GFP cells at damaged areas. However, only in the cuprizone model reacting GFP cells terminally differentiated to mature oligodendrocytes, thus contributing to remyelination. In EAE, GFP cells were blocked at immature stages and never became myelinating oligodendrocytes. We suggest these strikingly distinct fates be due to different permissiveness of the local CNS environment. Based on previously reported GPR17 activation by emergency signals (e.g., Stromal Derived Factor-1), we propose that a marked inflammatory milieu, such as that reproduced in EAE, induces GPR17 overactivation resulting in impaired downregulation, untimely and prolonged permanence in OPCs, leading, in turn, to differentiation blockade. Combined treatments with remyelinating agents and anti-inflammatory drugs may represent new potential adequate strategies to halt neurodegeneration and foster recovery.
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http://dx.doi.org/10.1002/glia.23305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5900886PMC
May 2018

BCAS1 expression defines a population of early myelinating oligodendrocytes in multiple sclerosis lesions.

Sci Transl Med 2017 Dec;9(419)

Max Planck Institute for Experimental Medicine, 37075 Göttingen, Germany.

Investigations into brain function and disease depend on the precise classification of neural cell types. Cells of the oligodendrocyte lineage differ greatly in their morphology, but accurate identification has thus far only been possible for oligodendrocyte progenitor cells and mature oligodendrocytes in humans. We find that breast carcinoma amplified sequence 1 (BCAS1) expression identifies an oligodendroglial subpopulation in the mouse and human brain. These cells are newly formed, myelinating oligodendrocytes that segregate from oligodendrocyte progenitor cells and mature oligodendrocytes and mark regions of active myelin formation in development and in the adult. We find that BCAS1 oligodendrocytes are restricted to the fetal and early postnatal human white matter but remain in the cortical gray matter until old age. BCAS1 oligodendrocytes are reformed after experimental demyelination and found in a proportion of chronic white matter lesions of patients with multiple sclerosis (MS) even in a subset of patients with advanced disease. Our work identifies a means to map ongoing myelin formation in health and disease and presents a potential cellular target for remyelination therapies in MS.
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http://dx.doi.org/10.1126/scitranslmed.aam7816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116798PMC
December 2017

Diversity of oligodendrocytes and their progenitors.

Curr Opin Neurobiol 2017 12 24;47:73-79. Epub 2017 Oct 24.

Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany; Institute of Neuronal Cell Biology, Technical University Munich, 80805 Munich, Germany; German Center for Neurodegenerative Disease (DZNE), 81377 Munich, Germany; Max Planck Institute of Experimental Medicine, Cellular Neuroscience, 37075 Göttingen, Germany. Electronic address:

The established function of oligodendrocytes and their progenitors is to drive the cellular events of myelination, a highly diversified process necessary to match the needs of various neuronal subtypes and networks. The morphological and molecular heterogeneity of oligodendrocytes and their progenitors point to functions beyond establishing saltatory nerve conduction. Here, we review the diversity in the oligodendroglial lineage as well as the classical and new functions identified for oligodendrocytes and their progenitors. Because oligodendroglia remain highly responsive to environmental changes, they likely contribute to various neurological and psychiatric diseases.
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http://dx.doi.org/10.1016/j.conb.2017.09.015DOI Listing
December 2017

Microglia contribute to normal myelinogenesis and to oligodendrocyte progenitor maintenance during adulthood.

Acta Neuropathol 2017 09 6;134(3):441-458. Epub 2017 Jul 6.

Institute of Neuropathology, Medical Faculty, University of Freiburg, Freiburg, Germany.

Whereas microglia involvement in virtually all brain diseases is well accepted their role in the control of homeostasis in the central nervous system (CNS) is mainly thought to be the maintenance of neuronal function through the formation, refinement, and monitoring of synapses in both the developing and adult brain. Although the prenatal origin as well as the neuron-centered function of cortical microglia has recently been elucidated, much less is known about a distinct amoeboid microglia population formerly described as the "fountain of microglia" that appears only postnatally in myelinated regions such as corpus callosum and cerebellum. Using large-scale transcriptional profiling, fate mapping, and genetic targeting approaches, we identified a unique molecular signature of this microglia subset that arose from a CNS endogenous microglia pool independent from circulating myeloid cells. Microglia depletion experiments revealed an essential role of postnatal microglia for the proper development and homeostasis of oligodendrocytes and their progenitors. Our data provide new cellular and molecular insights into the myelin-supporting function of microglia in the normal CNS.
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http://dx.doi.org/10.1007/s00401-017-1747-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5951721PMC
September 2017

The role of oligodendrocyte precursor cells expressing the GPR17 receptor in brain remodeling after stroke.

