Induced Pluripotent Stem Cells: The Past, Present and Future

by Lauren Lin

Induced pluripotent stem cells (or iPSC) are stem cells that are made by reprogramming already specialized adult cells into a pluripotent state that is similar to that of an embryonic stem cell.  As a result, these induced pluripotent stem cells are able to differentiate into any cell type in the body.  This technology was developed by Shinya Yamanaka and Kazutoshi Takahashi at Kyoto University in 2006 when they infected adult skin cells from mice with viruses to introduce 24 genes that they believed to be necessary for cells to behave like embryonic stem cells.  Later on, they were able to identify that there were only four genes, each of them encoding for a transcription factor, that were needed to reprogram adult cells into pluripotent cells.  These genes were Oct4, Sox2, Myc, and Klf4.

iPS cells are now widely used within many areas of research, but the iPS cell lines cultured in different labs don’t seem to be consistent, as many papers have reported results that other researchers haven’t been able to replicate.  Additionally, there is still research being done to investigate which types of adult cells are able to be reprogrammed, which cells the iPSC can differentiate into, and whether or not reprogramming can take place without Myc, since it has the potential to turn cells cancerous.  It has also been discovered that iPSCs aren’t exactly the same as embryonic stem cells, since they hold onto a certain kind of “epigenetic memory.”  This means that the cells have retained the chemical changes associated with whichever adult cell they originated from.  However, some scientists don’t believe that this epigenetic memory will end up interfering with the results of research conducted with iPSC.  

When iPSC techniques were first developed, researchers originally thought that it would be primarily used for regenerative medicine. It was thought that they could reprogram a person’s skin or blood cells into iPSCs, then differentiate these cells into whichever cell type was needed to treat a disease.  For example, people with neurological disorders could have new neurons made to treat their condition.  The idea that iPSCs could be used for regenerative medicine was especially exciting because it seemed to be able to avoid both the problem of immune rejection and the ethical issues that arise from using stem cells from embryos in therapy.  

In 2013, Masayo Takahashi worked with Yamanaka to develop stem cell treatments for retinal diseases.  Takahashi and her team reprogrammed skin cells from patients with an eye condition called age-related macular degeneration (AMD) into iPSCs, which were then used to make retinal pigment epithelium (RPE) cells.  Sheets of RPE cells were implanted into a patient in 2014, and the progression of the patient’s macular degeneration seemed to stop.  However, before a second trial was started, they found a few genetic changes in the second patient’s iPS cells and RPE cells.  It wasn’t conclusive whether or not the mutations were cancerous, but the trial was halted and only resumed in June 2016.  When Takahashi’s work was stopped, other researchers developing iPS-cell-based therapies also put their projects on hold.  Now that the clinical trials for AMD are set to begin again, researchers hope to start new clinical trials that examine the use of iPSCs for other diseases, such as Parkinson’s disease.

Currently, iPS cells are heavily used in research, especially for newly developed drugs and the progression of human diseases.  The ability to culture iPS cells and to differentiate these cells into any body cell has allowed researchers to culture human tissues that would have previously been difficult to access.  Additionally, while clinical trials have experienced setbacks, iPSC technology has been continuously refined and used for other studies.  For example, some researchers have been using CRISPR-Cas9, a gene-editing tool, to introduce mutations into iPS cells to look at the effects of the mutation and to compare the mutated cell lines with control cell lines.  The research that studied the link between the Zika virus and microcephaly, a condition in which an infant is born with a head that is abnormally small, used the ability of iPSCs to model early human development.  Dr. Guo-li Ming used cortical neural progenitor cells, iPSCs, and immature neurons to discover that the cells that go on to form the brain’s cortex are “potentially susceptible to the virus, and their growth could be disrupted by the virus.”
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Although it will still take a very long time to understand certain diseases and to develop new drugs or cell therapies, iPSCs are valuable tools that researchers can use, either as models for human tissue or as treatments themselves.  iPSCs have already contributed to many scientific advances, and there may be potential uses for them that have yet to be explored.