Stem cells are found in all multicellular organisms. They are a promising source for replacement therapies in diseases of the nervous system and are commonly used for interventions involving bone marrow transplantation, various cancers, and muscular dystrophy.
It is now possible to generate stem cells (named iPSC) from skin fibroblasts derived from patients suffering from chronic neurodegenerative diseases. This can be done by transducing a combination of pluripotency reprogramming factors to sustain the epigenetic status of the genome crucial in maintaining pluripotency. Currently, huge efforts are being made to find a simple and safe method free of exogenous DNA integration. These cells are similar to embryonic stem cells (ES) that may cause teratoma when transplanted. In order to develop iPSCs for clinical use, these cells have to be engineered to completely safety. One way to harness these cells is to differentiate them into desired specialised cells that are no longer capable to form tumours. In order to do so, it is important to understand how their gene expression will be altered to adopt new cell fates.
We study mechanisms of neuronal lineage commitment, focusing particularly on the orphan nuclear receptor TLX (Drosophila tail-less homologue, also named NR2E1), which is indispensable to maintain adult neural stems. TLX is expressed in the adult neural stem cells in close proximity of the lateral ventricles and in the hippocampus, where they are born and maintained in an undifferentiated state. We have recently discovered that TLX is enhanced by hypoxia, binding and inducing the pluripotency gene Oct3/4 promoter in adult hippocampal progenitors. The presence of FGF independently upregulates TLX, synergizing with hypoxia to stimulate proliferation and maintenance of progenitors. Conversely, depletion of TLX induces apoptosis of neuroprogenitors. We also study the role of TLX in the etiologies of common neuropsychiatric disorders, such as mood disorders, dementia, and states of cognitive deficit. TLX expression is enhanced in tumour-initiating cells (also known as cancer stem cells) of neuroblastoma, the most common solid tumour in childhood, and malignant glioma, a tumour of the brain or spine and one of the most therapy-resistant tumours in adulthood.