Cell Death Dis 2017 06 8;8(6):e2871. Epub 2017 Jun 8.

Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy.

Following stroke-induced neuronal damage, quiescent oligodendrocyte precursors (OPCs) are activated to proliferate and later to differentiate to myelin-producing cells. GPR17, a receptor transiently expressed on early OPCs, has emerged as a target to implement stroke repair through stimulation of OPC maturation. However, being GPR17 completely downregulated in myelin-producing oligodendrocytes, its actual role in determining the final fate of OPCs after cerebral ischemia is still uncertain. Here, to univocally define the spatiotemporal changes and final fate of GPR17-expressing OPCs, we induced ischemia by middle cerebral artery occlusion (MCAo) in reporter GPR17iCreER:CAG-eGreen florescent protein (GFP) mice, in which, upon tamoxifen treatment, cells expressing GPR17 become green and traceable for their entire life. Starting from 3 days and up to 2 weeks after MCAo, GFP cells markedly accumulated in regions surrounding the ischemic lesion; several of them proliferated, as shown by co-labeling of the DNA synthesis marker 5-Bromo-2'-deoxyuridine (BrdU). Almost all GFP/BrdU cells expressed the OPC early marker neural/glial antigen 2 (NG2), indicating that they were still precursors. Accumulation of GFP cells was also because of OPC recruitment from surrounding areas, as suggested in vivo by acquisition of typical features of migrating OPCs, shown in vitro in presence of the chemoattractant PDGF-AA and confirmed by transplantation of GFP-OPCs in wild-type MCAo mice. Eight weeks after MCAo, only some of these precociously recruited cells had undergone maturation as shown by NG2 loss and acquisition of mature myelinating markers like GSTpi. A pool of recruited GFP-OPCs was kept at a precursor stage to likely make it available for further insults. Thus, very early after ischemia, GFP-OPCs proliferate and migrate toward the lesion; however, most of these cells remain undifferentiated, suggesting functional roles other than myelination.
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http://dx.doi.org/10.1038/cddis.2017.256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5520912PMC
June 2017

Spinal poly-GA inclusions in a C9orf72 mouse model trigger motor deficits and inflammation without neuron loss.

Acta Neuropathol 2017 08 13;134(2):241-254. Epub 2017 Apr 13.

German Center for Neurodegenerative Diseases (DZNE) Munich, Feodor-Lynen-Straße 17, 81377, Munich, Germany.

Translation of the expanded (ggggcc) repeat in C9orf72 patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) causes abundant poly-GA inclusions. To elucidate their role in pathogenesis, we generated transgenic mice expressing codon-modified (GA) conjugated with cyan fluorescent protein (CFP). Transgenic mice progressively developed poly-GA inclusions predominantly in motoneurons and interneurons of the spinal cord and brain stem and in deep cerebellar nuclei. Poly-GA co-aggregated with p62, Rad23b and the newly identified Mlf2, in both mouse and patient samples. Consistent with the expression pattern, 4-month-old transgenic mice showed abnormal gait and progressive balance impairment, but showed normal hippocampus-dependent learning and memory. Apart from microglia activation we detected phosphorylated TDP-43 but no neuronal loss. Thus, poly-GA triggers behavioral deficits through inflammation and protein sequestration that likely contribute to the prodromal symptoms and disease progression of C9orf72 patients.
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http://dx.doi.org/10.1007/s00401-017-1711-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5508040PMC
August 2017

Glial Cells and Their Function in the Adult Brain: A Journey through the History of Their Ablation.

Front Cell Neurosci 2017 13;11:24. Epub 2017 Feb 13.

Physiological Genomics, Biomedical Center, Ludwig-Maximilians UniversityMunich, Germany; Munich Cluster for Systems NeurologyMunich, Germany; Molecular and Translational Neuroscience, Department of Neurology, University of UlmUlm, Germany.

