Stress gives cells a 'second childhood'

4 hours ago Figure 1: Within a week of exposure to acidic culture conditions, white blood cells gave rise to clusters of cells expressing the pluripotency gene Oct4 (green). Credit: Haruko Obokata, RIKEN Center for Developmental Biology

What doesn't kill cells may make them strongeror considerably more flexible, at least. New findings from Haruko Obokata of the RIKEN Center for Developmental Biology in Kobe and Charles Vacanti at Brigham and Women's Hospital in the United States suggest that exposing mouse cells to acidic stress can make them regress to an extremely developmentally immature state, transcending even that of embryonic stem (ES) cells.

ES cells have the developmental capacity to form any tissue type in the body and this 'pluripotency' makes them of great interest to both scientists and clinicians. As these cells must be harvested from early-stage embryos, however, human ES cell research remains a politically and ethically fraught issue. As an alternative, researchers can 'reprogram' adult cells into ES cell-like induced pluripotent stem (iPS) cells, which offer the advantage of being genetically matched to their donoran important consideration for regenerative medicine. However, the generation of iPS cells typically requires the introduction of reprogramming genes, which may affect their function or risk of cancerous transformation.

Obokata and colleagues have now discovered an alternative route to pluripotency, drawing on inspiration from the plant world. "Plants [such as] carrots can produce stem cells from totally differentiated cells when they are exposed to strong external stresses like dissection," Obokata said in a recent interview with Nature. "I instinctively felt that we may have a similar mechanism to plants." To test this hypothesis, she and her colleagues isolated white blood cells from newborn mice and examined how they responded to diverse external stresses.

Back to the beginning

The researchers genetically modified mouse cells so that they would express a fluorescent label when Oct4, a gene prominently associated with pluripotency, was activated. Using this indicator, Obokata and colleagues determined that less than 30 minutes of exposure to acidic conditions was sufficient to spur the formation of clusters of Oct4-expressing cells (Fig. 1). Although the treatment killed most of the initial cell population, around half of the cells that survived were fluorescently labeled after a week of culture in media favorable for stem cell growth.

The surviving cells showed many characteristics of ES cells, including the capacity to form all of the various 'germ layers'three distinct types of embryonic tissue that form early in development, each giving rise to a different subset of cell types. Furthermore, when these 'stimulus-triggered acquisition of pluripotency' (STAP) cells were injected into early-stage mouse embryos, they were incorporated into every tissue in the body (Fig. 2) and the embryos subsequently developed into healthy, fertile mice.

Unlike ES cells, however, the STAP cells grew poorly in culture. In an effort to bolster their proliferation, Obokata and colleagues grew the cells in stem-cell-culture medium supplemented with adrenocorticotropic hormone (ACTH), a molecule that promotes ES cell growth. The cells flourished, while apparently retaining their capacity to thoroughly integrate into developing embryos. The researchers termed these more culture-friendly cells 'STAP stem cells'.

The STAP cells also had other surprises in store for the researchers. Developing embryos are surrounded by a 'support tissue' known as the trophoblast, which ultimately forms the placenta. When ES cells are transplanted into an early-stage embryo, they are generally incorporated exclusively into the embryo and not into the trophoblast. In contrast, transplanted STAP cells were integrated into both the embryo and the trophoblast. Obokata and colleagues observed that STAP cells express several genes whose activity is normally associated with the trophoblast lineage. Cultivating STAP cells in the presence of the signaling protein fibroblast growth factor (FGF) increased their similarity to trophoblast stem cells, indicating that the treatment may push the STAP cells further along in a particular developmental path. Conversely, transplanted STAP stem cells were incapable of becoming incorporated into the trophoblast and thus appear to be on a set path of embryonic tissue development.

A developing mystery

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Stress gives cells a 'second childhood'