Regenerative Medicine – Treatment With Induced Pluripotent Stem Cells
New developments in the use of induced pluripotent stem cells (iPS cells) are appearing every month in the literature. The initial hurdle is to be able to reprogram adult human cells without using agents that might cause cancer. The first reprogramming method used a viral delivery system to introduce the reprogramming genes into cells. But a virus can insert into the cell’s genome, possibly causing severe unanticipated outcomes such as cancer.
Also, refinement of the reprogramming factors is necessary. The initial group was composed of Oct-4, c-Myc, Sox2, and Klf4 genes. c-Myc has potent oncogenic properties – expression of c-Myc can cause a cell to become cancerous. c-Myc was discovered in the late 1970s – expression of c-Myc has a profound role in the development of breast cancer and has a central role in most types of human malignancies.
In order for these cells to be used safely in humans, reprogramming alternatives to c-Myc needed to be identified. An optimal scenario would be to identify alternatives to using any gene for reprogramming. Inserting new genes into a cell could result in mutations, disruption of other normal genetic processes, and additional negative effects. Such deleterious outcomes would increase in number and severity as cells and tissues introduced into a patient continue to divide and replicate.
The field is moving forward quickly. Many research teams have been successfully investigating the use of small molecules as reprogramming factors. Small molecules include very short nucleotide segments (nucleotides comprise the basis of the genetic code), peptides (amino acid sequences), and short-chain sugars. Recently a team led by Dr. Hongyan Zhou at the Scripps Research Institute in La Jolla, CA, generated induced pluripotent stem cells using direct delivery of a set of reprogramming small molecules. This groundbreaking work provides a new method of creating safer cells for potential uses in treatment and transplantation.
Initial work is being done to use iPS cells for the treatment of many serious and life-threatening diseases. Important preliminary work has been done with amyotrophic lateral sclerosis (ALS), Parkinson’s disease, sickle cell anemia, thalassemia, muscular dystrophy, and diabetes.
For example, researchers have been able to generate large numbers of iPS cells from skin cells taken from an 82-year-old woman diagnosed with ALS. These cells could be directed to become motor neurons, which could be used to replace diseased nerve cells in a patient’s spinal cord. This research proves that sufficient induced pluripotent cells can be produced from cells taken from an elderly patient. iPS cells might be used to develop treatments for other diseases which specifically affect the aged.
Sickle cell anemia has been reversed in mice using induced pluripotent stem cells derived from their own cells. Somatic cells were obtained from humanized sickle cell anemia mouse models. The cells were reprogrammed to iPS cells. The genetic defect was corrected in the pluripotent cells which were then differentiated into blood cell precursors. These normal blood-forming cells were then transplanted into the original mice, who subsequently recovered from sickle cell anemia.
This successful proof-of-concept in humanized sickle cell anemia mice points the way toward using iPS cells in the treatment of a wide variety of deadly diseases.