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35 Publications visible to you, out of a total of 35
Astrocyte heterogeneity reveals region-specific astrogenesis in the white matter

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Abstract Astrocyte heterogeneity has been well explored, but our understanding of white matter (WM) astrocytes and their distinctions from gray matter (GM) astrocytes remains limited. Here, we compared …e compared astrocytes from cortical GM and WM/corpus callosum (WM/CC) using single-cell RNA sequencing and spatial transcriptomics of the murine forebrain. The comparison revealed similarities but also significant differences between WM and GM astrocytes, including cytoskeletal and metabolic hallmarks specific to WM astrocytes with molecular properties also shared with human WM astrocytes. When we compared murine astrocytes from two different WM regions, the cortex and cerebellum, we found that they exhibited distinct, region-specific molecular properties, with the cerebellum lacking, for example, a specific cluster of WM astrocytes expressing progenitor and proliferation genes. Functional experiments confirmed astrocyte proliferation in the WM/CC, but not in the cerebellar WM, suggesting that the WM/CC may be a source of continued astrogenesis.

Authors: Riccardo Bocchi, Manja Thorwirth, Tatiana Simon-Ebert, Christina Koupourtidou, Solène Clavreul, Keegan Kolf, Patrizia Della Vecchia, Sara Bottes, Sebastian Jessberger, Jiafeng Zhou, Gulzar Wani, Gregor-Alexander Pilz, Jovica Ninkovic, Annalisa Buffo, Swetlana Sirko, Magdalena Götz, Judith Fischer-Sternjak

Date Published: 24th Feb 2025

Publication Type: Journal Article

Mitochondrial calcium uniporter complex controls T-cell-mediated immune responses

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Abstract T-cell receptor (TCR)-induced Ca 2+ signals are essential for T-cell activation and function. In this context, mitochondria play an important role and take up Ca 2+ to support elevated …xt, mitochondria play an important role and take up Ca 2+ to support elevated bioenergetic demands. However, the functional relevance of the mitochondrial-Ca 2+ -uniporter (MCU) complex in T-cells was not fully understood. Here, we demonstrate that TCR activation causes rapid mitochondrial Ca 2+ ( m Ca 2+ ) uptake in primary naive and effector human CD4 + T-cells. Compared to naive T-cells, effector T-cells display elevated m Ca 2+ and increased bioenergetic and metabolic output. Transcriptome and proteome analyses reveal molecular determinants involved in the TCR-induced functional reprogramming and identify signalling pathways and cellular functions regulated by MCU. Knockdown of MCUa (MCUa KD ), diminishes m Ca 2+ uptake, mitochondrial respiration and ATP production, as well as T-cell migration and cytokine secretion. Moreover, MCUa KD in rat CD4 + T-cells suppresses autoimmune responses in an experimental autoimmune encephalomyelitis (EAE) multiple sclerosis model. In summary, we demonstrate that m Ca 2+ uptake through MCU is essential for proper T-cell function and has a crucial role in autoimmunity. T-cell specific MCU inhibition is thus a potential tool for targeting autoimmune disorders.

Authors: Magdalena Shumanska, Dmitri Lodygin, Christine S Gibhardt, Christian Ickes, Ioana Stejerean-Todoran, Lena C M Krause, Kira Pahl, Lianne J H C Jacobs, Andrea Paluschkiwitz, Shuya Liu, Angela Boshnakovska, Niels Voigt, Tobias J Legler, Martin Haubrock, Miso Mitkovski, Gereon Poschmann, Peter Rehling, Sven Dennerlein, Jan Riemer, Alexander Flügel, Ivan Bogeski

Date Published: 2nd Dec 2024

Publication Type: Journal Article

Single Cell Deletion of the Transcription Factors Trps1 and Sox9 in Astrocytes Reveals Novel Functions in the Adult Cerebral Cortex

Abstract (Expand)

