Molecular determinants of neural stem cell differentiation
Neurodegenerative diseases comprise a heterogeneous spectrum of neural disorders that cause severe and progressive cognitive and motor deficits. A histological hallmark of these disorders is the occurrence of disease-specific cell death in specific regional subpopulations of neurons, such as the loss of cholinergic neurons in Alzheimer’s disease, gaba-ergic interneurons in various forms of Batten’s disease, spiny interneurons of the basal ganglia in some forms of metabolic disease, etc. Neurodegenerative disease can also possibly occur from the loss or dysfunction of selected glial cell subsets, such as the dysfunction of supportive glial cells around somatic motor neurons in amyotrophic lateral sclerosis.
Differentiation of human pluripotent stem cells into cells of the neural lineage, therefore, has become a central focus of a number of laboratories. This has resulted in the description in the literature of several dozen methods for neural cell differentiation from human pluripotent stem cells. Among the problems associated with this are the wide variability of neural differentiation potential of different PSC lines and the lack of comparison of the resulting neural cells to those derived from the brain itself.
PSCs, because of their broad neuro-developmental potential, are expected to help provide a therapeutic cure for a wide variety of neurodegenerative diseases. To achieve this expectation, we need to identify all the factors involved in neural differentiation such that our understanding of the mechanisms involved becomes more complete. Moreover, we need to be capable of manipulating differentiation pathways such that desired subtypes of neuronal progenitors can be selected that will provide functional phenotypes upon transplantation.
We are taking a whole genome expression analysis approach to help identify markers and networks of gene associated with distinct stages of neural differentiation and also inhibition of neural differentiation. We hypothesize that once such factors are identified, we may be able to more readily generate and isolate a transplantable population of neural cells.
Current conservative estimates indicate that at least 16 million individuals in the US (2 million in California alone) are afflicted and currently living with a brain disease. This incidence may be higher as the estimates exclude rare disorders and childhood neurological disorders such as neuro-metabolic diseases and autism. An estimated 16% of California households may be dealing with the care of a loved one with brain disease. Many of the diseases (Alzheimer’s, Stroke and Parkinson’s) that affect the brain are progressive and their incidence and prevalence increase with age. By 2020, it is estimated that almost 1 million people will be aged 85+ in California alone, with a high proportion (36%) having moderate or severe neurological function. This represents an immense challenge to California’s health care system.
Neural stem cell (NSC) populations have great potential for revolutionizing medicine by providing successful neuroprotective or regenerative therapy for brain disease following transplantation. The use of neural stem cells in the clinical therapy of brain disease and injury continues to remain an area of intense focus. The recent groundbreaking work of the derivation of induced pluripotent stem cells (iPSCs) from human somatic cells has additionally created the reality of deriving immune matched NSCs from adult cells such as skin. However, difficulties in the development of these potential therapies relate to insufficient tools to isolate, identify and characterize NSC populations. We propose to further develop existing molecular pathway analysis tools to identify a "NeuroNet" or molecular fingerprint (s) specific for NSC and neural induction/differentiation pathways from embryonic - derived NSCs, brain - derived NSCs and iPSC - derived NSCs. Realizing the full potential of all such NSCs as a source of defined cells for cell based neurological therapies will ultimately require a critical in - depth knowledge of factors present within these cells that are responsible for inducing an early neural phenotype and for orchestrating differentiation down specific neural lineage(s). Defining the NeuroNet will be instrumental in facilitating both new discoveries in neural development and providing a means of simplifying characterization and quality control of these cells and, most importantly, guiding neural differentiation into clinically useful cell types.