Glial cells, consisting of microglia, astrocytes, and oligodendrocyte lineage cells as their major components, constitute a large fraction of the mammalian brain. Originally considered as purely non-functional glue for neurons, decades of research have highlighted the importance as well as further functions of glial cells. Although many aspects of these cells are well characterized nowadays, the functions of the different glial populations in the brain under both physiological and pathological conditions remain, at least to a certain extent, unresolved. To tackle these important questions, a broad range of depletion approaches have been developed in which microglia, astrocytes, or oligodendrocyte lineage cells (i.e., NG2-glia and oligodendrocytes) are specifically ablated from the adult brain network with a subsequent analysis of the consequences. As the different glial populations are very heterogeneous, it is imperative to specifically ablate single cell populations instead of inducing cell death in all glial cells in general. Thanks to modern genetic manipulation methods, the approaches can now directly be targeted to the cell type of interest making the ablation more specific compared to general cell ablation approaches that have been used earlier on. In this review, we will give a detailed summary on different glial ablation studies, focusing on the adult mouse central nervous system and the functional readouts. We will also provide an outlook on how these approaches could be further exploited in the future.
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http://dx.doi.org/10.3389/fncel.2017.00024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5303749PMC
February 2017

Transient Cnp expression by early progenitors causes Cre-Lox-based reporter lines to map profoundly different fates.

Glia 2017 02 3;65(2):342-359. Epub 2016 Nov 3.

Department of Neurosurgery, Experimental Neurophysiology, University Clinic Bonn, Bonn, 53105, Germany.

NG2 expressing oligodendroglial precursor cells are ubiquitous in the central nervous system and the only cell type cycling throughout life. Previous fate mapping studies have remained inconsistent regarding the question whether NG2 cells are capable of generating certain types of neurons. Here, we use CNP-Cre mice to map the fate of a sub-population of NG2 cells assumed to be close to differentiation. When crossing these mice with the ROSA26/YFP Cre-reporter line we discovered large numbers of reporter-expressing pyramidal neurons in the piriform and dorsal cortex. In contrast, when using Z/EG reporter mice to track the fate of Cnp-expressing NG2 cells only oligodendroglial cells were found reporter positive. Using BrdU-based birth dating protocols and inducible NG2CreER:ROSA26/YFP mice we show that YFP positive neurons are generated from radial glial cells and that these radial glial cells display temporary and low level activity of certain oligodendroglial genes sufficient to recombine the Cre-inducible reporter gene in ROSA26/YFP but not in Z/EG mice. Taken together, we did not obtain evidence for generation of neurons from NG2 cells. Our results suggest that with an appropriate reporter system Cnp activity can be used to define a proliferative subpopulation of NG2 cells committed to generate oligodendrocytes. However, the strikingly different results obtained from ROSA26/YFP versus Z/EG mice demonstrate that the choice of Cre-reporter line can be of crucial importance for fate mapping studies and other applications of the Cre-lox technology. GLIA 2017;65:342-359.
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http://dx.doi.org/10.1002/glia.23095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6813834PMC
February 2017

Transplanted embryonic neurons integrate into adult neocortical circuits.

Nature 2016 11 26;539(7628):248-253. Epub 2016 Oct 26.

Max Planck Institute of Neurobiology, D-82152 Martinsried, Germany.

The ability of the adult mammalian brain to compensate for neuronal loss caused by injury or disease is very limited. Transplantation aims to replace lost neurons, but the extent to which new neurons can integrate into existing circuits is unknown. Here, using chronic in vivo two-photon imaging, we show that embryonic neurons transplanted into the visual cortex of adult mice mature into bona fide pyramidal cells with selective pruning of basal dendrites, achieving adult-like densities of dendritic spines and axonal boutons within 4-8 weeks. Monosynaptic tracing experiments reveal that grafted neurons receive area-specific, afferent inputs matching those of pyramidal neurons in the normal visual cortex, including topographically organized geniculo-cortical connections. Furthermore, stimulus-selective responses refine over the course of many weeks and finally become indistinguishable from those of host neurons. Thus, grafted neurons can integrate with great specificity into neocortical circuits that normally never incorporate new neurons in the adult brain.
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http://dx.doi.org/10.1038/nature20113DOI Listing
November 2016

Decrease in newly generated oligodendrocytes leads to motor dysfunctions and changed myelin structures that can be rescued by transplanted cells.

