Embargo lifted 2am AEST Friday 24 July 2009
Two research groups in China have created whole mice from adult cells which have been reprogrammed to behave like embryonic stem cells.
The two groups have independently created the induced pluripotent stem (iPS) cell lines from adult mouse cells, before showing that these cells could go on to generate live mouse pups. The groups have published their research simultaneously in Nature and Cell Stem Cell.
This research is the first time that iPS cells have been shown to be truly pluripotent (capable of forming every cell type in the body) – a feat which has previously only been demonstrated with embryonic stem (ES) cells.
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Dr Andrew Laslett is Group Leader Human Embryonic Stem Cell Technology at the Australian Stem Cell Centre, based in Melbourne
“The research reported in these two papers independently and formally demonstrates, using the most stringent test available, that mouse iPS cells are capable of forming an entire mouse. In other words, these investigators have, for the first time, unequivocally demonstrated that the iPS lines they have generated are truly pluripotent. Further studies comparing these iPS cell lines to iPS cell lines that do not pass this most stringent test will yield valuable information on how to best make iPS cells. It should be noted that these types of studies are only possible in mice and illegal to carry out using human iPS cells. Moreover, the long term stability of both the iPS cell lines and the long term health of the mice generated using this procedure are yet to be reported. It will be interesting to see whether mice generated in this fashion have a higher propensity for tumour formation.”
Associate Professor Ernst Wolvetang is Group Leader of the Stem Cell Engineering Group at the Australian Institute for Bioengineering and Nanotechnology (AIBN), University of Queensland. He is also Stream Leader of the Reprogramming and Induction of Pluripotency Program of the Australian Stem Cell Centre.
“Tetraploid embryonic stem cell aggregation is a technique that is used to generate embryos completely derived from embryonic stem cells. It is the most stringent test of pluripotency (the ability to form any cell type of the body) that researchers have available.
These two papers independently demonstrate that committed mouse cells can be reprogrammed back to re-aquire the characteristics of genuine embryonic stem cells, namely the ability to form an entire mouse. Interestingly, not all iPS cell lines analysed were able to pass this test.
Further research is required to determine why it is that only some iPS cell lines can form whole embryos. This will yield important information about the various techniques and cell types that may be used to generate high quality iPS cells. Importantly, experiments in mice will inform research on human iPS cells where this type of experiments is obviously not possible due to ethical and legal reasons.
Although the long term health of the iPS cell generated mice still needs to be assessed, the demonstration that some iPS cells can behave like true embryonic stem-cells is an important step towards future use of iPS cells in patient specific regenerative medicine.”
Professor Andrew Elefanty is from the Embryonic Stem Cell Differentiation Laboratory at Monash Immunology and Stem Cell Laboratories, Victoria
“The two groups both from China have provided evidence that some of the induced pluripotent stem cell lines made from mouse fibroblasts have the ability to make an entire embryo. The assay that they use for this is called tetraploid complementation. This is an embryonic manipulation that is used to test whether the iPS cells can make an entire fully developed live embryo. This has not been published before for iPS cells, although scientists already knew, using other tests, that iPS cells could make every cell type in the adult animal.”
“The interesting thing is that it was only a small proportion of the iPS lines that retained this property – indicating that the reprogramming process was not entirely complete or normal. This is not surprising because iPS generation is very inefficient as is the tetraploid complementation assay.”
“The bottom line is that this is a proof that some iPS lines can be ‘completely’ reprogrammed but that there is still a lot to learn about making the process efficient and safe. These iPS cell lines carried reprogramming viruses in them that we know predispose to tumours.”
Professor Bob Williamson is Professor of Medical Genetics of the University of Melbourne
“These results are very important for children with genetic diseases such as cystic fibrosis, muscular dystrophy or ataxia, because they show that this type of stem cell (an induced pluripotent stem cell, or iPS), which can be made from skin cells from a patient, has the potential to give an animal. The techniques are very inefficient and do not work for all cells, which might be expected since it is known that iPS cells are not all identical, and also are not identical to embryonic stem cells (ES cells). However, there is every reason to think that human iPS cells made from a child with a genetic disease could also give every cell type, including those that are affected, and could in principle be used for therapy once the technology is shown to be safe.”
“Some of those opposed to stem cell research using spare embryos from IVF programmes thought that iPS cells did not pose the same ethical problems as embryonic stem cells. These papers show that iPS cells, like cells from embryos and cells made by nuclear transfer, have the potential to give mice. If these cells are used experimentally, will those who object to medical research using spare embryos (because they could, in theory, develop to give a person) also object to iPS cells from a child with a genetic disease, that might be used for new, safer forms of therapy? We are fortunate that the law in Australia, like the laws in Britain and the U.S.A., will permit this research to continue.”
Professor Richard Boyd is Deputy Director of the Monash Immunology and Stem Cell Laboratories
“iPS have rapidly emerged as one of the most exciting discoveries in cell biology – the reprogramming of somatic cells using stem cell related genes but their efficacy of production, safety and true proof of embryonic stem cell status by being able to generate a viable animal have been major drawbacks. These papers now clearly show that such cells can indeed contribute to the formation of normal live animals although using a technology called “tetraploid complementation”which involves support from non-iPS derived cells. Strictly speaking it doesn’t add greatly to what was known of iPS cells but the formation of live animals is formally new. The question now is – are the animals fully fertile and safe from disease.”
Dr Paul J. Verma and Corey Heffernan are with the Monash Institute of Medical Research
“The remarkable demonstration that the forced expression of a handful of genes has the ability to ‘reprogram’ or revert adult cells back to an embryonic like state (Takahashi and Yamanaka 2006), termed induced pluripotent stem cells (iPSCs), promises to generate patient specific stem cells without the use of oocytes or embryos. The tetraploid complementation (4NC) assay represents the most stringent assessment of acquisition of a pluripotent phenotype characteristic of embryonic stem (ES) cells.
As tetraploid cells are incompatible with embryonic development, diploid cells injected into tetraploid blastocysts assume the responsibility of establishing early, and subsequent, embryonic development. Although satisfying most other criteria for pluripotency, experimental evidence confirming generation of liveborn progeny exclusively from an iPS cell line by 4NC has been lacking. Now, two recent publications confirm the ability of particular iPSC lines to differentiate into all cell type of the developing (mouse) fetus, and sustain the cellular requirements of development to term (Zhao et al., 2009; Kang et al., 2009). Interestingly, Zhao et al., (2009) report differences in the ability of different iPSC lines to generate live progeny. Further dissection of these differences would enhance our understanding of what constitutes a truly pluripotent iPS cell and potentially provide approaches to identify iPSCs with clinical relevance.”