Research Highlights

Nature Reports Stem Cells
Published online: 9 October 2008 | doi:10.1038/stemcells.2008.134

Location, location, location

Elie Dolgin¹

Neural stem cells can adopt an alternative cell fate if placed in the mammary microenvironment

How could you make a brain stem cell behave like a cell in the breast? Put it into mammary tissue. A new report shows that neural stem cells contribute to mammary gland formation if mixed with mammary epithelial cells. In other words, stem cells from one tissue, when placed in the niche of another tissue, abandon their original programme to travel down the developmental path of the new tissue.

Last year, Gilbert Smith of the National Cancer Institute in Bethesda, Maryland, and his colleagues coaxed mouse testes cells into forming mammary progenitors by mixing them with normal mammary epithelial cells¹, but the researchers couldn't pin down which exact cells had undergone reprogramming. Now, Smith's team has repeated the results, this time starting with pure populations of labelled neural stem cells from both embryonic and adult mice. The work demonstrates that adult stem cells can be plastic depending on their environment, and it also offers a potential new approach to cell reprogramming.

Smith's team inoculated juvenile female mice with a mixture of mammary epithelial cells and neural stem cells containing a pregnancy-induced LacZ marker. After the mice matured, the researchers observed blue LacZ-expressing cells in all but 1 of the 23 mice with mammary outgrowths and in all 14 successful secondary transplants, indicating substantial neural-to-mammary cell reprogramming. The cells of neural origin contributed 5–7% of the chimeric mammary cells and could differentiate into several mammary lineages². Without the co-injected mammary epithelial cells, however, the neural stem cells never adopted a mammary fate. "This demonstrates that the specific microenvironment of the mammary gland dictates to the stem cells to change [their] differentiation repertoire," says Smith.

Adult stem cell plasticity is not only limited to neural stem cells, either. Smith has unpublished results showing that the mammary gland microenvironment can also reprogram many other multipotent cell types, including mouse bone marrow cells and cancer cells from both mice and humans. Indeed, the plasticity of the neural-derived cells might be greater than these results suggest because the LacZ transgene construct marks only the secretory lobules, not the branching ducts that penetrate the mammary fat pad. "We only have part of the answer so far," Smith says. "There may be other cell types in the mammary gland that are contributed by the neural stem cells." Next, Smith plans to repeat his experiments using a green fluorescent protein marker, which should reveal more cell types of neural origin.

Thea Tlsty, of the University of California, San Francisco, calls the paper "provocative," but notes that additional experiments are still needed, especially to conclusively rule out the possibility of cell-cell fusion between the neural stem cells and mammary epithelial cells. Smith's team performed a number of cell biological screens, but these may not have detected rare fusion events, which genetic-based assays should pick up, she notes. "In this paper, it's all inferred," Tlsty says, "but with genetics, you can nail that to the wall."

Chay Kuo, of the Duke University Medical Center in Durham, North Carolina, adds that the transgenic mouse lines used in the research have not been thoroughly studied. As such, the LacZ reporter might be activated by more than just mammary tissue growth. "Since it's a new mouse line," he says, "it needs to be a little better characterized until we can definitively say that transdifferentiation has taken place."

Smith says he's now using knockout mice to identify the genes involved in reprogramming. Although he hasn't yet nailed down any specific factors, his early experiments are providing some surprising results. Knocking out some genes, Smith says, blocks mammary epithelial cells from forming mammary growths in isolation, and yet these cells can still reprogram neural stem cells. What's more, the reprogrammed neural cells can rescue mammary function in the mutant mammary epithelial cells when co-injected. The microenvironment, it seems, not only induces plasticity, but also can respond with plasticity itself.