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Advancing neuroscience through data science, multimodal biology, and translational discovery.

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Journal Articles

2024 · Nature Communications

Interaction between subventricular zone microglia and neural stem cells impacts the neurogenic response in a mouse model of cortical ischemic stroke

Suvra Nath, Jose C. Martínez Santamaría, Yu-Hsuan Chu, James S. Choi, Pasquale Conforti, Jia-Di Lin, Roman Sankowski, Lukas Amann, Christos Galanis, Kexin Wu, et al.

After a stroke, the neurogenic response from the subventricular zone (SVZ) to repair the brain is limited. Microglia, as an integral part of the distinctive SVZ microenvironment, control neural stem / precursor cell (NSPC) behavior. Here, we show that discrete stroke-associated SVZ microglial clusters negatively impact the innate neurogenic response, and we propose a repository of relevant microglia–NSPC ligand–receptor pairs. After photothrombosis, a mouse model of ischemic stroke, the altered SVZ niche environment leads to immediate activation of microglia in the niche and an abnormal neurogenic response, with cell-cycle arrest of neural stem cells and neuroblast cell death. Pharmacological restoration of the niche environment increases the SVZ-derived neurogenic repair and microglial depletion increases the formation and survival of newborn neuroblasts in the SVZ. Therefore, we propose that altered cross-communication between microglial subclusters and NSPCs regulates the extent of the innate neurogenic repair response in the SVZ after stroke.

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2022 · Glia

Fibrinogen regulates lesion border-forming reactive astrocyte properties after vascular damage

Pasquale Conforti*, Szilvia Mezey*, Suvra Nath*, Yu-Hsuan Chu, Subash C. Malik, Jose C. Martínez Santamaría, Sachin S. Deshpande, Lauriane Pous, Barbara Zieger, Christian Schachtrup

Reactive astrocytes at the border of damaged neuronal tissue organize into a barrier surrounding the fibrotic lesion core, separating this central region of inflammation and fibrosis from healthy tissue. Astrocytes are essential to form the border and for wound repair but interfere with neuronal regeneration. However, the mechanisms driving these astrocytes during central nervous system (CNS) disease are unknown. Here we show that blood-derived fibrinogen is enriched at the interface of lesion border-forming elongated astrocytes after cortical brain injury. Anticoagulant treatment depleting fibrinogen reduces astrocyte reactivity, extracellular matrix deposition and inflammation with no change in the spread of inflammation, whereas inhibiting fibrinogen conversion into fibrin did not significantly alter astrocyte reactivity, but changed the deposition of astrocyte extracellular matrix. RNA sequencing of fluorescence-activated cell sorting-isolated astrocytes of fibrinogen-depleted mice after cortical injury revealed repressed gene expression signatures associated with astrocyte reactivity, extracellular matrix deposition and immune-response regulation, as well as increased gene expression signatures associated with astrocyte metabolism and astrocyte-neuron communication. Systemic pharmacologic depletion of fibrinogen resulted in the absence of elongated, border-forming astrocytes and increased the survival of neurons in the lesion core after cortical injury. These results identify fibrinogen as a critical trigger for lesion border-forming astrocyte properties in CNS disease.

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2022 · Cell and Tissue Research

P75 neurotrophin receptor controls subventricular zone neural stem cell migration after stroke

Sachin S. Deshpande, Subash C. Malik, Pasquale Conforti, Jia-Di Lin, Yu-Hsuan Chu, Suvra Nath, Franziska Greulich, Meike Ast-Dumbach, N. Henriette Uhlenhaut, Christian Schachtrup

Stroke is the leading cause of adult disability. Endogenous neural stem/progenitor cells (NSPCs) originating from the subventricular zone (SVZ) contribute to the brain repair process. However, molecular mechanisms underlying CNS disease-induced SVZ NSPC-redirected migration to the lesion area are poorly understood. Here, we show that genetic depletion of the p75 neurotrophin receptor (p75NTR−/−) in mice reduced SVZ NSPC migration towards the lesion area after cortical injury and that p75NTR−/− NSPCs failed to migrate upon BDNF stimulation in vitro. Cortical injury rapidly increased p75NTR abundance in SVZ NSPCs via bone morphogenetic protein (BMP) receptor signaling. SVZ-derived p75NTR−/− NSPCs revealed an altered cytoskeletal network- and small GTPase family-related gene and protein expression. In accordance, BMP-treated non-migrating p75NTR−/− NSPCs revealed an altered morphology and α-tubulin expression compared to BMP-treated migrating wild-type NSPCs. We propose that BMP-induced p75NTR abundance in NSPCs is a regulator of SVZ NSPC migration to the lesion area via regulation of the cytoskeleton following cortical injury.

