Inhalt:
Interneurons, the most abundant neuronal class in the CNS, are critical to transducing synaptic information within and between neural networks for proper neurologic function. In the hindbrain and spinal cord, ventral interneurons are key components of pattern generators that control respiration and locomotion. Disruption of the interneurons by disease or injury can disrupt the pattern generators and lead to debilitation. Elucidating how these interneuron populations develop, as well as their roles in pattern generation, can lead to potential repair strategies for damaged circuits. While murine models have provided insight on interneuron development and circuitry, human populations may develop and function differently. Human pluripotent stem cell (hPSC)-derived neural populations provide a source to study human development and circuitry when alternative tissues are unavailable. This dissertation describes three studies that derive caudal interneuron populations from hPSCs. In the first study, V2a interneurons, a population involved in respiratory control and left-right coordination are differentiated from hPSCs. The V2a interneurons appropriately mature and survive to form long extensions following transplantation into an uninjured murine spinal cord. In the second study, multiple interneuron populations critical to respiratory control are specified from hPSCs. This study demonstrates the ability to describe multiple tissue-specific populations from one combination of signaling molecules. In the final study, a respiratory organoid is described that contains populations critical to respiratory control. This model provides a platform to probe how disruption of neural networks leads to respiratory distress. Together, this work is the first to describe multiple interneuron populations from hPSCs. These caudal interneurons can be used to study human development, test new drugs, and establish therapies to reconnect neural networks following injury or disease. Additionally, these studies provided a systematic approach to co-emerge multiple neural populations that could be broadly applied to describe other neural populations.
Anmerkung:
Dissertation eScholarship, University of California 2018
Sprache:
Englisch