ABSTRACTAstrocytes play key roles in brain function, but how these are orchestrated by transcription factors (TFs) in the adult brain and aligned with astrocyte heterogeneity is largely unknown. Here … we examined the localization and function of the novel astrocyte TF Trps1 (Transcriptional Repressor GATA Binding 1) and the well‐known astrocyte TF Sox9 by Cas9‐mediated deletion using Mokola‐pseudotyped lentiviral delivery into the adult cerebral cortex. Trps1 and Sox9 levels showed heterogeneity among adult cortical astrocytes, which prompted us to explore the effects of deleting either Sox9 or Trps1 alone or simultaneously at the single‐cell (by patch‐based single‐cell transcriptomics) and tissue levels (by spatial transcriptomics). This revealed TF‐specific functions in astrocytes, such as synapse maintenance with the strongest effects on synapse number achieved by Trps1 deletion and a common effect on immune response. In addition, spatial transcriptomics showed non‐cell‐autonomous effects on the surrounding cells, such as oligodendrocytes and other immune cells with TF‐specific differences on the type of immune cells: Trps1 deletion affecting monocytes specifically, while Sox9 deletion acting mostly on microglia and deletion of both TF affecting mostly B cells. Taken together, this study reveals novel roles of Trps1 and Sox9 in adult astrocytes and their communication with other glial and immune cells.

Authors: Poornemaa Natarajan, Christina Koupourtidou, Thibault de Resseguier, Manja Thorwirth, Riccardo Bocchi, Judith Fischer‐Sternjak, Sarah Gleiss, Diana Rodrigues, Michael H. Myoga, Jovica Ninkovic, Giacomo Masserdotti, Magdalena Götz

Date Published: 28th Nov 2024

Publication Type: Journal Article

Nonvesicular lipid transfer drives myelin growth in the central nervous system

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AbstractOligodendrocytes extend numerous cellular processes that wrap multiple times around axons to generate lipid-rich myelin sheaths. Myelin biogenesis requires an enormously productive biosynthetic … machinery for generating and delivering these large amounts of newly synthesized lipids. Yet, a complete understanding of this process remains elusive. Utilizing volume electron microscopy, we demonstrate that the oligodendroglial endoplasmic reticulum (ER) is enriched in developing myelin, extending into and making contact with the innermost myelin layer where growth occurs. We explore the possibility of transfer of lipids from the ER to myelin, and find that the glycolipid transfer protein (GLTP), implicated in nonvesicular lipid transport, is highly enriched in the growing myelin sheath. Mice with a specific knockout of Gltp in oligodendrocytes exhibit ER pathology, hypomyelination and a decrease in myelin glycolipid content. In summary, our results demonstrate a role for nonvesicular lipid transport in CNS myelin growth, revealing a cellular pathway in developmental myelination.

Authors: Jianping Wu, Georg Kislinger, Jerome Duschek, Ayşe Damla Durmaz, Benedikt Wefers, Ruoqing Feng, Karsten Nalbach, Wolfgang Wurst, Christian Behrends, Martina Schifferer, Mikael Simons

Date Published: 11th Nov 2024

Publication Type: Journal Article

A multi-modal single-cell and spatial expression map of metastatic breast cancer biopsies across clinicopathological features

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Abstract Although metastatic disease is the leading cause of cancer-related deaths, its tumor microenvironment remains poorly characterized due to technical and biospecimen limitations. In this study, …his study, we assembled a multi-modal spatial and cellular map of 67 tumor biopsies from 60 patients with metastatic breast cancer across diverse clinicopathological features and nine anatomic sites with detailed clinical annotations. We combined single-cell or single-nucleus RNA sequencing for all biopsies with a panel of four spatial expression assays (Slide-seq, MERFISH, ExSeq and CODEX) and H&E staining of consecutive serial sections from up to 15 of these biopsies. We leveraged the coupled measurements to provide reference points for the utility and integration of different experimental techniques and used them to assess variability in cell type composition and expression as well as emerging spatial expression characteristics across clinicopathological and methodological diversity. Finally, we assessed spatial expression and co-localization features of macrophage populations, characterized three distinct spatial phenotypes of epithelial-to-mesenchymal transition and identified expression programs associated with local T cell infiltration versus exclusion, showcasing the potential of clinically relevant discovery in such maps.

