Investigation Of Direct Astrocyte-To-Neuron Conversion In Vivo In Spinal Cord Injury And ALS Mouse Models

Restricted (Penn State Only)
Author:
Redilla, Austin Scott
Area of Honors:
Biology
Degree:
Bachelor of Science
Document Type:
Thesis
Thesis Supervisors:
  • Dr. Gong Chen, Thesis Supervisor
  • Dr. Bernhard Lüscher, Honors Advisor
Keywords:
  • NeuroD1
  • Spinal Cord Injury
  • Amyotrophic Lateral Sclerosis
  • SCI
  • ALS
  • ND1
  • NGN2
  • ISL1
  • LHX3
  • astrocyte-to-neuron conversion
Abstract:
In cases of injury or disease, such as spinal cord injury (SCI) and Amyotrophic Lateral Sclerosis (ALS), the human central nervous system (CNS) has limited ability to repair itself through neurogenesis. One potential treatment would be to generate new neurons in these patients to replace the neurons dying from injury or disease. Previously, we have found the overexpression of NeuroD1 (ND1) in mature astrocytes is sufficient to reprogram these cells and transform them into adult, functional neurons. Herein, I have analyzed the utility of this astrocyte-to-neuron conversion technology in SCI and ALS mouse models. Both our stab injury and transgenic mouse models were able to accurately replicate the major pathological hallmarks of neuron loss, gliosis, and inflammation in reaction to injury and disease. In our SCI model, a suspension of viruses expressing the developmental genes NGN2, ISL1, and LHX3 was used to target astrocytes for conversion into motor neurons. In the area of viral infection a lower amount of neuron loss was observed 4 weeks post injury and some infected cells were identified as motor neurons. In our ALS model, the ND1 virus was expressed mostly in astrocytes at early time points, and mostly in neurons at later time points, suggesting conversion of astrocytes into neurons. Moreover, the discovery of cells in a transitional state from astrocyte to neuron and healthier appearing motor neurons in ND1 infected tissue further support the transformative and beneficial effects of the ND1 treatment. While these results are a promising start and begin to explain how ND1 and related transcription factors can be used in treating CNS injury and disease, more studies and a deeper investigation of the beneficial impacts are required to determine the full extent of its potential.