Promoting self-repair after Spinal Cord Injury
Lead Research Organisation:
University of Manchester
Department Name: School of Medical Sciences
Abstract
Mammals, including humans, have a poor ability to repair their spinal cord upon injury. About 27 million people worldwide suffer long-term disability following spinal cord injury (SCI). Depending on the severity of the injury it can cause irreversible damage, which can lead to the loss of motor and sensory function below the site of the damage. This has far reaching consequences for the life of patients affected by SCI as they face lifelong confinement in a wheelchair, dependency on medical care and the risk of premature death. Therefore, there is a high requirement for improving regenerative capabilities of the spinal cord after injury.
However, some vertebrates, such as zebrafish, the newt Axolotl and the tadpoles of the amphibian Xenopus can regenerate their spinal cord. Animal models are essential for biomedical research and Xenopus has unique advantages. It is easy to obtain large number of eggs, which develop externally and are accessible at all stages of development. The genome of Xenopus tropicalis has been sequenced and shows striking similarities with the human genome, meaning that findings from Xenopus provide insight into many human conditions and diseases. Finally, Xenopus sits at an interesting juncture in term of regeneration. During its tadpole stages, Xenopus can regenerate most tissues including its spinal cord however this ability is lost after metamorphosis, allowing comparative studies within one species.
We and others have developed tools and resources to make Xenopus a relevant model to study spinal cord development, function and regeneration. The spinal cord is a complex tissue comprising undifferentiated cells (called progenitors) and many different types of differentiated neurons that need to work together. We have shown that the Xenopus spinal cord is very similar to that of mammals, making it a relevant model to study its regeneration. A hallmark of successful repair of regeneration of neural tissue is the ability of progenitors to generate new neurons, a process known as neurogenesis.
The goal of this project is to uncover the mechanisms that promote neurogenesis during spinal cord regeneration in Xenopus. We will then use this knowledge to stimulate neurogenesis in a mammalian model of spinal cord injury. This research will provide an important platform to develop innovative strategies to improve the outcome of patients suffering from spinal cord injury.
However, some vertebrates, such as zebrafish, the newt Axolotl and the tadpoles of the amphibian Xenopus can regenerate their spinal cord. Animal models are essential for biomedical research and Xenopus has unique advantages. It is easy to obtain large number of eggs, which develop externally and are accessible at all stages of development. The genome of Xenopus tropicalis has been sequenced and shows striking similarities with the human genome, meaning that findings from Xenopus provide insight into many human conditions and diseases. Finally, Xenopus sits at an interesting juncture in term of regeneration. During its tadpole stages, Xenopus can regenerate most tissues including its spinal cord however this ability is lost after metamorphosis, allowing comparative studies within one species.
We and others have developed tools and resources to make Xenopus a relevant model to study spinal cord development, function and regeneration. The spinal cord is a complex tissue comprising undifferentiated cells (called progenitors) and many different types of differentiated neurons that need to work together. We have shown that the Xenopus spinal cord is very similar to that of mammals, making it a relevant model to study its regeneration. A hallmark of successful repair of regeneration of neural tissue is the ability of progenitors to generate new neurons, a process known as neurogenesis.
The goal of this project is to uncover the mechanisms that promote neurogenesis during spinal cord regeneration in Xenopus. We will then use this knowledge to stimulate neurogenesis in a mammalian model of spinal cord injury. This research will provide an important platform to develop innovative strategies to improve the outcome of patients suffering from spinal cord injury.
Technical Summary
Understanding how some organisms successfully achieve spinal cord (SC) regeneration is a longstanding question with profound implications for human health. This is especially true for the SC given the poor ability of mammals to regenerate their central nervous system. About 27 million people worldwide suffer long-term disability following SC injury (SCI).
In mammals, astrocyte activation, fibroblast/pericyte proliferation and the immune response contribute to a scar environment that is inhibitory to functional repair. However, many species such as zebrafish, axolotl and Xenopus tadpoles are able to regenerate their SCs after injury. After SCI in mammals, resident neural progenitor cells (NPCs) are activated, re-enter the cell cycle but differentiate into astrocytes. By contrast, in regenerative species NPCs differentiate into neurons. Furthermore, we have identified Foxm1 as an intrinsic factor promoting neuronal differentiation during regeneration in Xenopus. This led us to hypothesise that understanding the neurogenic programme of regenerative species will allow us to unlock the intrinsic ability of mammalian NPCs to differentiate into neurons promoting endogenous repair after SCI.
To test this hypothesis, we will use state of the art techniques such as single cell RNAseq, genome engineering and reprogramming of NPCs to (i) delineate the transcriptional trajectories leading to neurogenesis in intact and regenerating spinal cord in Xenopus (ii) functionally identify regeneration-specific key regulators (iii) develop a new ex vivo model to improve the neurogenic potential of mammalian NPCs and (iv) evaluate the effect of promoting neurogenesis after SCI in a mouse model.
In mammals, astrocyte activation, fibroblast/pericyte proliferation and the immune response contribute to a scar environment that is inhibitory to functional repair. However, many species such as zebrafish, axolotl and Xenopus tadpoles are able to regenerate their SCs after injury. After SCI in mammals, resident neural progenitor cells (NPCs) are activated, re-enter the cell cycle but differentiate into astrocytes. By contrast, in regenerative species NPCs differentiate into neurons. Furthermore, we have identified Foxm1 as an intrinsic factor promoting neuronal differentiation during regeneration in Xenopus. This led us to hypothesise that understanding the neurogenic programme of regenerative species will allow us to unlock the intrinsic ability of mammalian NPCs to differentiate into neurons promoting endogenous repair after SCI.
To test this hypothesis, we will use state of the art techniques such as single cell RNAseq, genome engineering and reprogramming of NPCs to (i) delineate the transcriptional trajectories leading to neurogenesis in intact and regenerating spinal cord in Xenopus (ii) functionally identify regeneration-specific key regulators (iii) develop a new ex vivo model to improve the neurogenic potential of mammalian NPCs and (iv) evaluate the effect of promoting neurogenesis after SCI in a mouse model.
