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32 Publications visible to you, out of a total of 32
Spatial Transcriptomics-correlated Electron Microscopy maps transcriptional and ultrastructural responses to brain injury.

Abstract (Expand)

Understanding the complexity of cellular function within a tissue necessitates the combination of multiple phenotypic readouts. Here, we developed a method that links spatially-resolved gene expression … of single cells with their ultrastructural morphology by integrating multiplexed error-robust fluorescence in situ hybridization (MERFISH) and large area volume electron microscopy (EM) on adjacent tissue sections. Using this method, we characterized in situ ultrastructural and transcriptional responses of glial cells and infiltrating T-cells after demyelinating brain injury in male mice. We identified a population of lipid-loaded "foamy" microglia located in the center of remyelinating lesion, as well as rare interferon-responsive microglia, oligodendrocytes, and astrocytes that co-localized with T-cells. We validated our findings using immunocytochemistry and lipid staining-coupled single-cell RNA sequencing. Finally, by integrating these datasets, we detected correlations between full-transcriptome gene expression and ultrastructural features of microglia. Our results offer an integrative view of the spatial, ultrastructural, and transcriptional reorganization of single cells after demyelinating brain injury.

Authors: P. Androvic, M. Schifferer, K. Perez Anderson, L. Cantuti-Castelvetri, H. Jiang, H. Ji, L. Liu, G. Gouna, S. A. Berghoff, S. Besson-Girard, J. Knoferle, M. Simons, O. Gokce

Date Published: 11th Jul 2023

Publication Type: Journal

T cells modulate the microglial response to brain ischemia.

Abstract (Expand)

Neuroinflammation after stroke is characterized by the activation of resident microglia and the invasion of circulating leukocytes into the brain. Although lymphocytes infiltrate the brain in small … number, they have been consistently demonstrated to be the most potent leukocyte subpopulation contributing to secondary inflammatory brain injury. However, the exact mechanism of how this minimal number of lymphocytes can profoundly affect stroke outcome is still largely elusive. Here, using a mouse model for ischemic stroke, we demonstrated that early activation of microglia in response to stroke is differentially regulated by distinct T cell subpopulations - with T(H1) cells inducing a type I INF signaling in microglia and regulatory T cells (T(REG)) cells promoting microglial genes associated with chemotaxis. Acute treatment with engineered T cells overexpressing IL-10 administered into the cisterna magna after stroke induces a switch of microglial gene expression to a profile associated with pro-regenerative functions. Whereas microglia polarization by T cell subsets did not affect the acute development of the infarct volume, these findings substantiate the role of T cells in stroke by polarizing the microglial phenotype. Targeting T cell-microglia interactions can have direct translational relevance for further development of immune-targeted therapies for stroke and other neuroinflammatory conditions.

Authors: C. Benakis, A. Simats, S. Tritschler, S. Heindl, S. Besson-Girard, G. Llovera, K. Pinkham, A. Kolz, A. Ricci, F. J. Theis, S. Bittner, O. Gokce, A. Peters, A. Liesz

Date Published: 13th Dec 2022

Publication Type: Journal

CD8(+) T cells induce interferon-responsive oligodendrocytes and microglia in white matter aging.

Abstract (Expand)

A hallmark of nervous system aging is a decline of white matter volume and function, but the underlying mechanisms leading to white matter pathology are unknown. In the present study, we found age-related … alterations of oligodendrocyte cell state with a reduction in total oligodendrocyte density in aging murine white matter. Using single-cell RNA-sequencing, we identified interferon (IFN)-responsive oligodendrocytes, which localize in proximity to CD8(+) T cells in aging white matter. Absence of functional lymphocytes decreased the number of IFN-responsive oligodendrocytes and rescued oligodendrocyte loss, whereas T-cell checkpoint inhibition worsened the aging response. In addition, we identified a subpopulation of lymphocyte-dependent, IFN-responsive microglia in the vicinity of the CD8(+) T cells in aging white matter. In summary, we provide evidence that CD8(+) T-cell-induced, IFN-responsive oligodendrocytes and microglia are important modifiers of white matter aging.

Authors: T. Kaya, N. Mattugini, L. Liu, H. Ji, L. Cantuti-Castelvetri, J. Wu, M. Schifferer, J. Groh, R. Martini, S. Besson-Girard, S. Kaji, A. Liesz, O. Gokce, M. Simons

Date Published: 26th Oct 2022

Publication Type: Journal

Diet triggers specific responses of hypothalamic astrocytes in time and region dependent manner.

