In this image of mouse embryonic fibroblasts undergoing reprogramming, each colored dot represents messenger RNA associated with a specific gene that is active in cells being reprogrammed. Red dots represent mRNA for the gene Sall4, green is Sox2, and blue is Fbxo15. The researchers determined that Sox2 activates Sall4 and then activates the downstream gene Fbxo15, creating a gene hierarchy in the later phase of reprogramming. Credit: Dina Faddah/Whitehead Institute

Several years ago, biologists discovered that regular body cells can be reprogrammed into pluripotent stem cellscells with the ability to become any other type of cell. Such cells hold great promise for treating many human diseases.

These induced pluripotent stem cells (iPSCs) are usually created by genetically modifying cells to overexpress four genes that make them revert to an immature, embryonic state. However, the procedure works in only a small percentage of cells.

Now, new genetic markers identified by researchers at Whitehead Institute and MIT could help make that process more efficient, allowing scientists to predict which treated cells will successfully become pluripotent.

The new paper, published in the Sept. 13 online edition of Cell, also identifies new combinations of reprogramming factors that produce iPSCs, according to the researchers.

Led by Rudolf Jaenisch, a Whitehead Founding Member and an MIT professor of biology, the study is the first to examine genetic changes that occur in individual cells as they become pluripotent. Previous studies have only looked at gene-expression changes in large populations of cellsnot all of which will actually reprogrammaking it harder to pick out genes involved in the process.

"In previous studies, you weren't able to detect the few cells that expressed predictive pluripotency markers. The really cool part of this study is that you can detect two or three cells that express these important genes early, which has never been done before," says Dina Faddah, a graduate student in Jaenisch's lab and one of the paper's lead authors.

The other lead author is Yosef Buganim, a postdoc at Whitehead Institute.

Single-cell analysis

In 2007, scientists discovered that adult human cells could be reprogrammed by overexpressing four genesOct4, Sox2, c-Myc and Klf4. However, in a population of cells in which those genes are overexpressed, only about 0.1 to 1 percent will become pluripotent.

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Scientists bring new efficiency to stem cell reprogramming