Scientists Identify A Mouse Embryonic Stem Cell More Like Our Own

The findings, reported on-line June 27 in Nature*, are the result of a collaborative effort among scientists at the National Institute of Neurological Disorders and Stroke (NINDS), the National Cancer Institute (NCI) – both part of NIH – and the University of Oxford, U.K.

Mouse ES cells are typically used as a proxy for human ES cells, even though they differ in several ways, from their appearance under a microscope to chemical modifications in their DNA.  The stem cells isolated by Dr. Ron McKay, Ph.D., the study's lead scientist and a senior investigator at NINDS, are a closer match to human ES cells by these measures and others.  Moreover, because they’re farther along the developmental timeline than the traditionally studied cells, they could offer scientists a unique glimpse at a critical point in the life of an ES cell – a time when it is poised to start producing mature cell types, including neurons, muscle and bone.

One key to isolating the new stem cells was to work with slightly older mouse embryos.  Traditionally studied mouse ES cells come from embryos that haven't yet implanted themselves in the uterine wall.  The new cells come from the epiblast,a cluster of cells that forms after implantation.  In mammals, the epiblast will give rise to all the cells that make up the adult animal, while surrounding tissues will become supportive structures like the placenta.

Another key was to grow the mouse epiblast cells using methods developed for growing human ES cells, an innovation made by Paul Tesar, a graduate student in the NIH-Oxford Biomedical Research Scholars program.  The program has allowed Mr. Tesar to split his time between the two institutions; it also provided a link between Dr. McKay and Professor Sir Richard Gardner, an expert on mouse embryonic development at Oxford.

To characterize the epiblast stem cells, the researchers first tested whether they are capable of becoming diverse cell types – a defining feature of ES cells.  The epiblast stem cells passed two such tests.  When grown in test tubes, the cells also morphed – or differentiated – into neuron-like cells, muscle cells, and cells found in the body's inner organs, depending on the growth medium.  When injected into immunodeficient mice, they formed teratomas – large tumors containing bits of cartilage, muscle, fat, skin and other tissues. 

Other experiments revealed how similar the epiblast stem cells are to human ES cells, and how different those two cell types are from the classic mouse ES cell.  For instance, human ES cells and mouse epiblast stem cells possess nearly the same set of active transcription factors – proteins that turn genes on and off.  They also have similar chemical tags on their DNA, making it more or less receptive to transcription factors.

"Understanding what stem cells are and how they grow in a dish are still central problems in medical research," said Dr. McKay.  "If we know how to control their growth and differentiation, we can regenerate cells lost to injury or disease."

With such knowledge, for example, adult human cells could be reprogrammed to act more like human ES cells.  One lab recently coaxed mouse skin cells to behave like classic mouse ES cells; the new mouse epiblast cell could be the key to extending this same trick to human tissue.

Dr. McKay emphasized that despite their importance, the new cells won't render the classic mouse ES cells obsolete.  The classic cells are easier to grow and are the primary tool that researchers use to create mouse models of human genetic diseases.

*Tesar PJ et al.  "New Cell Lines from Mouse Epiblast Share Defining Features with Human Embryonic Stem Cells."  Nature, published on-line June 27, 2007.