Editors of the journal Cloning and Stem Cells selected a paper by a research team at Worcester Polytechnic Institute's Life Sciences and Bioengineering Center (LSBC) at Gateway Park as one of two "very important" papers published in the September 2009 edition. This 'editor’s choice' designation means the subscription-based journal will now provide free copies of the paper to all who are interested, so the important findings can reach a wider scientific audience.
The paper,"Induction of Stem Cell Gene Expression in Adult Human Fibroblasts without Transgenes," documents the work of a research team comprised of WPI faculty and investigators at CellThera, a private company also located at the LSBC, that has discovered a new way to turn on stem cell genes in human fibroblasts (skin cells) without the risks associated with inserting extra genes or using viruses. This discovery opens a new avenue for reprogramming cells that could eventually lead to treatments for a range of human diseases and traumatic injuries by coaxing a patient's own cells to repair and regenerate the damaged tissues.
"This is an important advance in the science of reprogramming cells, and we are very pleased that the journal wants to shine a brighter spotlight on it," said Eric Overstrӧm, head of WPI's biology and biotechnology department and director of the LSBC.
Early on, this emerging field of regenerative medicine focused on embryonic stem cells, which are pluripotent, meaning they can grow into all the tissues of an adult organism. In the pluripotent state, several genes are known to be active, helping to control the stem cells. These genes, including OCT4, SOX2 and NANOG, are accepted as markers of pluripotency because they are active in stem cells, but become dormant once the stem cells begin to differentiate and head down the path to developing into a specific kind of cell type and tissue.
While the study of embryonic stem cells continues to yield important knowledge, research teams around the world are also working to change, or reprogram, fully-differentiated cells like skin cells, back to a more pluripotent state. Called induced pluripotent stem cells (iPS), these reprogrammed cells could be used to regenerate tissue without some of the problems associated with embryonic stem cells, including ethical questions and the potential for embryonic stem cells to be rejected by a patient's immune system or to grow out of control and cause tumors.
In the current study, the team at WPI and CellThera turned on the existing, yet dormant, stem cell genes OCT4, SOX2 and NANOG already in the skin cells by lowering the amount of atmospheric oxygen the cells were exposed to, and by adding a protein called fibroblast growth factor 2 (FGF2) to the culture medium. (FGF2 is a naturally occurring protein that is known to be vital for maintaining the pluripotency of embryonic stem cells.)
Furthermore, once the stem cell genes were activated and began expressing proteins, the team found those proteins migrated back into the nucleus of the skin cells, precisely as would occur in induced pluripotent stem cells. "This was an exciting observation," said Raymond Page, PhD, research assistant professor of biology and biotechnology at WPI and lead author on the paper. "Having these proteins localize to the nucleus is the first step of reprogramming these cells."
Even more surprising, the team found that the stem cell genes OCT4, SOX2 and NANOG were not completely dormant in untreated skins cells, as was presumed. Those genes were, in fact, sending out messages, but those messages were not being translated into the proteins that do the work of making cells pluripotent. "This was quite unexpected," said Tanja Dominko, DVM, PhD, associate professor of biology and biotechnology at WPI and president of CellThera. "Not only does this data force us to rethink what the true markers of pluripotency may be, it suggests there is a natural mechanism at work in these cells regulating the stem cell gene expression. That opens a whole new line of inquiry."
The work in the current study was supported by WPI startup funds and a grant to Dr. Dominko from the National Institutes of Health, and by funding to CellThera from the U.S. Defense Advanced Research Projects Agency (DARPA) and the Army Research Office (ARO).