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6 Publications visible to you, out of a total of 6
Shared inflammatory glial cell signature after stab wound injury, revealed by spatial, temporal, and cell-type-specific profiling of the murine cerebral cortex.

Abstract (Expand)

Traumatic brain injury leads to a highly orchestrated immune- and glial cell response partially responsible for long-lasting disability and the development of secondary neurodegenerative diseases. A … holistic understanding of the mechanisms controlling the responses of specific cell types and their crosstalk is required to develop an efficient strategy for better regeneration. Here, we combine spatial and single-cell transcriptomics to chart the transcriptomic signature of the injured male murine cerebral cortex, and identify specific states of different glial cells contributing to this signature. Interestingly, distinct glial cells share a large fraction of injury-regulated genes, including inflammatory programs downstream of the innate immune-associated pathways Cxcr3 and Tlr1/2. Systemic manipulation of these pathways decreases the reactivity state of glial cells associated with poor regeneration. The functional relevance of the discovered shared signature of glial cells highlights the importance of our resource enabling comprehensive analysis of early events after brain injury.

Authors: Christina Koupourtidou, Veronika Schwarz, Hananeh Aliee, Simon Frerich, Judith Fischer-Sternjak, Riccardo Bocchi, Tatiana Simon-Ebert, Xianshu Bai, Swetlana Sirko, Frank Kirchhoff, Martin Dichgans, Magdalena Götz, Fabian J Theis, Jovica Ninkovic

Date Published: 3rd Apr 2024

Publication Type: Journal

Injury-specific factors in the cerebrospinal fluid regulate astrocyte plasticity in the human brain.

Abstract (Expand)

The glial environment influences neurological disease progression, yet much of our knowledge still relies on preclinical animal studies, especially regarding astrocyte heterogeneity. In murine models … of traumatic brain injury, beneficial functions of proliferating reactive astrocytes on disease outcome have been unraveled, but little is known regarding if and when they are present in human brain pathology. Here we examined a broad spectrum of pathologies with and without intracerebral hemorrhage and found a striking correlation between lesions involving blood-brain barrier rupture and astrocyte proliferation that was further corroborated in an assay probing for neural stem cell potential. Most importantly, proteomic analysis unraveled a crucial signaling pathway regulating this astrocyte plasticity with GALECTIN3 as a novel marker for proliferating astrocytes and the GALECTIN3-binding protein LGALS3BP as a functional hub mediating astrocyte proliferation and neurosphere formation. Taken together, this work identifies a therapeutically relevant astrocyte response and their molecular regulators in different pathologies affecting the human cerebral cortex.

Authors: Swetlana Sirko, Christian Schichor, Patrizia Della Vecchia, Fabian Metzger, Giovanna Sonsalla, Tatiana Simon, Martina Bürkle, Sofia Kalpazidou, Jovica Ninkovic, Giacomo Masserdotti, Jean-Frederic Sauniere, Valentina Iacobelli, Stefano Iacobelli, Claire Delbridge, Stefanie M Hauck, Jörg-Christian Tonn, Magdalena Götz

Date Published: 8th Dec 2023

Publication Type: Journal

Parkinson's disease motor symptoms rescue by CRISPRa-reprogramming astrocytes into GABAergic neurons.

Abstract (Expand)

Direct reprogramming based on genetic factors resembles a promising strategy to replace lost cells in degenerative diseases such as Parkinson's disease. For this, we developed a knock-in mouse line … carrying a dual dCas9 transactivator system (dCAM) allowing the conditional in vivo activation of endogenous genes. To enable a translational application, we additionally established an AAV-based strategy carrying intein-split-dCas9 in combination with activators (AAV-dCAS). Both approaches were successful in reprogramming striatal astrocytes into induced GABAergic neurons confirmed by single-cell transcriptome analysis of reprogrammed neurons in vivo. These GABAergic neurons functionally integrate into striatal circuits, alleviating voluntary motor behavior aspects in a 6-OHDA Parkinson's disease model. Our results suggest a novel intervention strategy beyond the restoration of dopamine levels. Thus, the AAV-dCAS approach might enable an alternative route for clinical therapies of Parkinson's disease.

Authors: Jessica Giehrl-Schwab, Florian Giesert, Benedict Rauser, Chu Lan Lao, Sina Hembach, Sandrine Lefort, Ignacio L Ibarra, Christina Koupourtidou, Malte Daniel Luecken, Dong-Jiunn Jeffery Truong, Judith Fischer-Sternjak, Giacomo Masserdotti, Nilima Prakash, Jovica Ninkovic, Sabine M Hölter, Daniela M Vogt Weisenhorn, Fabian J Theis, Magdalena Götz, Wolfgang Wurst

Date Published: 9th May 2022

Publication Type: Journal

Innate Immune Pathways Promote Oligodendrocyte Progenitor Cell Recruitment to the Injury Site in Adult Zebrafish Brain.

