Editors' ChoiceStem Cells

Cooking Tips for Pluripotency: Add Acid and Squeeze

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Science Translational Medicine  12 Feb 2014:
Vol. 6, Issue 223, pp. 223ec29
DOI: 10.1126/scitranslmed.3008644

Eight years ago, Shinya Yamanaka stunned the world by converting “mono-tasking” differentiated cells into pluripotent cells. The simplicity of the molecular trick, which uses a bundle of transcription factors to turn the clock on cell differentiation, earned Yamanaka a Nobel Prize and heralded a dawn of regenerative human medicine.

The recent publication by Obokata et al. makes Yamanaka’s approach seem a collection of vintage molecular tools. In a surprisingly radical—if not heretical—twist, Obokata et al. presented us with a strikingly simple method of stem cell preparation. The procedure reads like a recipe for busy cooks: Take the mature cells, squeeze them at low pH, leave few cells to die, and collect the rest to serve as pluripotent stem cells. Everything goes: T cells, neurons, skin, lung, and liver cells could be converted with stunning ease into pluripotent stem cells.

The story of the discovery has a fairy-tale narrative with a happy ending. Obokata first observed morphological and molecular stem cell–like changes in mature cells upon squeezing them through a capillary. To convince herself, and later the skeptical referees, that the cells were not the stems cells to start with, she chose to manipulate mature T cells that are naturally tagged with a particular T cell antigen receptor DNA template. After squeezing T cells at low pH, Obokata et al. were able to trace the recombined DNA segment from the mature T cells to the reprogrammed pluripotent stem cells. The ultimate proof of true pluripotency came from the ability of these cells, once injected into a mouse embryo, to give rise to various tissues. Maybe most surprising, stem-like cells generated by the method were able to create placenta tissue.

The study, although already highly promising for regenerative medicine, is made even more exciting by raising the possibility of naturally occurring cell reprogramming within the human body. Numerous cells, especially cells of the immune system, need to squeeze hard to traverse through the blood vessel barriers. The cells that line our intestine and live in low-oxygen conditions are exposed to bacteria that produce lots of acidic substances and experience substantial mechanic pressure. Is there any chance that these mechanic stresses can lead to the generation of stem-like cells? If yes, is it possible that invasion of metastatic cells helps them to acquire pluripotency and hence make metastatic tumors highly adaptable to their new environment? All of these fascinating questions remain to be answered in the future, but for now, if shown to be equally applicable to human cells, Obokata’s approach is likely to help to make stem cell therapy a reality.

H. Obokata et al., Bidirectional developmental potential in reprogrammed cells with acquired pluripotency. Nature 505, 676–680 (2014). [Abstract]

H. Obokata et al., Stimulus-triggered fate conversion of somatic cells into pluripotency. Nature 505, 641–647 (2014). [Abstract]

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