Biology subjects

Thorwirth, M.

Publications and source records attributed to Thorwirth, M..

4 recordsLinked to original sources

bioRxiv2026

Antagonizing niche signals regulate the emergence of postnatal neural stem cells and allow enlargement of their pool

Adult neural stem cells (aNSCs) of the lateral ventricular sub-ventricular zone (V-SVZ) are set aside during embryogenesis from a pool of slowly dividing neural stem/progenitor cells (NSPCs) residing in the lateral ganglionic eminence (LGE). The time of aNSCs specification coincides with the peak of embryonic neurogenesis, raising the question of which mechanisms allow only a subpopulation of NSPCs to retain stem cell identity while others proceed to divide and differentiate into neurons. To address this, we isolated rapidly and slowly dividing NSPCs from the mouse LGE at mid-neurogenesis, when aNSCs are specified, and profiled the transcriptome at the single cell level. We find that slowly dividing NSPCs constitute a heterogeneous population encompassing both radial glia cells (RGCs) and intermediate progenitors (IPs) and characterized by different gene signatures. Focusing on RGCs, we show that slowly and rapidly dividing RGCs differentially express genes involved in the formation - such as Lamb2 - or degradation - such as Mmp15 - of the extracellular matrix (ECM), pointing to opposite niche-remodelling strategies as a potential mechanism of fate determination. In vivo perturbation of Lamb2 and Mmp15 affects the seeding and maintenance of NSCs in an opposing manner, with knockdown of Mmp15 increasing the NSC pool as also shown by single-cell RNA-sequencing. These findings suggest that opposite ECM remodelling by slowly and rapidly dividing RGCs constitutes a novel cross-regulatory niche-level mechanism regulating aNSCs emergence, opening new avenues for regulating their numbers and thereby long-term maintenance of the brains regenerative potential.

developmental biology↗

bioRxiv2026

Comprehensive single cell profiling of ageing glial cells reveals impaired Wnt signalling and Jun transcription factors regulating cortical astrocytes

Understanding age-related cellular dysfunction in the brain is essential for developing strategies to promote healthy ageing. Towards this aim, we took advantage of a previously established mild dissociation method to profile cells in the cerebral cortex grey matter of adult and aged mice. This revealed glial cells with largely up-regulated and other glia and neurons with largely down-regulated gene expression upon ageing. Astrocytes were involved in increased interactions with microglia and decreased interaction with neurons, high-lighting potent age-induced changes in their regulatory roles. Single cell RNA-seq and single nuclei multiome analysis of astrocytes uncovered down-regulation of Wnt-signalling with increased expression of its inhibitors and reduced RNA and protein levels of its effectors JunB/D, acting downstream of Wnt signalling in ageing. This was confirmed by RNA-scope and immunostainings, as well as in human data. Notably, injection of JunD-expressing viral vectors in astrocytes increased their proliferation and HMGB1 levels in the aged brain, indicative of a more youthful astrocyte state. Main pointsO_LITranscriptomic analysis uncovers cell type-specific impact of ageing in the cortical grey matter, including altered intercellular communication networks. C_LIO_LIMultiomic profiling identifies dysregulated Wnt signalling in ageing cortical astrocytes. C_LIO_LIAgeing astrocytes exhibit upregulation of the Wnt signalling regulators Maml2 and Daam2, accompanied by downregulation of the AP-1 transcriptional complex component JunD. C_LIO_LIOverexpression of JunD increases proliferation after mild injury in aged astrocytes. C_LI

neuroscience↗

bioRxiv2025

Multimodal synapse analysis reveals restricted integration of transplanted neurons remodeled by TREM2

Neuron transplantation offers a promising approach for circuit restoration after injury, but depends crucially on adequate synaptic integration. Yet, our knowledge of the effects of the host injury environment on transplanted neuron (tN) network integration remains limited. Here, we used a stab wound injury model to examine how tN synapses mature and integrate using multimodal read-outs. Morphological, ultrastructural and functional electrophysiological analysis of tN synapses indicated that tN integration and functional maturation are partially stunted. Spatial transcriptomics revealed persistent inflammatory signatures at the transplant site including Trem2 upregulation. Strikingly, in an environment devoid of TREM2, synaptic integration as well as functional maturation of tNs, including action potential maturation and spontaneous firing, were almost fully rescued. Spatial transcriptomics further showed reduced inflammatory pathways and improved maturation of tNs in Trem2-/- brains. This study highlights the importance of tackling chronic inflammation for adequate tN integration.

neuroscience↗

bioRxiv2021

Brain injury environment critically influences the connectivity of transplanted neurons

Cell transplantation is a promising approach for the reconstruction of neuronal circuits after brain damage. Transplanted neurons integrate with remarkable specificity into circuitries of the mouse cerebral cortex affected by neuronal ablation. However, it remains unclear how neurons perform in a local environment undergoing reactive gliosis, inflammation, macrophage infiltration and scar formation, as in traumatic brain injury (TBI). To elucidate this, we transplanted cells from the embryonic mouse cerebral cortex into TBI-injured, inflamed-only, or intact cortex of adult mice. Brain-wide quantitative connectomics unraveled graft inputs from correct regions across the brain in all conditions, with pronounced quantitative differences: scarce in intact and inflamed brain, versus exuberant after trauma. In the latter, excessive synapse pruning follows the initial overshoot of connectivity resulting in only a few connections left. Proteomic profiling identifies candidate molecules involved in the synaptic yield, a pivotal parameter to tailor for functional restoration of neuronal circuits. TeaserNeuronal grafts in a brain area affected by trauma receive excessive yet mostly vulnerable inputs from host circuits.

neuroscience↗