U of T researchers cast light on how stem cells “make decisions”

Toronto, ON – Researchers at the University of Toronto are part of an international collaboration which has shed new light on how stem cells “decide” what kinds of cells to become, opening up new opportunities for regenerative medicine such as cell-based therapies and even potential cancer treatments.

In a paper published today in Cell Stem Cell, William Stanford, Canada Research Chair in Stem Cell Bioengineering & Functional Genomics and Professor of Biomedical Engineering at the University of Toronto, and his collaborators found that a protein originally discovered in fruit flies called Polycomb-like 2 (PCL2) plays a critical role in mouse embryonic stem cell “decision making.”

Stem cells are undifferentiated cells that have the unique ability to divide and generate more stem cells as well as generate differentiated, specialized progeny. Human pluripotent stem cells such as induced pluripotent stem (iPS) cells and embryonic stem cells (or ES cells) have the ability to differentiate or specialize into all cell types of an adult. These cells have immense potential for regenerative medicine such as cell-based therapies. Not surprisingly, there is a lot of interest in what controls the stem cell decisions – the decision to become a stay a stem cell or differentiate into a specialized cell like a blood cell, for example.

“If scientists can understand these normal decisions, they hope to influence those decisions to treat disease, such as making more blood cells to treat anemia or influencing the stem cells to become pancreatic beta cells to treat diabetes,” said Prof Stanford. “In fact, we think that what researchers learn from ES cells can be applied to adult stem cells such as blood stem cells. After all, blood stem cells are similar in nature to ES cells – blood stem cells have the ability to divide to make more blood stem cells and all the cells of the blood system.”

When the PCL2 protein, was removed from mouse ES cells, these stem cells could no longer differentiate into the specialized cells, remaining stem cells even under conditions that should push the PCL2 mutant ES cells into neurons, muscle, or even liver cells. In fact, the inability of the PCL2 mutant stem cells to differentiate into specialized cells is reminiscent of cancer cells. Importantly, the lead author in this study, Stanford lab graduate student Emily Walker, found that she could rescue the ability of the mutant ES cells to differentiate by re-expressing PCL2 in these cells.

Next, the Stanford group analyzed all the genes regulated by PCL2 and drafted a regulatory or network map, the equivalent to a computer circuit. In fact, the regulatory network not only explains how PCL2 controls stem cell decisions but explains how stem cells can respond so quickly to signals that allow the stem cells to specialize into the more than 200 cells of our body. The regulatory network also showed that PCL2 controls many cancer causing genes, which has Stanford and Walker excited about the possibility that PCL2 could be an important new player in the war on cancer.