Stem cells have the unique ability to self-renew (make more stem cells) and differentiate (specialize into a number of different cell types). There are three main types of stem cells already on the scene: embryonic stem cells, adult stem cells and induced pluripotent stem (iPS) cells. iPS cells are engineered by reprogramming fully differentiated adult cells, often skin cells, back to a primitive state. Like their embryonic cousins, iPS cells can form all cell types. Researchers are currently working to harness the flexibility of stem cells to replace damaged tissue and treat conditions like diabetes and heart disease.
The iPS cell approach to regenerative medicine is tantalizing because these cells could be derived from a patient’s own cells and are therefore less likely to face immune rejection. In the past few weeks, however, a slew of papers have indicated that the therapeutic potential of iPS cells might be limited by reprogramming errors and genomic instability. Given these problems, researchers from Sanford-Burnham, Chung-Ang University in Korea, University of British Columbia, Harvard Medical School and elsewhere wondered if there might be a better way to regenerate lost tissue to treat conditions like heart disease and stroke. Writing March 4 in the Proceedings of the National Academy of Sciences, they outline a method to obtain a new kind of stem cell they call induced conditional self-renewing progenitor (ICSP) cells.
With the addition of a single gene, the team instructed neural progenitor cells – a type of brain cell that can generate other types of brain cells – to self-renew in a laboratory dish. Once they had enough, the researchers moved the ICSP cells to a rodent stroke model, where the cells stopped proliferating, started differentiating and improved brain function.
“It’s amazingly cool that we can dial adult cells all the way back to embryonic-like stem cells, but there are a lot of issues that still need to be addressed before iPS cells can be used to treat patients,” says Dr. Evan Y. Snyder, director of Sanford-Burnham’s Stem Cells and Regenerative Biology Program and one of the study’s senior authors. “So we wondered… if we just want to treat a brain disease, do we really have to start with a skin cell, which has nothing to do with the brain, and push it all the way back to the point that it has potential to become anything? In this study, we developed ICSP cells using a cell from the organ we’re already interested in – the nervous system, in this case – and pushed it back just enough so it continued to divide, giving us a quantity that we were able to apply efficiently, safely and effectively to treat stroke injury in a rodent model.”
Here’s how ICSP cells work: Researchers use a viral vector to introduce a gene called v-Myc into neural progenitor cells. Myc, one of four standard genes already used to generate iPS cells, triggers self-renewal, guiding cells through the replication process. Scientists are sometimes cautious when it comes to adding genes like Myc – if cells keep dividing after transplantation in a patient, cancer could develop – but v-Myc is known to be safer than other flavors of Myc. What’s more, the v-Myc used here is conditionally expressed. This means that ICSP cells can only produce v-Myc when the researchers add a compound called tetracycline to laboratory cultures. When tetracycline is removed, the cells cease dividing and start differentiating. Then, once transplanted into an animal model, ICSP cells are no longer exposed to tetracycline and take their growth and differentiation cues from their new environment.
In this study, ICSP cells differentiated into active neurons and other brain cell types with therapeutic payoff for an adult rat model of intracerebral hemorrhagic stroke – the rodents showed improved behavioral performance. Although the long-term genomic stability of ICSP cells remains to be seen, no adverse effects have arisen over five months of observation. The team envisions that this ICSP approach will also extend to progenitor cells obtained from other organs, such as heart, pancreas, or muscle, potentially accelerating the use of stem cell therapies for a broad range of diseases.
For more on the short history of reprogrammed stem cells, read Ed Yong’s Research into reprogrammed stem cells: an interactive timeline.
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Original Paper:
Kim, K., Lee, H., Jeong, H., Li, J., Teng, Y., Sidman, R., Snyder, E., & Kim, S. (2011). Self-renewal induced efficiently, safely, and effective therapeutically with one regulatable gene in a human somatic progenitor cell Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.1019743108