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2022 · Cell and Tissue Research

Id proteins: emerging roles in CNS disease and targets for modifying neural stem cell behavior

Yu-Hsuan Chu*, Jia-Di Lin*, Suvra Nath*, Christian Schachtrup

Neural stem/progenitor cells (NSPCs) are found in the adult brain and spinal cord, and endogenous or transplanted NSPCs contribute to repair processes and regulate immune responses in the CNS. However, the molecular mechanisms of NSPC survival and integration as well as their fate determination and functionality are still poorly understood. Inhibitor of DNA binding (Id) proteins are increasingly recognized as key determinants of NSPC fate specification. Id proteins act by antagonizing the DNA-binding activity of basic helix-loop-helix (bHLH) transcription factors, and the balance of Id and bHLH proteins determines cell fate decisions in numerous cell types and developmental stages. Id proteins are central in responses to environmental changes, as they occur in CNS injury and disease, and cellular responses in adult NSPCs implicate Id proteins as prime candidates for manipulating stemcell behavior. Here, we outline recent advances in understanding Id protein pleiotropic functions in CNS diseases and propose an integrated view of Id proteins and their promise as potential targets in modifying stemcell behavior to ameliorate CNS disease.

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2021 · Neural Regeneration Research

Fibrinogen triggered signaling pathways modify stem cell behavior in central nervous system disease

Jia-Di Lin*, Yu-Hsuan Chu*, Suvra Nath*, Christian Schachtrup

Neural stem/precursor cells (NSPCs) are a promising tool for central nervous system (CNS) repair, whether activated from endogenous sources or introduced by transplantation. Their survival, integration, and fate determination are still poorly understood, which limits their use for brain repair. This commentary builds on our recent study (Pous et al., 2020, Nature Communications), which showed that CNS disease alters the subventricular zone (SVZ) stem cell niche through the deposition of blood-derived factors. We found that one of these factors, fibrinogen, drives NSPC differentiation into astrocytes via BMP signaling. Here we summarize the relevance of these findings for NSPC biology in CNS disease and consider their implications for other stem cell niches and other CNS disorders. We also discuss how this knowledge could be used to steer NSPC fate and function and so promote CNS repair.

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2020 · Nature Communications

Fibrinogen induces neural stem cell differentiation into astrocytes in the subventricular zone via BMP signaling

Lauriane Pous, Sachin S. Deshpande, Suvra Nath, Szilvia Mezey, Subash C. Malik, Sebastian Schildge, Christian Bohrer, Könül Topp, et al.

Neural stem/progenitor cells (NSPCs) originating from the subventricular zone (SVZ) contribute to brain repair during CNS disease. The microenvironment within the SVZ stem cell niche controls NSPC fate. However, extracellular factors within the niche that trigger astrogliogenesis over neurogenesis during CNS disease are unclear. Here, we show that blood-derived fibrinogen is enriched in the SVZ niche following distant cortical brain injury in mice. Fibrinogen inhibited neuronal differentiation in SVZ and hippocampal NSPCs while promoting astrogenesis via activation of the BMP receptor signaling pathway. Genetic and pharmacologic depletion of fibrinogen reduced astrocyte formation within the SVZ after cortical injury, reducing the contribution of SVZ-derived reactive astrocytes to lesion scar formation. We propose that fibrinogen is a regulator of NSPC-derived astrogenesis from the SVZ niche via BMP receptor signaling pathway following injury.

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2020 · Advanced Healthcare Materials

Synthetic Polymers Provide a Robust Substrate for Functional Neuron Culture

Yichuan Zhang, Seshasailam Venkateswaran, Gustavo A. Higuera, Suvra Nath, Guy Shpak, Jeffrey Matray, Lidy E. Fratila-Apachitei, Amir A. Zadpoor, et al.

Defined, reproducible substrates for neuronal culture are essential for neural tissue engineering, disease modelling and cell-based therapies, yet the field still relies on laminin, a biological extracellular matrix protein that is costly, unstable and subject to batch-to-batch variation. Synthetic alternatives that match its capacity to support neuronal attachment, differentiation and function have remained elusive. Here we use a high-throughput polymer screen to identify synthetic materials that sustain primary mouse cerebellar neurons with high viability, including under serum-free conditions. Lead polymers supported the attachment of both primary neurons and neural progenitor cells, maintained high expression of neuronal markers and promoted the maturation of progenitors into neurons. Neurons grown on these substrates were electrophysiologically active, which demonstrates functional network competence rather than survival alone. The substrates were also compatible with CRISPR-based genome editing, enabling genetic perturbation of cultured neurons. Together, these findings establish synthetic polymers as scalable, chemically defined alternatives to laminin that unite functional readouts with genetic manipulation. This platform opens routes to standardized neuronal assays and to biomaterials for neural implantation.

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* Equal contribution