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- Molecular and Cellular Transitions from ES Cells to Mature Functioning Human Neurons
Human embryonic stem cells (hESCs) are pluripotent entities, capable of generating a whole-body spectrum of distinct cell types. We have developmental procedures for inducing hESCs to develop into pure populations of human neural stem cells (hNS), a step required for generating authentic mature human neurons. Several protocols have currently been developed to differentiate hESCs to what appear to be differentiated dopaminergic neurons (important in Parkinson’s disease (PD) and cholinergic motor neurons (important in Amyolateral Sclerosis (ALS) in culture dishes. We have developed methods to stably insert new genes in hESC and we have demonstrated that these transgenic cells can become mature neurons in culture dishes. We plan to over express alpha synuclein and other genes associated with PD and superoxide dismutase (a gene mutated in ALS) into hESCs and then differentiate these cells to neurons, and more specifically to dopaminergic neurons and cholinergic neurons using existing protocols. These transgenic cells can be used not only for the discovery of cellular and molecular causes for dopaminergic or cholinergic cell damage and death in these devastating diseases, but also can be used as assays to screen chemical libraries to find novels drugs that may protect against the degenerative process. Until recently the investigation of the differentiation of these human cells has only been observed in culture dishes or during tumor formation. Our recent results show that hESC implanted in the brains of mice can survive and become active functional human neurons that successfully integrate into the adult mouse forebrain. This method of transplantation to generate models of human disease will permit the study of human neural development in a living environment, paving the way for the generation of new models of human neurodegenerative and psychiatric diseases. It also has the potential to speed up the screening process for therapeutic drugs.
We plan to develop procedures to induce human ES cells into mature functioning neurons that carry genes that cause the debilitating human neurological diseases, Parkinson’s disease and Amyolateral Sclerosis (ALS). We will use the cells to reveal the genes and molecular pathways inside the cells that are responsible for how the mutant genes cause damage to specific types of brain cells. We also will make the cells available to other researchers as well as biotech companies so that other investigators can use these cells to screen small molecule and chemical libraries to discover new drugs that can interfere with the pathology caused by these mutant cells that mimic human disease, in hopes of accelerating the pace of discovery.
Publications
- Nature (2012) Probing sporadic and familial Alzheimer's disease using induced pluripotent stem cells. (PubMed: 22278060)
- Cell Stem Cell (2012) Modeling brain disease in a dish: really? (PubMed: 22704498)
- Proc Natl Acad Sci U S A (2012) Cord blood-derived neuronal cells by ectopic expression of Sox2 and c-Myc. (PubMed: 22814375)
- Curr Protoc Stem Cell Biol (2012) Dopaminergic differentiation of human pluripotent cells. (PubMed: 22872424)
- Eur J Neurosci (2011) Neurodegenerative disease and adult neurogenesis. (PubMed: 21395858)
- Mol Ther (2011) Rapid and Efficient Generation of Functional Motor Neurons From Human Pluripotent Stem Cells Using Gene Delivered Transcription Factor Codes. (PubMed: 21772256)
- Hum Mol Genet (2011) Induced pluripotent stem cells (iPSC) and neurologic disease modeling: Progress and Promises. (PubMed: 21828073)
- Proc Natl Acad Sci U S A (2011) Ataxia telangiectasia mutated (ATM) modulates long interspersed element-1 (L1) retrotransposition in human neural stem cells. (PubMed: 22159035)
- PLoS One (2010) High-efficient generation of induced pluripotent stem cells from human astrocytes. (PubMed: 21170306)
- Cell (2010) A model for neural development and treatment of rett syndrome using human induced pluripotent stem cells. (PubMed: 21074045)
- Hum Mol Genet (2010) Pluripotent stem cells in neurodegenerative and neurodevelopmental diseases. (PubMed: 20418487)
- Cell (2010) Mechanisms underlying inflammation in neurodegeneration. (PubMed: 20303880)
- Nat Struct Mol Biol (2009) An RNA code for the FOX2 splicing regulator revealed by mapping RNA-protein interactions in stem cells. (PubMed: 19136955)
- Cell (2009) A Nurr1/CoREST pathway in microglia and astrocytes protects dopaminergic neurons from inflammation-induced death. (PubMed: 19345186)
- Nature (2009) L1 retrotransposition in human neural progenitor cells. (PubMed: 19657334)
- Hum Mol Genet (2008) Multiple layers of molecular controls modulate self-renewal and neuronal lineage specification of embryonic stem cells. (PubMed: 18632700)
- Cell Stem Cell (2008) Non-cell-autonomous effect of human SOD1 G37R astrocytes on motor neurons derived from human embryonic stem cells. (PubMed: 19041781)
- PLoS Comput Biol (2007) Alternative splicing events identified in human embryonic stem cells and neural progenitors. (PubMed: 17967047)