The role of small molecules in reprogramming human astroglial cells into neurons

Open Access
Lee, Grace
Area of Honors:
Bachelor of Science
Document Type:
Thesis Supervisors:
  • Gong Chen, Thesis Supervisor
  • Kevin Douglas Alloway, Honors Advisor
  • chemical reprogramming
  • small molecules
  • neurons
  • astrocytes
  • NeuroD1
  • conversion
  • NGN2
Previous studies have demonstrated that overexpression of a single neural transcription factor NeuroD1 can efficiently reprogram mice astrocytes into functional neurons both in vitro and in vivo (Guo et al., 2014). In this study, a combination of nine small molecules were sequentially applied to convert human astroglial cells into neurons in vitro within 8-10 days with a conversion efficiency of 67%. Protein and gene expression analyses during astrocyte-to-neuron conversion process reveal that small molecules, which modulate GSK3/WNT, TGFβ/BMP, Notch, retinoic acid, and sonic hedgehog signaling crucial for neurodevelopment, work together to activate transcription and translation of neural transcription factors NGN2 and NeuroD1. Small molecules mediate chemical reprogramming by largely inducing neuronal signals and suppressing glial fate of the human astrocytes. Small-molecule-derived human neurons are either excitatory glutamatergic or inhibitory GABAergic, and electrophysiology data show that the neurons can fire action potentials and have synchronous burst activities. This study suggests that chemical reprogramming enables a new approach to using regenerative medicine as a therapy for neurodegenerative diseases and brain injuries in future applications.