Glia 2016 12 12;64(12):2201-2218. Epub 2016 Sep 12.

Physiological Genomics, Biomedical Center, Ludwig-Maximilians University, Munich, Germany.

NG2-glia in the adult brain are known to proliferate and differentiate into mature and myelinating oligodendrocytes throughout lifetime. However, the role of these newly generated oligodendrocytes in the adult brain still remains little understood. Here we took advantage of the Sox10-iCreER x CAG-eGFP x Esco2 mouse line in which we can specifically ablate proliferating NG2-glia in adult animals. Surprisingly, we observed that the generation of new oligodendrocytes in the adult brain was severely affected, although the number of NG2-glia remained stable due to the enhanced proliferation of non-recombined cells. This lack of oligodendrogenesis led to the elongation of the nodes of Ranvier as well as the associated paranodes, which could be locally rescued by myelinating oligodendrocytes differentiated from transplanted NG2-glia deriving from wildtype mice. Repetitive measurements of conduction velocity in the corpus callosum of awake animals revealed a progressive deceleration specifically in the mice lacking adult oligodendrogenesis that resulted in progressive motor deficits. In summary, here we demonstrated for the first time that axon function is not only controlled by the reliable organization of myelin, but also requires a dynamic and continuous generation of new oligodendrocytes in the adult brain. GLIA 2016;64:2201-2218.
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http://dx.doi.org/10.1002/glia.23055DOI Listing
December 2016

NG2-glia, More Than Progenitor Cells.

Adv Exp Med Biol 2016 ;949:27-45

Physiological Genomics, Biomedical Center, Ludwig-Maximilians-University, Großhaderner Str. 9, 82152, Planegg-Martinsried, Germany.

NG2-glia are a mysterious and ubiquitous glial population with a highly branched morphology. Initial studies suggested that their unique function is the generation and maintenance of oligodendrocytes in the central nervous system (CNS), important for proper myelination and therefore for axonal support and fast conduction velocity. Over the last years this simplistic notion has been dramatically changed: the wide and homogeneous distribution of NG2-glia within all areas of the developing CNS that is maintained during the whole lifespan, their potential to also differentiate into other cell types in a spatiotemporal manner, their active capability of maintaining their population and their dynamic behavior in altered conditions have raised the question: are NG2-glia simple progenitor cells or do they play further major roles in the normal function of the CNS? In this chapter, we will discuss some important features of NG2-glia like their homeostatic distribution in the CNS and their potential to differentiate into diverse cell types. Additionally, we will give some further insights into the properties that these cells have, like the ability to form synapses with neurons and their plastic behavior triggered by neuronal activity, suggesting that they may play a role specifically in myelin and more generally in brain plasticity. Finally, we will briefly review their behavior in disease models suggesting that their function is extended to repair the brain after insult.
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http://dx.doi.org/10.1007/978-3-319-40764-7_2DOI Listing
September 2017

Editorial.

Authors:
Leda Dimou

Brain Res 2016 05;1638(Pt B):115

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http://dx.doi.org/10.1016/j.brainres.2016.04.028DOI Listing
May 2016

Adult NG2-Glia Are Required for Median Eminence-Mediated Leptin Sensing and Body Weight Control.

Cell Metab 2016 05;23(5):797-810

Department of Medicine, McGill University Health Center Research Institute, McGill University, Montreal, QC H4A 3J1, Canada. Electronic address:

While leptin is a well-known regulator of body fat mass, it remains unclear how circulating leptin is sensed centrally to maintain energy homeostasis. Here we show that genetic and pharmacological ablation of adult NG2-glia (also known as oligodendrocyte precursors), but not microglia, leads to primary leptin resistance and obesity in mice. We reveal that NG2-glia contact the dendritic processes of arcuate nucleus leptin receptor (LepR) neurons in the median eminence (ME) and that these processes degenerate upon NG2-glia elimination, which explains the consequential attenuation of these neurons' molecular and electrical responses to leptin. Our data therefore indicate that LepR dendrites in the ME represent the principal conduits of leptin's anorexigenic action and that NG2-glia are essential for their maintenance. Given that ME-directed X-irradiation confirmed the pharmacological and genetically mediated ablation effects on body weight, our findings provide a rationale for the known obesity risk associated with cranial radiation therapy.
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http://dx.doi.org/10.1016/j.cmet.2016.04.013DOI Listing
May 2016

GPR17 expressing NG2-Glia: Oligodendrocyte progenitors serving as a reserve pool after injury.

