Expert comment on mouse stem cell paper in Nature

Stem cells made from skin likely possess the same potential as embryonic ones to grow into organ replacements, according to two studies of baby mice, published in Nature and Cell Stem Cell this week.

The Australian Science Media Centre (AusSMC) rounded up comment from a scientist who co-authored the Nature paper.:

Prof Robin Lovell-Badge, Head of Division, MRC National Institute For Medical Research, said:

“This work is important as it demonstrates that the reprogramming methods applied to mouse cells can give truly pluripotent cells, but it has to be stressed that it is not directly applicable to similar work with human cells. For ethical and practical reasons, these cannot be tested in chimeras made by introducing the cells into early human embryos. We urgently need to develop alternative tests that we can use with human iPS cells to prove their pluripotentiality and ability to give rise to cell types that can function and are safe.”

He goes on to say:

“It is a fairly straightforward demonstration that the authors have succeeded in making very good pluripotent iPS cells. The main conclusions I would make are:

1. Varying the methods slightly, both in culture conditions and the time at which the iPS cell lines were established, seems to have encouraged reprogramming to a stable mouse true ES-like state. The tetraploid complementation assay is the most exacting test of pluripotency for mouse cells. It will work essentially every time with cells taken directly from mouse blastocysts, and sometimes, but not always, with mouse ES cells. It is not clear why this worked for their iPS cells and not others, but this deserves further investigation.

2. They were using the original methods developed by Yamanaka to introduce the four reprogramming factors, i.e. with retroviral vectors. We have seen several papers in recent months where alternative methods have been employed, from excisable vectors and non-integrating vectors to the use of proteins engineered to enter cells. Some of these papers, especially the latter, fell far short of showing pluripotency in a robust manner. The scientists who are developing these other methods will now have to compare their cells with those reported in the current paper.

3. It is not possible to test human iPS cells in the same way: (a) it would be unethical to make chimeras with diploid or tetraploid human embryos and either implant them or keep them beyond 14 days in culture. (b) Human ES and iPS cells seem to correspond more closely to mouse “Epi stem cells” (EpiSC), which are derived from a later stage of embryos than mouse ES cells. EpiSC do not contribute to chimeras at all when injected into blastocyst stage embryos – they are beyond the developmental stage when they can do this. Therefore it seems probable that the pluripotency of human ES and iPS cells could not be tested in this way, even if it was allowed.

“Therefore, this work does not directly relate to human pluripotent cells. However, it emphasises the need to develop new ways of ascertaining whether human iPS cells are both pluripotent and safe to use. These might involve differentiating the cells in culture to derive specific cell types, e.g. nerves, muscle, liver, etc, and then testing these in animal models to see whether they function correctly. The “gold standard” iPS cells described in this paper, will provide something against which human iPS cells can be compared in their ability to function in animals.”