Live mice from stem cells!

ResearchBlogging.orgNews today has spread about new stem cell research out of China. Two teams used mouse fibroblasts, a kind of cell found in skin connective tissues, to create induced pluripotent skin cells (iPS), which were then used to create living mice.

Their breakthrough research suggests that both cloning full animals from stem cells and the creation of completely pluripotent stem cells from skin cells are both not only possible, but a current reality. The two teams published separately, in Nature and Cell - Stem Cell, both very prestigious journals.

The first task for either study was to create stem cells from non stem cells. Embryonic stem cells, controversial because they often come from the destruction of live embryos, are what is called "pluripotent," which means they can become any cell in the body. To be able to create cells that act like embryonic stem cells, without the embryo part, opens to door to a fascinating and less-controversial field of medical research, including organ repair or even full organ replacements that are guaranteed to match the host's body. Just imagine never having to look for donors for bone marrow or a heart, and you can get the idea of how amazing this research could be.

These teams are not the first to have created such cells - other studies have created stem cells from a variety of other cells, though some work better than others, and exactly how pluripotent they are is still up for debate. This team created stem cells, called iPS cells, from fibroblasts, the most common cell in connective tissue, from late stage embryos by using a viral vector to introduce genes which allowed the cells to "reprogram" into any cell type.

To prove that these iPS cells really could become anything, they tested them over and over again, including looking at whether they had the same cell surface markers as embryonic stem cells. They used fluorescent staining to show that the created cells did, indeed, have the same markers as embryonic stem cells (Left).

Both groups decided that the truest test of their iPS cells, however, was to attach them to a sham embryo called a tetraploid embryo, which can create a placenta but no actual animal. The only way a mouse would form from the union was if the iPS cells were able to divide and differentiate into the necessary tissues to become a living animal.

The first group, published in Nature, included a dominant black coat color allele into their stem cells, then placed the embryos into white mice, giving them an initial visual check. If the young were black, they had to have come from the stem cells. When the first black baby mouse was born, further DNA tests confirmed that Tiny (as he was named) had indeed arisen from the iPS line. It took them over 250 developing embryos before they achieved a live mouse. Out of the 37 stem cell lines created, 3 produced live mice, and out of a total of 624 injected embryos from the best cell line, they got only 22 live births. That's a success rate of only 3.5%.

Even these mice, though born live, were not all perfect. Some were chimeric, having somehow taken genetic material from both the iPS cells and the host mom or tetraploid embryo. Even those that were fully iPS generated had flaws. Some died just days later, and many were deformed or physically abnormal. 12, however, were able to pass a reproductive biologists strict test of health: they were fertile, producing hundreds of second and third generation mice (like the one on the right). Even still, there is a lot that isn't known about these stem-cell derived mice, like whether their children develop diseases more readily than normal mice, or are as healthy in general.

The other group, who published in Cell, followed the same basic procedure. They were able to create 187 tetraploid embryos and implant them in receptive female mice. Of those, however, they only had 2 live births (1.1%), one of which died in infancy.

Both teams are now looking deeper into the differences between iPS and embryonic stem cells to understand what causes the high mortality, abnormality and failure rates of these embryos. It also remains a mystery as to whether adult fibroblasts can become iPS cells which have the same pluripotent abilities, as both teams used the skin cells from late stage embryos to create their stem cell lines.

If adult cells work, too, it would mean that we might be able to clone adult mammals using their skin. The authors vehemently deny any connection or plans of utilizing this research for human cloning - and at a rate of 1.1%-3.5% just to produce a live birth, let alone further complications, I agree with them. There's still far too much uncertainty to even think of applying this method to humans.

However, the fact that these stem cells were able to be pluripotent, even 1.1% of the time, gives a lot of hope to future medical research. Indeed, we might just be able to create tissues or organs on demand from a patient's own cells in the next 50 years, which would save the lives of many suffering from a variety of diseases. More interestingly, however, is that these cloned animals may lead to a better understanding of how cells develop, divide, and fail, leading to breakthroughs in prevention and treatments of conditions like cancer instead of just patches to prolong life after the disease has set in.

Lan Kang, Jianle Wang, Yu Zhang, Zhaohui Kou, & Shaorong Ga (2009). iPS cells produce viable mice through tetraploid complementation Nature DOI: 10.1038/nature08267

Kang, L., Wang, J., Zhang, Y., Kou, Z., & Gao, S. (2009). iPS Cells Can Support Full-Term Development of Tetraploid Blastocyst-Complemented Embryos Cell Stem Cell DOI: 10.1016/j.stem.2009.07.001

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