Glia 2016 Feb 14;64(2):287-99. Epub 2015 Oct 14.

Physiological Genomics, Biomedical Center, Ludwig-Maximilians University, Munich, 80336, Germany.

In the adult brain NG2-glia continuously generate mature, myelinating oligodendrocytes. To which extent the differentiation process is common to all NG2-glia and whether distinct pools are recruited for repair under physiological and pathological conditions still needs clarification. Here, we aimed at investigating the differentiation potential of adult NG2-glia that specifically express the G-protein coupled receptor 17 (GPR17), a membrane receptor that regulates the differentiation of these cells at postnatal stages. To this aim, we generated the first BAC transgenic GPR17-iCreER(T2) mouse line for fate mapping studies. In these mice, under physiological conditions, GPR17(+) cells--in contrast to GPR17(-) NG2-glia--did not differentiate within 3 months, a peculiarity that was overcome after cerebral damage induced by acute injury or ischemia. After these insults, GPR17(+) NG2-glia rapidly reacted to the damage and underwent maturation, suggesting that they represent a 'reserve pool' of adult progenitors maintained for repair purposes.
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http://dx.doi.org/10.1002/glia.22929DOI Listing
February 2016

Astrocyte reactivity after brain injury-: The role of galectins 1 and 3.

Glia 2015 Dec 6;63(12):2340-61. Epub 2015 Aug 6.

Physiological Genomics, Biomedical Center, Ludwig-Maximilians-University Munich, Germany.

Astrocytes react to brain injury in a heterogeneous manner with only a subset resuming proliferation and acquiring stem cell properties in vitro. In order to identify novel regulators of this subset, we performed genomewide expression analysis of reactive astrocytes isolated 5 days after stab wound injury from the gray matter of adult mouse cerebral cortex. The expression pattern was compared with astrocytes from intact cortex and adult neural stem cells (NSCs) isolated from the subependymal zone (SEZ). These comparisons revealed a set of genes expressed at higher levels in both endogenous NSCs and reactive astrocytes, including two lectins-Galectins 1 and 3. These results and the pattern of Galectin expression in the lesioned brain led us to examine the functional significance of these lectins in brains of mice lacking Galectins 1 and 3. Following stab wound injury, astrocyte reactivity including glial fibrillary acidic protein expression, proliferation and neurosphere-forming capacity were found significantly reduced in mutant animals. This phenotype could be recapitulated in vitro and was fully rescued by addition of Galectin 3, but not of Galectin 1. Thus, Galectins 1 and 3 play key roles in regulating the proliferative and NSC potential of a subset of reactive astrocytes.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5042059PMC
http://dx.doi.org/10.1002/glia.22898DOI Listing
December 2015

Oligodendrocyte precursor cells synthesize neuromodulatory factors.

PLoS One 2015 12;10(5):e0127222. Epub 2015 May 12.

Molecular Cell Biology, Department of Biology, Johannes Gutenberg University Mainz, D-55122 Mainz, Germany.

NG2 protein-expressing oligodendrocyte progenitor cells (OPC) are a persisting and major glial cell population in the adult mammalian brain. Direct synaptic innervation of OPC by neurons throughout the brain together with their ability to sense neuronal network activity raises the question of additional physiological roles of OPC, supplementary to generating myelinating oligodendrocytes. In this study we investigated whether OPC express neuromodulatory factors, typically synthesized by other CNS cell types. Our results show that OPC express two well-characterized neuromodulatory proteins: Prostaglandin D2 synthase (PTGDS) and neuronal Pentraxin 2 (Nptx2/Narp). Expression levels of the enzyme PTGDS are influenced in cultured OPC by the NG2 intracellular region which can be released by cleavage and localizes to glial nuclei upon transfection. Furthermore PTGDS mRNA levels are reduced in OPC from NG2-KO mouse brain compared to WT cells after isolation by cell sorting and direct analysis. These results show that OPC can contribute to the expression of these proteins within the CNS and suggest PTGDS expression as a downstream target of NG2 signaling.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0127222PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4429067PMC
February 2016

Premigratory and migratory neural crest cells are multipotent in vivo.

