July 19, 2013
Researchers Take More Nuanced Approach To Making Stem Cells
Brett Smith for redOrbit.com - Your Universe Online
Stem cell studies are producing some of the most promising research results for replacing or regenerating damaged tissue, and a new study from a team of Spanish and American scientists has described a more flexible approach to creating the valuable cells.
Nobel Prize laureate Shinya Yamanaka developed the initial formula for developing induced pluripotent stem cells (iPSCs), or stem cells created by reverse-engineering a patient's own cells. The Nobel-winning formula is a stringent recipe that allows for a narrow degree of variations in human cells.
To determine the success of Yamanaka's method, stem cells' pluripotency - or the ability to differentiate into other types of cells - was evaluated by functional assays, meaning if it acts like a stem cell, then it is a stem cell.
The new study, which appeared in the journal Cell Stem Cell, turned this assumption-based analysis on its head. Led by the Salk Institute's Juan Carlos Izpisua Belmonte, the team realized pluripotency is not a type of cell, but a state achieved by a balance of opposing differentiation forces.
"Prior to this series of experiments, most researchers in the field started from the premise that they were trying to impose an 'embryonic-like' state on mature cells," said Belmonte. "Accordingly, major efforts had focused on the identification of factors that are typical of naturally occurring embryonic stem cells, which would allow or further enhance reprogramming."
Once the team realized the pursuit of an embryonic-like state wasn't essential, they were able to question the changes to four genes believed to be necessary to the process according to the prevailing method. Instead, the team found that changing the equilibrium of "lineage specifier" genes already found in a patient's cell could induce pluripotency.
"One of the implications of our findings is that stem cell identity is actually not fixed but rather an equilibrium that can be achieved by multiple different combinations of factors that are not necessarily typical of (stem cells taken from embryos)," said study co-author Ignacio Sancho-Martinez, a postdoctoral researcher at the Salk Institute.
According to the study, seven additional genes can allow for the reprogramming of cells to iPSCs. The team was also able to replace a gene from the original method called Oct4, which was thought to be indispensable to the process. Along with replacing another gene once thought essential, called SOX2, the researchers showed a completely different way for conceptualizing stem cell development.
"It was generally assumed that development led to cell/tissue specification by 'opening' certain differentiation doors," said Emmanuel Nivet, a post-doctoral researcher at the Salk Institute.
However, the researchers say their study showed just the opposite.
"Pluripotency is like a room with all doors open, in which differentiation is accomplished by 'closing' doors," Nivet said. "Inversely, reprogramming to pluripotency is accomplished by opening doors."
Belmonte noted the route taken by his team in developing the new method could assist in future cancer treatments.
"Recent studies in cancer, many of them done by my Salk colleagues, have shown molecular similarities between the proliferation of stem cells and cancer cells, so it is not surprising that oncogenes [genes linked to cancer] would be part of the iPSC recipe," he said.
"Since we have shown that it is possible to replace genes thought essential for reprogramming with several different genes that have not been previously involved in tumorigenesis, it is our hope that this study will enable iPSC research to more quickly translate into the clinic," Belmonte added.