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Researchers Create Embryonic Stem Cells Without Embryo (2014-02-13)

Researchers from Brigham and Women's Hospital (BWH), in collaboration with the RIKEN Center for Developmental Biology in Japan, have demonstrated that any mature adult cell (a "somatic" cell) has the potential to turn into the equivalent of an embryonic stem cell. Published in the January 30, 2014 issue of Nature, researchers demonstrate in a preclinical model, a novel and unique way that cells can be reprogrammed, a phenomenon they call stimulus-triggered acquisition of pluripotency (STAP). Importantly, this process does not require the introduction of new outside DNA, the process commonly used to induce adult cells back into a state of pluripotentency. Mouse cells exposed to acidic environments undergo an apparent metamorphosis into stem cells with unprecedented developmental flexibility.

 


 

Since the discovery of human embryonic stem cells, scientists have had high hopes for their use in treating a wider variety of diseases because they are pluripotent, which means they are capable of differentiating into one of many cell types in the body.

However, the acquisition of human embryonic stem cells from an embryo can cause the destruction of the embryo, thus raising ethical concerns. In 2006, researchers introduced an alternative to harvesting embryonic stem cells called induced pluripotent stem (iPS) cells. They provided evidence that it was possible to send a normal adult cell back to an undifferentiated, pluripotent stem cell state by introducing genetic material ("outside" DNA) into the cell, a process that alters the original state of the cell. To avoid the use of embryonic stem cells, other researchers have focused more on the use of adult stem cells, but the use is of these cells is limited because unlike embryonic stem cells that grow into any type of mature cell, adult stem cells can only grow into certain cell types.

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.
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.

Beginning with mature adult cells, researchers let them multiply. After stressing the cells almost to the point of death by exposing them to various stressful environments including trauma, a low oxygen environments and an acidic environment, researchers discovered that within a period of only a few days, the cells survived and recovered from the stressful stimulus by naturally reverting into a state that is equivalent to an embryonic stem cell.
The stem cells created by exposure to the external stimuli were then able to redifferentiate and mature into any type of cell and grow into any type of tissue, depending on the environment into which they were placed.

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’.

Many other questions also remain. Obokata and colleagues successfully derived STAP cells from a wide range of source tissues in week-old mice, but it is unclear whether cells harvested from older or adult animals would retain the same capacity for pH-induced reprogramming, or whether the same protocol would work for human cells. The evolutionary advantage of having such a reprogramming pathway is also uncertain. “Why do somatic cells latently possess this self-driven ability for nuclear reprogramming?” asks Obokata. “And how is this reprogramming mechanism normally suppressed?” Resolving these questions and piecing together the events that transpire in the cellular interior during STAP reprogramming will be a top priority for her team moving forward.

In the meantime, the remarkable properties demonstrated by STAP cells and STAP stem cells suggest that they could offer an unexpectedly simple and unobtrusive mechanism by which researchers can generate pluripotent cells for research—and perhaps even clinical—applications that previously required the laborious isolation of ES or iPS cells. “It’s exciting to think about the new possibilities these findings open up, not only in areas like regenerative medicine, but perhaps in the study of cellular senescence and cancer as well,” says Obokata.

Researchers note that the next step is to explore this process in more sophisticated mammals and ultimately in humans. If this same process can be demonstrated in human cells, then some day, through a skin biopsy or blood sample, without the need for genetic manipulation,, researchers may be able to create embryonic stem cells specific to each individual, which in turn could be used to create tissue without the need to insert any outside genetic material into that cell, creating endless possibilities for therapeutic options.

Researchers write that further questions exist; Vacanti and colleagues are interested in exploring why and how stressful stimuli drive reprogramming to create the pluripotent state.

Collaborators involved in this research include: The first author of the manuscript, Haruko Obokata, from the Laboratory for Genomic Reprogramming and the Laboratory for Organogenesis and Neurogenesis at the RIKEN Center for Developmental biology , Teruhiko Wakayama from the Laboratory for Organogenesis and Neurogenesis at the RIKEN Center for Developmental biology, Yoshiki Sasai, from the Laboratory for Organogenesis and Neurogenesis at the RIKEN Center for Developmental biology; Koji Kojima, from the Laboratory for Tissue Engineering and Regenerative Medicine, Brigham and Women's Hospital; Martin P. Vacanti from from the Laboratory for Tissue Engineering and Regenerative Medicine, Brigham and Women's Hospital and the Department of Pathology at the Irwin Army Community Hospital; Hitoshi Niwa, from the Laboratory for Pluripotent Stem Cell Studies at the RIKEN Center for Developmental Biology; Masayuki Yamato, from the Institute of Advanced Biomedical Engineering and Science and the Tokyo Women's Medical University; and the senior author, Charles A. Vacanti, director of the Laboratory for Tissue Engineering and Regenerative Medicine, Brigham and Women's Hospital and Harvard Medical School.

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