Abstract (Expand)

Hypothalamic astrocytes are particularly affected by energy-dense food consumption. How the anatomical location of these glial cells and their spatial molecular distribution in the arcuate nucleus of … the hypothalamus (ARC) determine the cellular response to a high caloric diet remains unclear. In this study, we investigated their distinctive molecular responses following exposure to a high-fat high-sugar (HFHS) diet, specifically in the ARC. Using RNA sequencing and proteomics, we showed that astrocytes have a distinct transcriptomic and proteomic profile dependent on their anatomical location, with a major proteomic reprogramming in hypothalamic astrocytes. By ARC single-cell sequencing, we observed that a HFHS diet dictates time- and cell- specific transcriptomic responses, revealing that astrocytes have the most distinct regulatory pattern compared to other cell types. Lastly, we topographically and molecularly characterized astrocytes expressing glial fibrillary acidic protein and/or aldehyde dehydrogenase 1 family member L1 in the ARC, of which the abundance was significantly increased, as well as the alteration in their spatial and molecular profiles, with a HFHS diet. Together, our results provide a detailed multi-omics view on the spatial and temporal changes of astrocytes particularly in the ARC during different time points of adaptation to a high calorie diet.

Authors: Luiza Maria Lutomska, Viktorian Miok, Natalie Krahmer, Ismael González García, Tim Gruber, Ophélia Le Thuc, Cahuê Db Murat, Beata Legutko, Michael Sterr, Gesine Saher, Heiko Lickert, Timo D Müller, Siegfried Ussar, Matthias H Tschöp, Dominik Lutter, Cristina Garcia-Caceres

Date Published: 8th Jul 2022

Publication Type: Journal

Spatial centrosome proteome of human neural cells uncovers disease-relevant heterogeneity.

Abstract (Expand)

The centrosome provides an intracellular anchor for the cytoskeleton, regulating cell division, cell migration, and cilia formation. We used spatial proteomics to elucidate protein interaction networks … at the centrosome of human induced pluripotent stem cell-derived neural stem cells (NSCs) and neurons. Centrosome-associated proteins were largely cell type-specific, with protein hubs involved in RNA dynamics. Analysis of neurodevelopmental disease cohorts identified a significant overrepresentation of NSC centrosome proteins with variants in patients with periventricular heterotopia (PH). Expressing the PH-associated mutant pre-mRNA-processing factor 6 (PRPF6) reproduced the periventricular misplacement in the developing mouse brain, highlighting missplicing of transcripts of a microtubule-associated kinase with centrosomal location as essential for the phenotype. Collectively, cell type-specific centrosome interactomes explain how genetic variants in ubiquitous proteins may convey brain-specific phenotypes.

Authors: Adam C O'Neill, Fatma Uzbas, Giulia Antognolli, Florencia Merino, Kalina Draganova, Alex Jäck, Sirui Zhang, Giorgia Pedini, Julia P Schessner, Kimberly Cramer, Aloys Schepers, Fabian Metzger, Miriam Esgleas, Pawel Smialowski, Renzo Guerrini, Sven Falk, Regina Feederle, Saskia Freytag, Zefeng Wang, Melanie Bahlo, Ralf Jungmann, Claudia Bagni, Georg H H Borner, Stephen P Robertson, Stefanie M Hauck, Magdalena Götz

Date Published: 17th Jun 2022

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

Neuronal mitochondria transport Pink1 mRNA via synaptojanin 2 to support local mitophagy.

Abstract (Expand)

PTEN-induced kinase 1 (PINK1) is a short-lived protein required for the removal of damaged mitochondria through Parkin translocation and mitophagy. Because the short half-life of PINK1 limits its ability … to be trafficked into neurites, local translation is required for this mitophagy pathway to be active far from the soma. The Pink1 transcript is associated and cotransported with neuronal mitochondria. In concert with translation, the mitochondrial outer membrane proteins synaptojanin 2 binding protein (SYNJ2BP) and synaptojanin 2 (SYNJ2) are required for tethering Pink1 mRNA to mitochondria via an RNA-binding domain in SYNJ2. This neuron-specific adaptation for the local translation of PINK1 provides distal mitochondria with a continuous supply of PINK1 for the activation of mitophagy.

Authors: Angelika B Harbauer, J Tabitha Hees, Simone Wanderoy, Inmaculada Segura, Whitney Gibbs, Yiming Cheng, Martha Ordonez, Zerong Cai, Romain Cartoni, Ghazaleh Ashrafi, Chen Wang, Fabiana Perocchi, Zhigang He, Thomas L Schwarz

Date Published: 4th May 2022

Publication Type: Journal

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