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Single-cell RNA sequencing reveals Treponema pallidum infection inhibits neurodevelopment in brain organoids

Core Concepts
Treponema pallidum infection inhibits the differentiation of neural progenitor cell subcluster 1B, reducing the number of hindbrain neurons and affecting the neurodevelopment of brain organoids.
The study used single-cell RNA sequencing (scRNA-seq) to analyze the effects of Treponema pallidum (T. pallidum) infection on the development of brain organoids derived from induced pluripotent stem cells (iPSCs). Key findings: T. pallidum infection reduced the overall size of brain organoids and disrupted the formation of neural rosette-like structures. scRNA-seq analysis revealed that T. pallidum infection decreased the proportion of neural progenitor cells (NPCs) and neurons in the organoids. Specifically, T. pallidum inhibited the differentiation of the subNPC1B subcluster, leading to a reduction in the number of hindbrain neurons. The transcription factor TCF3 and the notch signaling pathway were identified as potential mediators of the inhibitory effects of T. pallidum on the subNPC1B-hindbrain neuron differentiation axis. These findings provide insights into the pathogenesis of congenital neurodevelopmental impairment associated with T. pallidum infection and suggest that the brain organoid model can be a useful platform for studying the impact of congenital infections on human brain development.
The size of T. pallidum-infected brain organoids was significantly smaller than the control group (P<0.01). The expressions of endodermal markers Ve-cad, KDR, and SOX17 were significantly upregulated in the T. pallidum group (P < 0.05), while the expressions of ectodermal genes MAP2, Nestin, and SOX2 were significantly decreased (P < 0.05). The proportion of neural progenitor cell (NPC)1, NPC2 and neuron population were 12.5%, 1.72%, and 9.1%, respectively, following T. pallidum infection (P < 0.05). The proportion of the CD71-/CD49b- neuron population in the T. pallidum group was significantly lower than the control group (P < 0.01). The expressions of hindbrain neuron markers MAGEH1, MEIS3 and USP47 were significantly decreased following T. pallidum infection (P<0.05–0.01).
"T. pallidum infection influenced the formation of neural rosette structures and affected the neurodevelopment of the brain organoid." "T. pallidum reduced the cell number of subNPC1B subclusters and affected brain organoid development." "T. pallidum inhibited the differentiation of hindbrain neurons in the brain organoids."

Deeper Inquiries

How can the brain organoid model be further optimized to better recapitulate the complex neurodevelopmental processes and enable more comprehensive disease modeling?

The brain organoid model can be further optimized in several ways to better recapitulate complex neurodevelopmental processes and enhance disease modeling. Firstly, improving the maturation process of the organoids by extending the culture period or introducing specific growth factors can help mimic the intricate developmental stages of the human brain more accurately. This extended maturation can promote the formation of more mature neuronal networks and cell types, providing a more comprehensive representation of neurodevelopment. Secondly, enhancing the cellular diversity within the organoids by incorporating multiple cell types found in the developing brain can better simulate the complex interactions and cellular heterogeneity present in vivo. This can be achieved by introducing different cell populations, such as glial cells, microglia, and vascular cells, to create a more physiologically relevant microenvironment within the organoids. Furthermore, incorporating vascularization into the organoid model can improve nutrient and oxygen delivery to the cells, better mimicking the in vivo conditions of the developing brain. This vascularization can be achieved through the introduction of endothelial cells or by implementing microfluidic systems to facilitate nutrient exchange and waste removal within the organoids. Additionally, incorporating functional readouts such as electrophysiological recordings or calcium imaging can provide valuable insights into the activity and connectivity of neuronal networks within the organoids. These functional assays can help assess the functionality of the neurons and their ability to communicate with each other, enhancing the disease modeling capabilities of the organoid system.

What are the potential mechanisms by which T. pallidum infection specifically targets the subNPC1B subcluster and disrupts the differentiation of hindbrain neurons?

The specific targeting of the subNPC1B subcluster and disruption of hindbrain neuron differentiation by T. pallidum infection may involve several potential mechanisms. One possible mechanism is the dysregulation of key transcription factors and signaling pathways that are crucial for the differentiation of neural progenitor cells into hindbrain neurons. T. pallidum infection may alter the expression of genes involved in neural development, leading to the inhibition of subNPC1B differentiation and hindbrain neuron maturation. Moreover, T. pallidum may directly interact with neural progenitor cells within the subNPC1B subcluster, affecting their proliferation, differentiation, or survival. This interaction could disrupt the normal developmental trajectory of these cells, leading to impaired hindbrain neuron formation. Additionally, T. pallidum infection may induce inflammatory responses or oxidative stress within the brain organoids, creating a hostile microenvironment that hinders proper neurodevelopment. These inflammatory processes can impact the differentiation and maturation of neural cells, including hindbrain neurons, contributing to the observed disruptions in the organoid model. Overall, the specific mechanisms by which T. pallidum targets the subNPC1B subcluster and disrupts hindbrain neuron differentiation likely involve a combination of altered gene expression, direct cellular interactions, and inflammatory responses that collectively impact neurodevelopment in the organoids.

Given the involvement of the notch signaling pathway, are there any therapeutic interventions targeting this pathway that could be explored to mitigate the adverse effects of T. pallidum infection on fetal brain development?

The involvement of the notch signaling pathway in the adverse effects of T. pallidum infection on fetal brain development suggests that targeting this pathway could be a potential therapeutic strategy to mitigate these effects. Several therapeutic interventions that modulate the notch signaling pathway could be explored in the context of T. pallidum infection: Notch pathway inhibitors: Small molecule inhibitors targeting key components of the notch signaling pathway, such as gamma-secretase inhibitors, can block notch receptor activation and downstream signaling. By inhibiting notch signaling, these compounds could potentially counteract the disruptive effects of T. pallidum on hindbrain neuron differentiation. Notch pathway activators: Conversely, notch pathway activators or agonists could be used to enhance notch signaling and promote neurogenesis and neuronal differentiation in the presence of T. pallidum infection. These compounds could stimulate the development of hindbrain neurons and counteract the inhibitory effects of the infection on neurodevelopment. Gene therapy targeting notch signaling: Gene therapy approaches that modulate notch pathway components or regulators could be explored to restore normal notch signaling activity in the brain organoids infected with T. pallidum. By genetically manipulating the expression of notch pathway genes, it may be possible to rescue the hindbrain neuron differentiation process and mitigate the developmental impairments caused by the infection. Overall, targeting the notch signaling pathway through pharmacological or genetic interventions represents a promising avenue for developing therapeutic strategies to mitigate the adverse effects of T. pallidum infection on fetal brain development in the context of the brain organoid model.