Cell Stem Cell 2015 Mar;16(3):314-22

Institute of Anatomy, University of Zurich, 8057 Zurich, Switzerland. Electronic address:

The neural crest (NC) is an embryonic stem/progenitor cell population that generates a diverse array of cell lineages, including peripheral neurons, myelinating Schwann cells, and melanocytes, among others. However, there is a long-standing controversy as to whether this broad developmental perspective reflects in vivo multipotency of individual NC cells or whether the NC is comprised of a heterogeneous mixture of lineage-restricted progenitors. Here, we resolve this controversy by performing in vivo fate mapping of single trunk NC cells both at premigratory and migratory stages using the R26R-Confetti mouse model. By combining quantitative clonal analyses with definitive markers of differentiation, we demonstrate that the vast majority of individual NC cells are multipotent, with only few clones contributing to single derivatives. Intriguingly, multipotency is maintained in migratory NC cells. Thus, our findings provide definitive evidence for the in vivo multipotency of both premigratory and migrating NC cells in the mouse.
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http://dx.doi.org/10.1016/j.stem.2015.02.017DOI Listing
March 2015

Sox2-mediated conversion of NG2 glia into induced neurons in the injured adult cerebral cortex.

Stem Cell Reports 2014 Dec 20;3(6):1000-14. Epub 2014 Nov 20.

Physiological Genomics, Institute of Physiology, Ludwig-Maximilians University Munich, 80336 Munich, Germany; Institute for Stem Cell Research, National Research Center for Environment and Health, 85764 Neuherberg, Germany; Munich Cluster for Systems Neurology (SyNergy), 80336 Munich, Germany. Electronic address:

The adult cerebral cortex lacks the capacity to replace degenerated neurons following traumatic injury. Conversion of nonneuronal cells into induced neurons has been proposed as an innovative strategy toward brain repair. Here, we show that retrovirus-mediated expression of the transcription factors Sox2 and Ascl1, but strikingly also Sox2 alone, can induce the conversion of genetically fate-mapped NG2 glia into induced doublecortin (DCX)(+) neurons in the adult mouse cerebral cortex following stab wound injury in vivo. In contrast, lentiviral expression of Sox2 in the unlesioned cortex failed to convert oligodendroglial and astroglial cells into DCX(+) cells. Neurons induced following injury mature morphologically and some acquire NeuN while losing DCX. Patch-clamp recording of slices containing Sox2- and/or Ascl1-transduced cells revealed that a substantial fraction of these cells receive synaptic inputs from neurons neighboring the injury site. Thus, NG2 glia represent a potential target for reprogramming strategies toward cortical repair.
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http://dx.doi.org/10.1016/j.stemcr.2014.10.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4264057PMC
December 2014

Glial cells as progenitors and stem cells: new roles in the healthy and diseased brain.

Physiol Rev 2014 Jul;94(3):709-37

Physiological Genomics, Institute of Physiology, Ludwig-Maximilians University, Munich, Germany; Institute for Stem Cell Research, HelmholtzZentrum, Neuherberg, Germany; and Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.

The diverse functions of glial cells prompt the question to which extent specific subtypes may be devoted to a specific function. We discuss this by reviewing one of the most recently discovered roles of glial cells, their function as neural stem cells (NSCs) and progenitor cells. First we give an overview of glial stem and progenitor cells during development; these are the radial glial cells that act as NSCs and other glial progenitors, highlighting the distinction between the lineage of cells in vivo and their potential when exposed to a different environment, e.g., in vitro. We then proceed to the adult stage and discuss the glial cells that continue to act as NSCs across vertebrates and others that are more lineage-restricted, such as the adult NG2-glia, the most frequent progenitor type in the adult mammalian brain, that remain within the oligodendrocyte lineage. Upon certain injury conditions, a distinct subset of quiescent astrocytes reactivates proliferation and a larger potential, clearly demonstrating the concept of heterogeneity with distinct subtypes of, e.g., astrocytes or NG2-glia performing rather different roles after brain injury. These new insights not only highlight the importance of glial cells for brain repair but also their great potential in various aspects of regeneration.
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http://dx.doi.org/10.1152/physrev.00036.2013DOI Listing
July 2014

Transplantation reveals regional differences in oligodendrocyte differentiation in the adult brain.

