June, 25th 2005
Immortal DNA in skeletal muscle stem cells
Researchers at the Pasteur Institute show for the first time the mechanism which adult skeletal muscle stem cells can use to protect their genome from mutations. Before cell division, DNA is duplicated, and each daughter cell inherits one copy. During DNA synthesis, however, errors can arise from this imperfect process. Over time, repeated rounds of cell divisions result in the accumulation of these mutations which can perturb normal cellular processes, and provoke cancers. In an Article published in Nature Cell Biology, researchers provide convincing evidence that muscle stem cells retain the original DNA strands which have not been copied. By doing so, the stem cells can avoid accumulating mutations in their DNA, which may provoke carcinogenesis. This mechanism which preserves the "immortal" DNA involves complex molecular and cellular regulation which remains to be explored.
RStem cells represent a promising tool for the development of therapeutic strategies. To regulate their numbers correctly in the organism, stem cells can self-renew by asymmetric cells divisions. In other words, they can give rise to two different daughter cells: one daughter which retains the properties of the stem cell, and another daughter which will contribute to the tissue. A key question is how stem cells retain their original state without being altered, as well as their potent capacity to regenerate the tissue over extended periods, often decades.
The research laboratory Stem Cells & Development directed by Shahragim Tajbakhsh at the Pasteur Institute, has taken a significant step in validating a controversial hypothesis proposed 3 decades ago (Cairns, Nature, 1975), that of immortal DNA. This theory suggested that only the differentiating cells will inherit the newly "photocopied" DNA strands, which contain errors. The stem cells retain the unmodified original DNA strands, which consequently remain "immortal" after repeated cell divisions.
The researchers used sophisticated experimental approaches including videomicroscopy to follow the fate of mouse skeletal muscle stem cells, called satellite cells, during cell divisions. By following either the original DNA strands, or those that were newly synthesised, they showed that the original DNA strands are distributed to only one of the daugher cells, the one which will maintain satellite cell characteristics. This phenomenon was demonstrated in muscle cells placed in culture, and also directly on the skeletal muscle fibres in vivo, which not a trivial feat.
This segregation, which results in the original and newly synthesised DNA strands being distributed to different daughter cells during cell division, clearly defies the basic rules of cell biology and genetics which implied that the duplicated genetic material is distributed randomly. These findings suggest that the DNA strands of the double helix are not equivalent, and that during cell division, the cellular machinery distinguishes old from newly synthesised DNA. This would result in the stem cell escaping mutations over time. The regulatory mechanisms which direct this facinating phenomenon are not yet explored.
The events which result in the faithful preservation of the inherited genetic material in stem cells will have an impact on numerous fields of research. The understanding of these mechanisms is crucial to ultimately culture and maintain the integrity of stem cells for their use in cell therapies. In addition, it is known that some of the most aggressive cancers can arise from cells which have stem cell characteristics, and which escape cell division to proliferate uncontrollably. The key to this regulated proliferation may lie in the preservation of the integrity of the inherited genetic material which contains the information defining the original stem cell.
Vasily Shinin, Barbara Gayraud-Morel, Danielle Gomès et Shahragim Tajbakhsh
Groupe de recherche Cellules Souches et Développement, Institut Pasteur, CNRS
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