Regulation of Stem Cell Differentiation in Development and Disease
Neural Stem Cells
My laboratory is interested in studying the differentiation of stem cells into specifictypes of neurons, in particular ventral midbrain dopaminergic neurons that degenerate in Parkinson’s disease and spinal motor neurons that are lost in spinal muscular atrophy (SMA) and amyotrophic lateralsclerosis (ALS). We want to understand what gene expression programs and epigenetic modifications are utilized to direct stem cells to adopt a specific fate. To address this question, we use induced pluripotent stem (iPS) cells reprogrammed from fibroblasts, mouse embryonic stem (ES) cells, embryonic chick neural tubes, and genetically modified mice as model systems.
A fundamental question in developmental neurobiology is how a relatively homogeneous population of neural stem cells/progenitors differentiates into an enormously diverse array of neuronal cell-types, which interconnect with extraordinary specificity to form functional neural circuits. Midbrain dopaminergic neuron differentiation represents a unique and interesting system to address this question. Dopaminergic neurons located at the ventral midbrain control movement, emotional behavior and mechanisms of reward. Degeneration of midbrain dopaminergic neurons leads to Parkinson’sdisease, which affects one in every thirty-five people over the age of sixty. Dysregulation of dopaminergic transmission has also been implicated in the development of drug addiction, depression and schizophrenia. Recently, it was found that basic helix-loop-helix transcription factor Neurogenin2 (Ngn2) is expressed in midbrain dopaminergic neural progenitors and is essential for their differentiation. This discovery provided a molecular handle for the first time to study the specification of dopaminergic cell fate in proliferating neural progenitors. In addition, although morphogen sonic hedgehog (Shh) and fibroblast growth factor 8 (FGF8) have been shown to play critical roles in inducing midbrain dopaminergic neuron formation, a critical gap exists in our understanding of the mechanisms by which cell-extrinsic signals regulate intrinsic transcriptional programs to control neural stem cell fate specification. We want to use Ngn2 as an entry point to identify the transcriptional networks controlling dopaminergic fate specification. We also hope to learn what epigenetic modifications induced by cell-extrinsic signals are utilized to control the activation and repression of genes during stem cell differentiation.
Guided differentiation of stem cells to adefined type of neuron holds great promise for cell replacement therapy, disease modeling and regenerative medicine. It is our hope that studying these mechanisms will not only provide a better understanding of fundamental developmental issues such as stem cell fate specification and progenitor domain patterning, but also eventually lead to the development of novel therapies for Parkinson’sdisease and other neurodegenerative disorders.
Cancer Stem Cells
We are also interested in characterizing cancer stem cells from various tumors including medulloblastoma, the most prevalent pediatric tumor, to facilitate the development of therapeutics capable of eliminating them. The traditional model of cancer development considers that tumors arise from a series of sequential mutations. More recently, a new model has been proposed that tissue stem cells undergo mutations that deregulate their self-renewal pathways, leading to tumor formation. We are interested in:
1. Isolating and characterizing cancer stem cells from solid tumors by using genetic cell-lineage tracing approach;
2. Identifying the defects that lead to the development of cancer stem cells;
3. Developing novel models that are capable of interrogating the effect of therapeutics on cancer stem cells.