Authors: Johanna Klughammer, Daniel L. Abravanel, Åsa Segerstolpe, Timothy R. Blosser, Yury Goltsev, Yi Cui, Daniel R. Goodwin, Anubhav Sinha, Orr Ashenberg, Michal Slyper, Sébastien Vigneau, Judit Jané‐Valbuena, Shahar Alon, Chiara Caraccio, Judy Chen, Ofir Cohen, Nicole Cullen, Laura K. DelloStritto, Danielle Dionne, Janet Files, Allison Frangieh, Karla Helvie, Melissa E. Hughes, Stephanie Inga, Abhay Kanodia, Ana Lako, Colin MacKichan, Simon Mages, Noa Moriel, Evan Murray, Sara Napolitano, Kyleen Nguyen, Mor Nitzan, Rebecca Ortiz, Miraj Patel, Kathleen L. Pfaff, Caroline B. M. Porter, Asaf Rotem, Sarah Strauss, Robert Strasser, Aaron R. Thorner, Madison Turner, Isaac Wakiro, Julia Waldman, Jingyi Wu, Jorge Gómez Tejeda Zañudo, Diane Zhang, Nancy U. Lin, Sara M. Tolaney, Eric P. Winer, Edward S. Boyden, Fei Chen, Garry P. Nolan, Scott J. Rodig, Xiaowei Zhuang, Orit Rozenblatt-Rosen, Bruce E. Johnson, Aviv Regev, Nikhil Wagle

Date Published: 30th Oct 2024

Publication Type: Journal Article

Twin study identifies early immunological and metabolic dysregulation of CD8 <sup>+</sup> T cells in multiple sclerosis

Abstract (Expand)

Multiple sclerosis (MS) is an inflammatory neurological disease of the central nervous system with a subclinical phase preceding frank neuroinflammation. CD8 + T cells are abundant within MS lesions, …ndant within MS lesions, but their potential role in disease pathology remains unclear. Using high-throughput single-cell RNA sequencing and single-cell T cell receptor analysis, we compared CD8 + T cell clones from the blood and cerebrospinal fluid (CSF) of monozygotic twin pairs in which the cotwin had either no or subclinical neuroinflammation (SCNI). We identified peripheral MS-associated immunological and metabolic alterations indicative of an enhanced migratory, proinflammatory, and activated CD8 + T cell phenotype, which was also evident in cotwins with SCNI and in an independent validation cohort of people with MS. Together, our in-depth single-cell analysis indicates a disease-driving proinflammatory role of infiltrating CD8 + T cells and identifies potential immunological and metabolic therapeutic targets in both prodromal and definitive stages of the disease.

Authors: Vladyslav Kavaka, Luisa Mutschler, Clara de la Rosa del Val, Klara Eglseer, Ana M. Gómez Martínez, Andrea Flierl-Hecht, Birgit Ertl-Wagner, Daniel Keeser, Martin Mortazavi, Klaus Seelos, Hanna Zimmermann, Jürgen Haas, Brigitte Wildemann, Tania Kümpfel, Klaus Dornmair, Thomas Korn, Reinhard Hohlfeld, Martin Kerschensteiner, Lisa Ann Gerdes, Eduardo Beltrán

Date Published: 27th Sep 2024

Publication Type: Journal Article

TFEB activation hallmarks antigenic experience of B lymphocytes and directs germinal center fate decisions

Abstract (Expand)

Abstract Ligation of the B cell antigen receptor (BCR) initiates humoral immunity. However, BCR signaling without appropriate co-stimulation commits B cells to death rather than to differentiation into …fferentiation into immune effector cells. How BCR activation depletes potentially autoreactive B cells while simultaneously primes for receiving rescue and differentiation signals from cognate T lymphocytes remains unknown. Here, we use a mass spectrometry-based proteomic approach to identify cytosolic/nuclear shuttling elements and uncover transcription factor EB (TFEB) as a central BCR-controlled rheostat that drives activation-induced apoptosis, and concurrently promotes the reception of co-stimulatory rescue signals by supporting B cell migration and antigen presentation. CD40 co-stimulation prevents TFEB-driven cell death, while enhancing and prolonging TFEB’s nuclear residency, which hallmarks antigenic experience also of memory B cells. In mice, TFEB shapes the transcriptional landscape of germinal center B cells. Within the germinal center, TFEB facilitates the dark zone entry of light-zone-residing centrocytes through regulation of chemokine receptors and, by balancing the expression of Bcl-2/BH3-only family members, integrates antigen-induced apoptosis with T cell-provided CD40 survival signals. Thus, TFEB reprograms antigen-primed germinal center B cells for cell fate decisions.

Authors: Matthias Münchhalfen, Richard Görg, Michael Haberl, Jens Löber, Jakob Willenbrink, Laura Schwarzt, Charlotte Höltermann, Christian Ickes, Leonard Hammermann, Jan Kus, Björn Chapuy, Andrea Ballabio, Sybille D. Reichardt, Alexander Flügel, Niklas Engels, Jürgen Wienands

Date Published: 14th Aug 2024

Publication Type: Journal Article

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