Mechanism and Utility of Direct Neuronal Conversion with a MicroRNA-Chromatin Switch
Many human diseases and injuries that affect the brain and nervous system could potentially be treated by either introducing healthy neurons or persuading the cells that normally provide supporting functions to become functioning neurons. A number of barriers must be traversed to bring these goals to practical therapies. Recently our laboratory and others have found ways of converting different human cell types to functioning neurons. Surprisingly, two routes for the production of neurons have been discovered. Our preliminary evidence indicates that these two routes are likely to work together and therefore more effective ways of producing neurons can likely be provided by understanding these two routes, which is one aim of this application. Another barrier to effective treatment of human neurologic diseases has been the inability to develop good models of human neurologic disease due to inability to sample tissues from patients with these diseases. Hence we will understand ways of making neurons from blood cells and other cells, which can be easily obtained from patients with little or no risk. Our third goal will be to understand how different types of neurons can be produced from patient cells. We would also like to understand the barriers and check points that keep one type of cell from becoming another another type of cell. Understanding these mysterious processes could help provide new sources of human cells for replacement therapies and disease models.
The state of California and its citizens are likely to benefit from the work described in this proposal by the development of more accurate models for the testing of drugs and new means of treatment of human neurologic diseases. Presently these diseases are among the most common afflicting Californians, as well as others and will become more common in an aging population. Common and devastating diseases such as Alzheimer’s, Schizophrenia, Parkinson's Disease, and others lack facile cell culture models that allow one to probe the basis of the disease and to test therapies safely and without risk to the patient. Our work is already providing these models, but we hope to make even better ones by understanding the fundamental processes that allow one cell type (such as a skin cell or blood cell) to be converted to human neurons, where the disease process can be investigated. In the past the inability to make neurons from patients with specific diseases has been a major roadblock to treatment. In the future the studies described here might be able to provide healthy neurons to replace ones loss through disease or injury.
During the past year, our laboratory has investigated the way that human skin cells can be changed to neurons. To do this, we have used a natural switch that occurs as embryonic cells decide to become neurons. We have found that this process proceeds in a highly ordered series of stages that involve first a resetting of fundamental cell biologic processes characteristic of neurons. This is followed by activation of genes encoding proteins that allow different types of neurons to interact and develop communication between one another. This finding surprised us since we expected to find changes in transcription factors, which instruct the formation of neurons. Instead, we find that the natural switching mechanism in neurons first regulates cell-to-cell communication.
We are exploring the way that normal human skin and other types of cells can be converted to neurons. We have found that there are at least two fundamental genetic pathways of doing this that are influenced by different genes and may therefore represent a fertile ground for developing new methods for converting cells of different types to neurons. This could perhaps be useful for replacing neurons from other cell types in states where neurons are damaged or lost such as a variety of neurodegenerative diseases.
- J Neurosci (2013) Kinetic Analysis of npBAF to nBAF Switching Reveals Exchange of SS18 with CREST and Integration with Neural Developmental Pathways. (PubMed: 23785148)
- Nat Rev Genet (2013) From neural development to cognition: unexpected roles for chromatin. (PubMed: 23568486)