Nat Neurosci 2013 Oct 1;16(10):1370-2. Epub 2013 Sep 1.

1] Physiological Genomics, Institute of Physiology, Ludwig-Maximilians University, Munich, Germany. [2] Institute for Stem Cell Research, HelmholtzZentrum, Neuherberg, Germany. [3] Department of Pharmacological Sciences, University of Milan, Milan, Italy.

To examine the role of gray and white matter niches for oligodendrocyte differentiation, we used homo- and heterotopic transplantations into the adult mouse cerebral cortex. White matter-derived cells differentiated into mature oligodendrocytes in both niches with equal efficiency, whereas gray matter-derived cells did not. Thus, white matter promotes oligodendrocyte differentiation, and cells from this niche differentiate more easily, even in the less supportive gray matter environment.
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http://dx.doi.org/10.1038/nn.3503DOI Listing
October 2013

NG2 regulates directional migration of oligodendrocyte precursor cells via Rho GTPases and polarity complex proteins.

J Neurosci 2013 Jun;33(26):10858-74

Molecular Cell Biology, Department of Biology, Johannes Gutenberg University of Mainz, D-55122 Mainz, Germany.

The transmembrane proteoglycan NG2 is expressed by oligodendrocyte precursor cells (OPC), which migrate to axons during developmental myelination and remyelinate in the adult after migration to injured sites. Highly invasive glial tumors also express NG2. Despite the fact that NG2 has been implicated in control of OPC migration, its mode of action remains unknown. Here, we show in vitro and in vivo that NG2 controls migration of OPC through the regulation of cell polarity. In stab wounds in adult mice we show that NG2 controls orientation of OPC toward the wound. NG2 stimulates RhoA activity at the cell periphery via the MUPP1/Syx1 signaling pathway, which favors the bipolar shape of migrating OPC and thus directional migration. Upon phosphorylation of Thr-2256, downstream signaling of NG2 switches from RhoA to Rac stimulation. This triggers process outgrowth through regulators of front-rear polarity and we show using a phospho-mimetic form of NG2 that indeed NG2 recruits proteins of the CRB and the PAR polarity complexes to stimulate Rac activity via the GEF Tiam1. Our findings demonstrate that NG2 is a core organizer of Rho GTPase activity and localization in the cell, which controls OPC polarity and directional migration. This work also reveals CRB and PAR polarity complexes as new effectors of NG2 signaling in the establishment of front-rear polarity.
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http://dx.doi.org/10.1523/JNEUROSCI.5010-12.2013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6618486PMC
June 2013

Oligodendrogliogenic and neurogenic adult subependymal zone neural stem cells constitute distinct lineages and exhibit differential responsiveness to Wnt signalling.

Nat Cell Biol 2013 Jun 5;15(6):602-13. Epub 2013 May 5.

Department of Physiological Genomics, Institute of Physiology, Ludwig-Maximilians University Munich, Munich, Germany.

The adult mouse subependymal zone (SEZ) harbours adult neural stem cells (aNSCs) that give rise to neuronal and oligodendroglial progeny. However it is not known whether the same aNSC can give rise to neuronal and oligodendroglial progeny or whether these distinct progenies constitute entirely separate lineages. Continuous live imaging and single-cell tracking of aNSCs and their progeny isolated from the mouse SEZ revealed that aNSCs exclusively generate oligodendroglia or neurons, but never both within a single lineage. Moreover, activation of canonical Wnt signalling selectively stimulated proliferation within the oligodendrogliogenic lineage, resulting in a massive increase in oligodendrogliogenesis without changing lineage choice or proliferation within neurogenic clones. In vivo activation or inhibition of canonical Wnt signalling respectively increased or decreased the number of Olig2 and PDGFR- α positive cells, suggesting that this pathway contributes to the fine tuning of oligodendrogliogenesis in the adult SEZ.
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http://dx.doi.org/10.1038/ncb2736DOI Listing
June 2013

Reactive glia in the injured brain acquire stem cell properties in response to sonic hedgehog. [corrected].

