In this project, we established a human-in-mouse transplantation model to study the integration of human transplanted neurons (tNs) in an in vivo setting. Additionally, we conducted mouse-in-mouse transplantations to explore fundamental principles of neuronal integration. Using a multi-parametric approach to analyze the synaptic landscape of tNs, we found that although transplanted neurons undergo maturation over time, a subset of their characteristics remains immature.
To further understand the host environment’s influence on tN integration, we performed spatial transcriptomic analyses to identify molecular signatures at the transplantation site. This revealed a significant presence of microglia, with TREM2 being the most upregulated microglial sensome marker. When transplantations were performed in a TREM2-deficient environment, we observed alterations in tN integration and connectivity, highlighting the critical role of microglia in shaping the transplanted neurons' synaptic development.
The findings from this project contribute valuable insights that may enhance neuronal transplantation strategies and accelerate their translation into clinical applications. Our results provide a novel understanding of how the host environment regulates the development and integration of tNs, emphasizing the need to consider environmental factors when developing transplantation-based therapies.
While most neuronal transplantation studies have focused on Parkinson’s disease—where dopaminergic neurons are transplanted at ectopic sites—our work addresses a different and clinically relevant challenge: restoring neuronal function in homotopic lesions, such as those found in the cerebral cortex after traumatic brain injury. Additionally, while postnatal transplantation models have been widely used to study human synapse development in vivo, adult brain repair requires the integration of transplanted neurons into long-established neural circuits that have been damaged or degenerated.
By identifying key mechanisms governing tN integration and demonstrating how modifications to the injured environment impact connectivity, this study paves the way for future research exploring how host environment manipulation can optimize tN survival, maturation, and functional incorporation. To facilitate further advancements in the field, our findings have been made available through BioRxiv, providing an open-access resource for researchers working on neuronal transplantation and brain repair.
