Investigating human neuronal transplantation integration and interaction at the single cell level

Project Information

NeurTransHet

Grant agreement ID: 101024862

DOI

10.3030/101024862

Project closed

EC signature date 20 April 2021

Start date 1 January 2022

End date 6 December 2024

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 162 806,40

EU contribution

€ 162 806,40

Coordinated by

LUDWIG-MAXIMILIANS-UNIVERSITAET MUENCHEN
Germany

Periodic Reporting for period 1 - NeurTransHet (Investigating human neuronal transplantation integration and interaction at the single cell level)

Reporting period: 2022-01-01 to 2023-12-31

Summary of the context and overall objectives of the project

Neuronal loss is a hallmark of various brain disorders, such as Alzheimer’s disease, and injuries, like traumatic brain injury. However, the brain's ability to replace lost neurons from its own neural stem cells is highly limited and restricted to specific regions. One promising strategy to restore function is the transplantation of exogenous neuronal cells directly into the affected areas. While previous studies have focused on the connectivity of transplanted neurons (tNs), little is known about the diversity within the transplanted cell population and how the local brain environment influences their integration.

This project aimed to provide a clinically relevant understanding of how tNs integrate into the injured brain. By characterizing the heterogeneity of tNs, we specifically examined the diversity of their synaptic interactions within the host tissue. Furthermore, we investigated the role of the local environment in shaping tN integration. Notably, we identified an upregulation of the immune receptor Trem2 at the transplantation site. When TREM2 was removed from the environment, we observed altered connectivity between tNs and the host neural network. These findings contribute to a deeper understanding of neuronal transplantation and may help refine future therapeutic approaches for brain repair.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

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.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

A deeper understanding of the interactions and synaptic connectivity of transplanted neurons (tNs) is essential for advancing neuronal transplantation as a viable therapeutic strategy. This project has significantly contributed to the field by characterizing the heterogeneity of tNs and their microenvironment while also demonstrating that modulating the host environment can directly influence tN synaptic connectivity. These insights go beyond the current state of the art by shifting the focus from solely optimizing the transplanted cells to considering how the host environment can be harnessed to improve integration outcomes.

The potential clinical impact of these findings is substantial. Neurological disorders and brain injuries often result in irreversible damage, leading to long-term disability and a significant reliance on healthcare and assisted living services. This not only affects patients and their families but also places a considerable financial burden on healthcare systems. According to the Organization for Economic Co-operation and Development (OECD), long-term patient care accounts for an average of 1.7% of a country’s GDP, with neurodegenerative diseases such as Alzheimer’s contributing substantially to these costs. Developing effective neuronal transplantation therapies could help reduce the economic strain by promoting functional recovery and reducing the need for prolonged care.

Beyond economic implications, the societal benefits of advancing neuronal transplantation are profound. For individuals suffering from neurodegenerative diseases or traumatic brain injuries, restoring neuronal function could vastly improve their quality of life, enabling greater independence and participation in daily activities. Furthermore, by providing a deeper mechanistic understanding of how neurons integrate into existing neural circuits, this research may also contribute to broader applications in regenerative medicine and neurotechnology.

Looking ahead, these findings pave the way for further research into optimizing tN survival, maturation, and connectivity through targeted manipulation of the host environment. By refining transplantation approaches based on these insights, future studies can work toward making neuronal replacement therapies a realistic and effective option for patients.

tN integration in a SWI is TREM2 dependent