New Light on Stem Cell Self-renewal

Research discovers method to duplicate primitive stem cells and prevent cell differentiation Wednesday, 21 May 2008 Researchers from California (USC), United Kingdom and Canada have discovered a new mechanism to allow embryonic stem cells to divide indefinitely and remain undifferentiated. The study, which will be published in the May 22 issue of the journal Nature, also reveals how embryonic stem cell multiplication is regulated, which may be important in understanding how to control tumour cell growth. “Our study suggests that what we believe about how embryonic stem cell self-renewal is controlled is wrong,” says Qi-Long Ying, Ph.D., assistant professor of Cell and Neurobiology at the Keck School of Medicine of USC, researcher at the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, and lead author of the paper. “Our findings will likely change the research direction of many stem cell laboratories.” Contrary to the current understanding of stem cell self-renewal and differentiation, the findings suggest that embryonic stem cells will remain undifferentiated if they are shielded from differentiation signals. By applying small molecules that block the chemicals from activating the differentiation process, the natural default of the cell is to self-renew, or multiply, as generic stem cells. Pluripotent mouse embryonic stem (ES) cells are usually maintained by using various empirical combinations of feeder cells, conditioned media, cytokines, growth factors, hormones, foetal calf serum, and other serum extracts. ES-cell self-renewal has therefore generally been considered to be dependent on stimulation of a multitude of factors in transcriptional control, specially the activation of STAT3 by cytokines. Here the researchers show that external stimuli are dispensable for the derivation, propagation and pluripotency of ES cells. Self-renewal is enabled by the elimination of differentiation-inducing signals from mitogen-activated protein kinase and glycogen synthase kinase 3. Furthermore, isolating ES cells genetically devoid of STAT3 confirmed that the cytokine signalling pathways can be bypassed while self-renewal of the ES cells were maintained. Therefore the researchers conclude that ES cells have an inborn programme for self-replication that does not require extrinsic instructions. “This study presents a completely new paradigm for understanding how to grow embryonic stem cells in the laboratory,” says Martin Pera, Ph.D., director of the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC. “The discovery has major implications for large scale production of specialized cells, such as brain, heart muscle and insulin producing cells, for future therapeutic use.” Embryonic stem cells have only been derived from a very small number of species. “We believe the process we discovered in mice may facilitate the derivation of embryonic stem cells from species like pigs, cows or other large animals, which have not been done before,” continues Ying. “If deriving embryonic stem cells from cows, for instance, is possible, then perhaps in the future cows might be able to produce milk containing medicines.” With better understanding of the multiplication process of embryonic stem cells, researchers have additional insight on tumour cell growth as these cells share similar qualities. “Our study reveals part of the little known process of how embryonic stem cells multiplication is regulated. This is important for us in understanding how to control tumour cell growth moving forward in cancer research,” says Ying. This research was funded by the Medical Research Council and the Biotechnology and Biological Sciences Research Council of the UK, the Canadian Institutes of Health Research, and by the European Commission Framework VI project EuroStemCell. Reference: The ground state of embryonic stem cell self-renewal Qi-Long Ying, Jason Wray, Jennifer Nichols, Laura Batlle-Morera, Bradley Doble, James Woodgett, Philip Cohen & Austin Smith Nature 453, 519-523 (22 May 2008) doi:10.1038/nature06968 ......... ZenMaster

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