Project description
Changing human glial cells into neurons could revolutionise nervous system repair
The human brain contains billions of neurons and glial cells, the latter of which perform critical functions that help neurons do their jobs well. With the discovery that cells other than stem cells can be reprogrammed after 'maturity' to change their identities, the prospect of reprogramming human glial cells to become neurons has exciting implications for nervous system repair and rehabilitation. There have been few studies to date on the subject and no conclusive evidence on its clinical relevance. ReproXimera may change that with novel in vivo investigations reprogramming human glial cells that have been transplanted into a mouse's brain.
Objective
Studies during last decade have shown that the genetic programs underlying cell identity are plastic even in fully differentiated cells. Direct lineage reprogramming takes advantage of this plasticity to induce cell fate conversions from one cell type into another. The host laboratory is among those who have pioneered successful lineage reprogramming of glial cells into induced functional neurons in vitro and in vivo. These studies have largely focused on murine glia. While there is sparse evidence that also human glia can be reprogrammed into induced neurons, it is unclear whether such lineage conversion can occur within the constraints of the in vivo tissue context by fully integrated mature human glia. In this project I propose an experimental model to study direct lineage reprogramming of human astrocytes into induced neurons at distinct developmental stages within the context of the adult mouse brain in vivo. This model is based on previous findings that show that human astroglial progenitors can integrate into the mouse brain following grafting, maintaining hallmarks that are specific to human astroglia which differ markedly in their complexity from their murine counterparts. Here I will combine this model system with the directed glial differentiation of induced human pluripotent stem cells (hiPSC) and state-of-the-art genome-editing via CRISPR-Cas9 technology. This will enable me to derive transplantable glial progenitors that can be induced to undergo lineage conversion in a humanized in vivo context at distinct maturation stages. With this approach I will obtain important insights into the fundamental question of how the state of maturation and functional integration determines the capacity of human astroglia to undergo lineage conversion into functional neurons in vivo. I expect that the data resulting from this approach will have important implications towards the translation of direct lineage reprogramming into new strategies for brain repair.
Programme(s)
Funding Scheme
MSCA-IF-EF-ST - Standard EFCoordinator
WC2R 2LS London
United Kingdom