Abstract (Expand)

The oligodendrocyte progenitors (OPCs) are at the front of the glial reaction to the traumatic brain injury. However, regulatory pathways steering the OPC reaction as well as the role of reactive OPCs … remain largely unknown. Here, we compared a long-lasting, exacerbated reaction of OPCs to the adult zebrafish brain injury with a timely restricted OPC activation to identify the specific molecular mechanisms regulating OPC reactivity and their contribution to regeneration. We demonstrated that the influx of the cerebrospinal fluid into the brain parenchyma after injury simultaneously activates the toll-like receptor 2 (Tlr2) and the chemokine receptor 3 (Cxcr3) innate immunity pathways, leading to increased OPC proliferation and thereby exacerbated glial reactivity. These pathways were critical for long-lasting OPC accumulation even after the ablation of microglia and infiltrating monocytes. Importantly, interference with the Tlr1/2 and Cxcr3 pathways after injury alleviated reactive gliosis, increased new neuron recruitment, and improved tissue restoration.

Authors: Rosario Sanchez-Gonzalez, Christina Koupourtidou, Tjasa Lepko, Alessandro Zambusi, Klara Tereza Novoselc, Tamara Durovic, Sven Aschenbroich, Veronika Schwarz, Christopher T Breunig, Hans Straka, Hagen B Huttner, Martin Irmler, Johannes Beckers, Wolfgang Wurst, Andreas Zwergal, Tamas Schauer, Tobias Straub, Tim Czopka, Dietrich Trümbach, Magdalena Götz, Stefan H Stricker, Jovica Ninkovic

Date Published: 2nd Feb 2022

Publication Type: Journal

Adult neural stem cell activation in mice is regulated by the day/night cycle and intracellular calcium dynamics.

Abstract (Expand)

Neural stem cells (NSCs) in the adult brain transit from the quiescent state to proliferation to produce new neurons. The mechanisms regulating this transition in freely behaving animals are, however, … poorly understood. We customized in vivo imaging protocols to follow NSCs for several days up to months, observing their activation kinetics in freely behaving mice. Strikingly, NSC division is more frequent during daylight and is inhibited by darkness-induced melatonin signaling. The inhibition of melatonin receptors affected intracellular Ca<sup>2+</sup> dynamics and promoted NSC activation. We further discovered a Ca<sup>2+</sup> signature of quiescent versus activated NSCs and showed that several microenvironmental signals converge on intracellular Ca<sup>2+</sup> pathways to regulate NSC quiescence and activation. In vivo NSC-specific optogenetic modulation of Ca<sup>2+</sup> fluxes to mimic quiescent-state-like Ca<sup>2+</sup> dynamics in freely behaving mice blocked NSC activation and maintained their quiescence, pointing to the regulatory mechanisms mediating NSC activation in freely behaving animals.

Authors: Archana Gengatharan, Sarah Malvaut, Alina Marymonchyk, Majid Ghareghani, Marina Snapyan, Judith Fischer-Sternjak, Jovica Ninkovic, Magdalena Götz, Armen Saghatelyan

Date Published: 4th Feb 2021

Publication Type: Journal

Defining the Adult Neural Stem Cell Niche Proteome Identifies Key Regulators of Adult Neurogenesis.

Abstract (Expand)

The mammalian brain contains few niches for neural stem cells (NSCs) capable of generating new neurons, whereas other regions are primarily gliogenic. Here we leverage the spatial separation of the … sub-ependymal zone NSC niche and the olfactory bulb, the region to which newly generated neurons from the sub-ependymal zone migrate and integrate, and present a comprehensive proteomic characterization of these regions in comparison to the cerebral cortex, which is not conducive to neurogenesis and integration of new neurons. We find differing compositions of regulatory extracellular matrix (ECM) components in the neurogenic niche. We further show that quiescent NSCs are the main source of their local ECM, including the multi-functional enzyme transglutaminase 2, which we show is crucial for neurogenesis. Atomic force microscopy corroborated indications from the proteomic analyses that neurogenic niches are significantly stiffer than non-neurogenic parenchyma. Together these findings provide a powerful resource for unraveling unique compositions of neurogenic niches.

Authors: Jacob Kjell, Judith Fischer-Sternjak, Amelia J Thompson, Christian Friess, Matthew J Sticco, Favio Salinas, Jürgen Cox, David C Martinelli, Jovica Ninkovic, Kristian Franze, Herbert B Schiller, Magdalena Götz

Date Published: 6th Feb 2020

Publication Type: Journal

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