Processes that lead to dysfunction or even death of neurons are causing irreversible and devastating damage to the brain, and thereby gravely affect the life of millions of patients, the people close to them, and the societies in which they live. One approach followed by researchers and clinicians aims at replacing dysfunctional or degenerated neurons. Classically, such cell-based therapy has been conceived as grafting new neurons in the brain area or close to where the original neurons had degenerated. Indeed, animal studies as well as ongoing clinical trials indicate that cell replacement can be a viable strategy towards restoring lost brain function.
However, we are exploring an alternative strategy that is based on the plasticity of cells to change their cell identity by rewiring their gene expression programmes. This process is referred to as lineage reprogramming. Recent years have provided evidence for the possibility of converting brain support cells referred to as glia into induced neurons in vivo by imposing the expression of key regulators of cell fate such as transcription factors. These play often a key role in determining neuronal fate during embryonic development but can be experimentally reused to induce an alternative fate that is in demand because of disease. The conceptual advantage of such glia-to-neuron conversion for brain repair is that cells generated in this way have the same genetic makeup as all other cells around, and hence do not cause an immunogenic response. Moreover, it is possible to envisage that ultimately this strategy could become largely non-invasive, albeit there are still many technical challenges to be overcome prior to that.
However, before such approach could become a clinical reality, important questions need to be addressed experimentally. The molecular processes by which glial cells give up their original identity and adopt a neuronal fate remains by and large enigmatic. We need to know how similar induced neurons can become to those they ought to replace. Moreover, it is unclear how neurons induced from glia may integrate into the pre-existing circuits of non-neurogenic brain regions such as the cerebral cortex which normally do not accommodate new neurons ever during an entire lifetime. Finally, can they participate in cortical information processing and even restore dysfunctional cortical circuits? In the project IMAGINE, we aim at elucidating these questions.
