Basic and clinical neuroscience applications of embryonic stem cells.

There have been recent dramatic advances in our understanding of the molecular mechanisms governing the elaboration of mature tissue-specific cellular subpopulations from embryonic stem (ES) cells. These investigations have generated a range of new biological and potential therapeutic reagents to allow us to dissect specific stages of mammalian development that were previously experimentally inaccessible. Ultimately, we will be able to reconstitute seminal signaling pathways to promote regeneration of the nervous system. Totipotent ES cells possess an unlimited proliferative capacity that make them attractive candidates for use in a series of innovative transplantation paradigms. Elucidation of the molecular and physiologic properties of ES cells also has important implications for our understanding of the integrative cellular processes underlying neural induction, patterning of the neural tube, neural lineage restriction and commitment, neuronal differentiation, regional neuronal subtype specification, and the specific pathological consequences of alterations in discrete components of these fundamental neurodevelopmental pathways. In addition, recent experimental observations suggest that neurodegenerative disease pathology may involve alterations in a range of progressive neural inductive and neurodevelopmental events through novel biological mechanisms that result in sublethal impairments in cellular homeostasis within evolving regional neuronal precursor populations containing the mutant proteins, culminating in increased vulnerability of their differentiated neuronal progeny to late-onset apoptosis. Future discoveries in ES cell research will offer unique conceptual and therapeutic perspectives that representing an alternative to neural stem cell therapeutic strategies for ameliorating the pathologic consequences of a broad range of genetic and acquired insults to the developing, adult, and aging brain. Evolving regenerative strategies for both neurodevelopmental and neurodegenerative diseases will likely involve the targeting of vulnerable regional neural precursor populations during "presymptomatic" clinicopathological stages prior to the occurrence of irrevocable neural cell injury and cell death.