To self-renew or differentiate? New insight on how stem cells choose

When dividing, adult stem cells have to stay on their toes: They must assess external cues to determine whether to commit themselves to becoming more-specialized, tissue-specific progeny or instead to generate daughter stem cells, which would be held in reserve for future use.

Now medical school scientists have found that a family of important cell-signaling proteins is involved in encouraging stem cells in the developing brains of mice to self-renew.

Harnessing the power of this Wnt (pronounced 'wint') family of proteins may allow researchers to grow more readily these neural stem cells in the lab and better understand how adult stem cells perform their complicated dance.

It's not the first time Wnt proteins have been implicated in brain development and stem cell maintenance. Mice missing some Wnt family members have malformed brains; conversely, animals with higher-than-normal levels of Wnt signaling have enlarged brains. But until now it wasn't known how Wnt proteins influence the stem-cells' decision-making process.

The research was published Oct. 21 in the online early edition of the Proceedings of the National Academy of Sciences.It was conducted in the laboratories of Theo Palmer, PhD, associate professor of neurosurgery, and Roeland Nusse, PhD, professor of developmental biology. Irving Weissman, MD, director of Stanford's Stem Cell Biology and Regenerative Medicine Institute, which was created in 2003 to foster interdisciplinary collaborations focused on exploring the creation, regulation and differentiation of stem cells, also collaborated on the research. The institute's future $200 million home, for which construction is about to begin, is projected to be the nation's largest stem cell research center. Palmer, Nusse and Weissman are all members of Stanford's Cancer Center.

In this latest research, graduate student Yashar Kalan and post-doctoral scholar Samuel Cheshier, MD, PhD, found that Wnt treatment approximately doubled the ability of individual cells from mouse fetal brain to form colonies - a key test for the presence of active stem cells. Cells from these colonies can differentiate into three important types of neural cells.

In contrast, treatment with a protein that inhibited Wnt signaling markedly reduced the efficiency of colony formation. Colonies formed from Wnt-treated cells were smaller and more uniform in size and shape than those that occurred in the presence of the Wnt signaling inhibitor. Colonies from untreated cells were more variable.

The researchers confirmed that Wnt treatment was causing the stem cells to self-renew, rather than proliferate, by testing the efficiency of former colony members to create colonies of their own. Tellingly, cells from colonies formed in the presence of Wnt formed about 10 times as many colonies as compared to controls when exposed to Wnt the second time around.

This indicates that Wnt treatment increased the overall number of stem cells in the first colony.



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