Author: Caitlin E. Devor
Institution: Allegheny College
Date: September 2012
A new stem-cell derived model of metabolic diseases affecting neurons was developed at Virginia Commonwealth University in an effort to solve the short comings of current paradigms.
Studies of human disease rely on models in order to avoid experiments with human subjects. Some models use whole organisms, such as fruit flies or mice, while other models use individual cells growing in dishes. The better a model is at replicating real life conditions, the more desirable it is for researchers.
Current models for diseases affecting the mitochondria are imperfect replicas of the cells in patients with these diseases. When a model uses cells with a different developmental origin than that of the diseased cells in a patient, it creates a gap between discoveries made using the model and potential applications in patients.
One of the most common mitochondrial disorders, Leber's hereditary optic neuropathy (LHON), is a genetic disease that causes loss of central vision due to atrophy of the optic nerve. The current models for LHON rely on tumor cells carrying mitochondria originally taken out of blood cells. Tumor cells have different metabolisms than nerve cells, and the mitochondria from blood cells may not be identical to those in nerve cells.
These imperfections in the current LHON model were addressed by researchers from Virginia Commonwealth University, who developed a new model of neurological mitochondrial disease. The new model uses human neural progenitor cells (hNP), which are derivatives of stem cells that are capable of developing into any type of nerve cell. The hNPs were depleted of their own mitochondria by exposure to a chemical called dideoxycytidine. Dideoxycytidine (ddC) does kill some of the hNP cells, but those that survive express their normal mitochondria genes between 83 and 59 percent less than before ddC treatment.
DNA from the mitochondria of a patient with LHON was then allowed to enter the cells treated with ddC. With this DNA, cells started to express the disease mutations, making them a realistic LHON model. To ensure the cells could stay stable for a useful length of time, the researchers monitored mitochondrial gene expression over the next 48 hours. Excitingly, those model cells continued to express the disease mutations for the entirety of those 48 hours. Additionally, cells carrying LHON mutations could differentiate into different types of nerve cells exactly as is expected of control hNPs, indicating the manipulations used to develop the model do not change the overall biology of the cells.
The development of a new cell culture model of mitochondrial disease in neurons represents opportunities to study LHON in greater detail. Furthermore, the method of introducing mitochondrial DNA with disease causing mutations into hNPs can also be applied to other diseases with metabolic and neurological origins.
The full article, "Mitochondrial gene replacement in human pluripotent stem cell-derived neural progenitors" was published in the 19 May 2012 edition of Gene Therapy.