New discovery by University of Georgia scientists

Stem  cells might be thought of as trunks in the tree of life. All multi-cellular  organisms have them, and they can turn into a dazzling variety other  cells—kidney, brain, heart or skin, for example. One class, pluripotent stem  cells, has the capacity to turn into virtually any cell type in the body,  making them a focal point in the development of cell therapies, the conquering  of age-old diseases or even regrowing defective body parts.

Now,  a research team at the University of Georgia has shown for the first time that  a gene called Myc (pronounced "mick") may be far more important in the  development and persistence of stem cells than was known before. Myc is  traditionally thought of as a cancer-causing gene, or oncogene, but recent  studies from the UGA team have established critical roles for it in stem cell  biology. The discovery has important implications for the basic understanding  of developmental processes and how stem cells can be used for therapeutic  purposes.

"This  new research has uncovered a really unexpected role for Myc," said Stephen  Dalton, GRA Eminent Scholar of Molecular Cell Biology and Georgia Cancer  Coalition Distinguished Scientist at UGA. "Our work here represents the first  mechanistic characterization of how Myc controls the pluripotent stem cell  state."

The  research was published in Cell Stem Cell. Other  authors of the paper include Keriayn Smith and Amar Singh of the Dalton lab at  UGA. Smith left recently to begin a postdoc at the University of North  Carolina. Dalton also is a member of the department of biochemistry and  molecular biology in the Franklin College of Arts and Sciences and is  affiliated with the UGA Cancer Center and the Biomedical and Health Sciences  Institute.
  In  previous work, Dalton and his colleagues showed that Myc is critical for stem  cell maintenance and that it affects widespread changes in gene expression.  This latter function is crucial when stem cells differentiate into more  specific cell types. In the new research, Dalton's team showed that Myc  sustains the important pluripotency process by repressing a "master regulator"  gene called GATA6.

"Pluripotency  is the inherent property of a cell to create all cell types, from an embryo to  an adult organism," said Dalton. "It's an extremely important biological  process, and knowing how it is controlled is crucial not only from a basic  developmental perspective but also so that we can harness the potential of stem  cells for the development of therapies, including those for diabetes,  cardiovascular disease and a range of neurological disorders. Through a  detailed understanding of early development, we hope to apply this information  so that pluripotent stem cells can be differentiated into therapeutically  useful cell types. These cells can then be used in a clinical setting to cure  degenerative diseases and treat acute injury."

The  finding that Myc inhibits GATA6 came as a big surprise to the Dalton team and  points out that researchers have only seen the tip of the "molecular iceberg"  in terms of what Myc does in stem cells. It now seems likely that understanding  Myc's role in further detail will reshape current ideas about the basic biology  of stem cells.

Dalton's  new work addressed the uncertainty about how Myc maintains the pluripotency of  stem cells by examining what happens when two forms of Myc—c-Myc and N-Myc—are  inactivated in pluripotent stem cells. What he found was that either c- or  N-Myc is sufficient to maintain pluripotency, but that the absence of both  triggers the differentiation of pluripotent stem cells. Myc is therefore acting  as a "brake" to restrain differentiation. When the "differentiation brake" is  removed, cells lose their stem cell properties, and, potentially, they can  become any one of over a hundred different cell types.

Pluripotent  stem cells can now be made from skin fibroblasts and even from blood samples.  (Fibroblasts are cells common in connective tissues of animals and play an  important role in the healing of wounds, among many functions.) The conversion  of mature fibroblast or blood cells back to pluripotent stem cells is called  "reprogramming." Myc also has a critical role in this process. The ability to  make stem cells from a patient's blood or skin is going to revolutionize  medicine as it opens the way for patient-specific stem cells that would  circumvent problems associated with immune rejection, said Dalton.

"During  the reprogramming of cells, Myc represses genes associated with the  differentiated state and primes them for the expression of stem cell genes," he  said. "We now speculate that during the early reprogramming stage, Myc serves  to change the cell cycle so that stem cells can divide for long periods of time  without aging. This is also what Myc does in cancer cells."  Dalton  said that there is an intriguing relationship between normal stem cells and  cancer cells. Since Myc is crucial for maintenance of stem cells and for the  development of cancer, pluripotent stem cells represent a good model for tumor  biologists. Cancer is thought to be initiated by rogue stem cells found in  different tissues, further highlighting the link between stem cell biology,  cancer and Myc.

"This  is clearly going to be a major area of research for many years to come," Dalton  said.   The  research was supported by grants to Dalton from the National Institute of Child  Health and Development and the National Institute for General Medical Sciences.