February 23, 2005

Newly-Discovered Class of Genes Determines – and Restricts – Stem Cell Fate

(Philadelphia, PA) – Research on adult stem cells found in the skin hints at a new class of genes, according to a study from investigators at the University of Pennsylvania School of Medicine. These genes – dubbed pangenes – can both govern a stem cell’s fate and put a hold on future differentiation until the time is right. Understanding the molecular control of these genes has implications for therapies that involve tissue regeneration.

The researchers found that Pax3, a gene critical in embryonic development of melanocytes – cells that make and store the pigments in the skin and hair – is also expressed in adult stem cells in the skin.

“Our findings told us that a recapitulation of an embryonic program is occurring in resident stem cells in adult skin,” explains Jon Epstein, MD, Professor of Medicine, Cardiovascular Division. “These few rare stem cells were expressing genes that previously had only been known to be expressed in a developing embryo. That was the first clue that we were on to something new.” Epstein and colleagues report their findings in the February 24^th issue of Nature.

The scientists found that Pax3 plays dual – and somewhat seemingly contradictory – roles in adult stem cells: it directs them to become melanocytes, but simultaneously prevents them from differentiating completely. “It gets the show going, but at the same time, prevents the final act,” says Epstein. “I call this dual function a “biological capacitor,” because Pax3 tells the cell: Get ready to go, but at the same time won’t let it proceed.”

Pangenes Express Behavioral Qualities of Pan and Peter Pan
Epstein notes that this research is conceptually new since he suggests that a single gene can both tell a cell what it should become and restrict its fate by preventing differentiation. The ability of a single biochemical factor or complex of factors to have this dual role may represent a new general paradigm for developmental and stem-cell biology. “My idea is that this is a new family of genes—they can both determine the cell type, but also put the breaks on differentiation,” says Epstein. “We have named them pangenes, after the Greek god Pan and Peter Pan, who were able to orchestrate complex events while never growing old.”

Epstein thinks that this concept may also be important for understanding the cell of origin for a number of tumors. Pax3 is known to be involved in some tumors, which adds evidence to the stem-cell origin for some cancers. This theory proposes that many cancers may arise from normally scarce resident stem cells that grow uncontrollably, rather than from the vast majority of differentiated cells that make up organs where cancers are found. If this theory is correct, resident stem cells in the skin could be the cells that turn into skin cancers like melanoma. Understanding stem cell biology may therefore be important for developing new therapies for cancer.

Adult resident stem cells have been identified in many types of organs and may be a potential reservoir for tissue regeneration. A fundamental understanding of the molecular programs that regulate stem-cell differentiation is necessary for harnessing this potential.

This work was supported by grants from the National Institutes of Health. Epstein’s coauthors are Deborah Lang, Min Min Lu, Li Huang, Kurt A. Engleka, Maozhen Zhang, Emily Y. Chu, and Sarah Millar from Penn; and Shari Lipner and Arthur Skoultchi from the Albert Einstein College of Medicine.

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This release is available online at http://www.uphs.upenn.edu/news/News_Releases/feb05/Pax3.htm