Australasian Science: Australia's authority on science since 1938

Stem Cells Reset Inside Mice

Spanish researchers have successfully reset stem cells so they can become any cell type within the bodies of live mice, bypassing the need for transplantation.

The ability to change multiple different cell types in a living mouse back into iPS cells (induced pluripotent stem cells), that can turn into any cell type in that mouse or even into an entire new mouse, is unprecedented. This research provides a better understanding of the reprogramming process in mice and will enable further investigations into applications targeted at treating specific diseases and injuries.

The reprogramming method described is not suitable for use in humans, but its use for research in mice could ultimately provide information critical for the safe use of reprogramming technology in humans to address unmet healthcare needs.

A/Prof Andrew Laslett is Research Group Leader, Stem Cells, at CSIRO Materials Science & Engineering.

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These findings are a genuine leap forward in understanding the possibilities of reprogramming cells in many different organs in animals, bringing the promise of therapies that fundamentally alter the make-up of cells a little closer to clinical use.

The Spanish research team have built on the seminal work of Professor Shinya Yamanaka from Kyoto University in Japan, who won a 2012 Nobel Prize for the discovery that only four genes are required to turn a skin cell back into a cell capable of making a vast spectrum of different tissues. Professor Yamanaka’s method revolutionised stem cell research, producing a new category of cells called “induced pluripotent stem cells”, or iPS cells, hailed as a way of avoiding the controversial use of embryonic tissues to make stem cells.

The newly published research addresses the shortcomings of iPS cells, which do not have the same range of capacities as embryonic stem cells; a point of difference for stem cell researchers and a cause of ongoing debate for ethicists.

The research team has been able to develop embryonic-like tumours in mice, in lots of different organs. Cells of these embryonic growths, teratomas, can make a vast variety of different cell types such as muscle, bone and skin, indicating that cells from a range of organs can be “reprogrammed” to revert to an embryonic state.

Most importantly, these “in animal” reprogrammed cells were more primitive than the iPS cells made using Professor Yamanaka’s test-tube method, heralding a new range of research techniques to study the development of many diseases, including cancer.

Prof Rob Ramsay is Head of the Cancer Cell Biology Program at Melbourne’s Peter MacCallum Cancer Centre, a member of the International Society for Stem Cell Research and a member of the Australasian Society for Stem Cell Research.

Reprogramming in vitro has allowed any cell of the body to be turned into pluripotent stem cells, meaning they can produce any cell in the body, in the petri dish in the laboratory. What this paper shows for the first time is that this can now be achieved directly in vivo in mice.

This paper is very exciting. Clearly nobody wishes to do this for therapeutic purposes because this leads to the formation of tumours called teratomas. However this is a proof of concept that pluripotency can be achieved in vivo. This opens up opportunities to investigate ways to partially reprogram cells in the body to a desired state of dedifferentiation. In principle, these partially dedifferentiated cells could then be induced to differentiate to the cell type of choice, inducing regeneration in vivo without the need of transplantation.

Dr Ilaria Bellantuono is Reader in Stem Cell and Skeletal Ageing at the MRC/Arthritis Research-UK Centre for Integrated Research into Musculoskeletal Ageing, University of Sheffield.

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The fact that it is possible to get reprogramming in vivo to give iPS cells is quite predictable, and I think most labs would not have tried this because it was likely to be detrimental to the animals, with little scientific gain. The paper does highlight one useful piece of knowledge of relevance to safety – we need to be careful how we handle the reprogramming factors, especially if they are contained within viral vectors, otherwise people exposed to them are very likely to develop teratomas, which are not going to be very good for the person.

Nevertheless, they did find something that could be scientifically very interesting, namely that the in vivo iPS cells (or at least some of them) appear to correspond to a very early embryonic stage. But at this stage the data is simply phenomenological. Why should reprogramming in vivo give a different outcome to reprogramming in vitro? It suggests that the latter is missing something – perhaps something complex like an immune system that selects for cells characteristic of an earlier embryonic stage, or something simple, like the levels of oxygen, which is generally lower in vivo than in standard tissue culture conditions.

However, as it is, I can't see this being useful with respect to making human iPS cells – I would not volunteer to have the factors expressed within me. Although one interesting possibility would be to begin with a mouse containing human cells or tissues, and to use this as the in vivo system to obtain the human iPS cells.

Prof Robin Lovell-Badge is Head of Developmental Genetics at the MRC National Institute for Medical Research, UK.

AusSMC: Nature (2013), doi:10.1038/nature12586