Spinal cord repair from endogenous stem cells in the spinal niche

Spinal cord injury in humans leads to permanent loss of function. This is despite the presence of
stem cell like cells in the spinal cord. In contrast, zebrafish regain full swimming capacity after a
lesion and their spinal stem cells make new neurons that contribute to the repair.

Here we plan to identify the signals acting on the stem cells in the fish to then use them to improve
the reaction of stem cells of humans (in a dish) and spinal cord repair in rat models. In the course
of the project, we will develop tools that will aid our research, but also contribute to the work of our
colleagues in the community: We will develop small proteins that can be used to drive stem cells
into a repair type, we will adapt a new microscopy technique to monitor repair in live fish and rats
as it happens, and we will develop new stem cell lines directly from human spinal cord material.

This project will identify repair factors that could then be taken into clinical trials. Our team
comprises colleagues from the UK, Germany, Belgium, France and Poland, among them basic
neuroscientists and neurosurgeons.

We hypothesize that small differences in the environment of zebrafish and mammals spinal stem/progenitor cells determine regenerative success or failure. We need to characterize and compare the cellular diversity and differential properties of adult spinal cord stem cell niches in zebrafish, rodents and human. We will elucidate the molecular mechanisms controlling niche dormancy vs activation and stem cell fate after spinal cord injury, exploring why mammals spinal cord stem cell do not generate neurons after SCI. We will explore the human spinal cord stem cell niche and generate human spinal cord stem cell lines for further investigation of human niche cell properties. We aim to enhance functional repair after mammalian spinal cord injury by defining innovative tools (nanobodies) and identifying molecules to manipulate the activity and fate of spinal cord neural stem and progenitor cells after injury.

This is a collaborative proposal generating a European consortium of researchers in the UK, Germany, France, Belgium, and Poland. Translation is a cornerstone of this project. It will generate significant knowledge on the mechanisms of endogenous spinal cord repair, functionally tested in an in vivo (rat) spinal cord model, with direct human validation (through expression and in vitro studies of human material/cells). Furthermore, valuable tools will be created which will drive innovation and
development of therapies.

We will train PhD students, postdocs, and MSc students, exposing them to the problem of spinal cord injury and the inability of mammals, including humans to repair damage to the spinal cord. This will hopefully lead to more young researchers entering the field.

Tools and findings from this research will be widely shared, increasing the likelihood of successful translation of the project's finding into therapies.

We will be running an active and wide public engagement programme increasing awareness of and support for spinal cord injury research and offering access to scientific thinking/concepts to pupils in schools/areas with poor access to such work.