Cell Stem Cell 2013 Apr;12(4):426-39

Physiological Genomics, Institute of Physiology, Ludwig-Maximilians University Munich, D-80336, Germany.

As a result of brain injury, astrocytes become activated and start to proliferate in the vicinity of the injury site. Recently, we had demonstrated that these reactive astrocytes, or glia, can form self-renewing and multipotent neurospheres in vitro. In the present study, we demonstrate that it is only invasive injury, such as stab wounding or cerebral ischemia, and not noninvasive injury conditions, such as chronic amyloidosis or induced neuronal death, that can elicit this increase in plasticity. Furthermore, we find that Sonic hedgehog (SHH) is the signal that acts directly on the astrocytes and is necessary and sufficient to elicit the stem cell response both in vitro and in vivo. These findings provide a molecular basis for how cells with neural stem cell lineage emerge at sites of brain injury and imply that the high levels of SHH known to enter the brain from extraneural sources after invasive injury can trigger this response.
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http://dx.doi.org/10.1016/j.stem.2013.01.019DOI Listing
April 2013

Live imaging of astrocyte responses to acute injury reveals selective juxtavascular proliferation.

Nat Neurosci 2013 May 31;16(5):580-6. Epub 2013 Mar 31.

Physiological Genomics, Institute of Physiology, Ludwig-Maximilians University Munich, Munich, Germany.

Astrocytes are thought to have important roles after brain injury, but their behavior has largely been inferred from postmortem analysis. To examine the mechanisms that recruit astrocytes to sites of injury, we used in vivo two-photon laser-scanning microscopy to follow the response of GFP-labeled astrocytes in the adult mouse cerebral cortex over several weeks after acute injury. Live imaging revealed a marked heterogeneity in the reaction of individual astrocytes, with one subset retaining their initial morphology, another directing their processes toward the lesion, and a distinct subset located at juxtavascular sites proliferating. Although no astrocytes actively migrated toward the injury site, selective proliferation of juxtavascular astrocytes was observed after the introduction of a lesion and was still the case, even though the extent was reduced, after astrocyte-specific deletion of the RhoGTPase Cdc42. Thus, astrocyte recruitment after injury relies solely on proliferation in a specific niche.
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http://dx.doi.org/10.1038/nn.3371DOI Listing
May 2013

Dynamic changes in myelin aberrations and oligodendrocyte generation in chronic amyloidosis in mice and men.

Glia 2013 Feb 22;61(2):273-86. Epub 2012 Oct 22.

Department of Physiological Genomics, Institute of Physiology, Ludwig-Maximilians University, Munich, Germany.

Myelin loss is frequently observed in human Alzheimer's disease (AD) and may constitute to AD-related cognitive decline. A potential source to repair myelin defects are the oligodendrocyte progenitor cells (OPCs) present in an adult brain. However, until now, little is known about the reaction of these cells toward amyloid plaque deposition neither in human AD patients nor in the appropriate mouse models. Therefore, we analyzed cells of the oligodendrocyte lineage in a mouse model with chronic plaque deposition (APPPS1 mice) and samples from human patients. In APPPS1 mice defects in myelin integrity and myelin amount were prevalent at 6 months of age but normalized to control levels in 9-month-old mice. Concomitantly, we observed an increase in the proliferation and differentiation of OPCs in the APPPS1 mice at this specific time window (6-8 months) implying that improvements in myelin aberrations may result from repair mechanisms mediated by OPCs. However, while we observed a higher number of cells of the oligodendrocyte lineage (Olig2+ cells) in APPPS1 mice, OLIG2+ cells were decreased in number in postmortem human AD cortex. Our data demonstrate that oligodendrocyte progenitors specifically react to amyloid plaque deposition in an AD-related mouse model as well as in human AD pathology, although with distinct outcomes. Strikingly, possible repair mechanisms from newly generated oligodendrocytes are evident in APPPS1 mice, whereas a similar reaction of oligodendrocyte progenitors seems to be strongly limited in final stages of human AD pathology.
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http://dx.doi.org/10.1002/glia.22432DOI Listing
February 2013

Shaping barrels: activity moves NG2+ glia.

Nat Neurosci 2012 Sep;15(9):1176-8

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http://dx.doi.org/10.1038/nn.3191DOI Listing
September 2012
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