Biology subjects

Herwerth, M.

Publications and source records attributed to Herwerth, M..

4 recordsLinked to original sources

bioRxiv2026

A longitudinal two-photon imaging platform for focal astrocyte ablation in vivo

Investigating the consequences of astrocyte loss in the intact brain is both important and challenging. As integral components of the neuro-glia-vascular unit, astrocytes are involved in a variety of brain processes including water homeostasis, metabolic supply, regulation of cerebral blood flow, and coordination of neuronal circuit activity. Astrocyte impairment has been associated with numerous neurological disorders. However, experimental models combining focal astrocyte ablation with longitudinal in vivo imaging in the intact adult brain have been lacking, limiting efforts to define the causal contribution of astrocyte loss to central nervous system (CNS) pathology and repair. Here, we present an in vivo model of antibody-mediated astrocyte ablation that enables longitudinal imaging and detailed investigation of ensuing cellular responses. It integrates focal induction of aquaporin-4 antibody-mediated astrocyte loss, chronic in vivo two-photon imaging, genetically encoded sensors, and reporter mouse lines. This advancement allows visualization and quantification of cellular and subcellular events in living organisms during lesion progression and recovery. It overcomes many longstanding limitations of previous models that are either constrained by non-specific hypoxic or mechanical tissue damage or require sacrificing animals at discrete time points, hindering the ability to monitor dynamic biological processes over time. In contrast, the selective targeting of astrocytes prevents the formation of the glial border, enabling the investigation of CNS response in a scar-free environment. Overall, this new approach represents a significant technical advancement, enabling comprehensive longitudinal studies of CNS responses to astrocyte loss, thus opening new avenues for understanding astrocytopathy-driven pathology, evaluating therapeutic interventions, and promoting translational research.

neuroscience↗

bioRxiv2026

Early demyelination by off-target complement injury in a mouse model of neuromyelitis optica

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune CNS disease characterized by serum antibodies targeting astrocytes for complement-mediated lysis. NMOSD lesions show not only astrocyte loss but also early demyelination and oligodendrocyte injury - histological hallmarks that converge with those of other primary demyelinating conditions. How pathology spreads to cause demyelination, particularly in early lesions, remains unclear. Using spinal cord imaging in an acute mouse NMOSD model, we directly observe the spread of pathology from astrocytes to oligodendrocytes in evolving lesions. This spread is characterized by initial calcium dyshomeostasis in oligodendrocytes followed by delayed, non-lytic cell death. Oligodendrocyte death is driven not by astrocyte loss per se but by spill-over of soluble complement proteins, as oligodendrocytes can be cell-autonomously preserved by the cell-type-specific expression of the complement inhibitor CD59. Our findings explain the convergence of glial pathology in antibody-mediated CNS autoimmunity and point towards new approaches to prevent secondary glial injury.

neuroscience↗

bioRxiv2025

Mapping Leukocyte Dynamics during Neuroinflammation Identifies Meningeal Monocyte-Derived Macrophages as Drivers of Progressive Disease

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by increasing disability. The cellular and molecular drivers of clinical transition towards progressive disease are poorly understood. Here, we combine single-cell profiling technologies with genetic and pharmacological perturbations across the course of murine CNS inflammation to dissect the role of the local immune landscape in disease progression. We uncover a chronic monocyte-to-phagocyte transition as a hallmark of progressive disease, characterized by the emergence of maladaptive, lipid-associated macrophages (LAMs) marked by lysosomal activation and fibrotic features. Spatial transcriptomics and multiplexed imaging revealed that these LAMs localized to the leptomeninges in close proximity to parenchymal colony-stimulating factor (CSF)-1 producing disease-associated microglia (DAMs) and meningeal granulocyte-macrophage (GM)-CSF-expressing T helper cells that license their differentiation. Interference with this local cytokine network revealed a protective role for resident microglia and implicated monocyte-derived phagocytes as key drivers of progressive neuroinflammation. Notably, LAM-like macrophages could also be identified in the meninges of people with MS, indicating a homology to human disease. By elucidating their ontogeny, spatial niche, and regulatory cytokine milieu, we provide a mechanistic framework for targeting harmful myeloid states while preserving reparative CNS immunity in progressive MS.

immunology↗

bioRxiv2024

Astrocytes adopt a progenitor-like migratory strategy for regeneration in adult brain

Mature astrocytes become activated upon non-specific tissue damage and contribute to glial scar formation. Proliferation and migration of adult reactive astrocytes after injury is considered very limited. However, the regenerative behavior of individual astrocytes following selective astroglial loss, as seen in astrocytopathies, such as neuromyelitis optica spectrum disorder, remains unexplored. Here, we performed longitudinal in vivo imaging of cortical astrocytes after focal astrocyte ablation in mice. We discovered that perilesional astrocytes develop a remarkable plasticity for efficient lesion repopulation. A subset of mature astrocytes transforms into reactive progenitor-like (REPL) astrocytes that not only undergo multiple asymmetric divisions but also remain in a multinucleated interstage. This regenerative response facilitates efficient migration of newly formed daughter cell nuclei towards unoccupied astrocyte territories. Our findings define the cellular principles of astrocyte plasticity upon focal lesion, unravelling the REPL phenotype as a fundamental regenerative strategy of mature astrocytes to restore astrocytic networks in the adult mammalian brain. Promoting this regenerative phenotype bears therapeutic potential for neurological conditions involving glial dysfunction.

neuroscience↗