Ordinarily, if you want to produce a stem cell without destroying an embryo, you must subject a somatic cell—a mature, differentiated cell—to fairly invasive treatment. You either resort to nuclear transfer or insert transcription factors, altering the original state of the cell. Either way, you can end up with an induced pluripotent stem cell, or an adult stem cell, which is fine, except adult stem cells can only grow into certain cell types. Adult stem cells lack the plasticity of embryonic stem cells, which can grow into any type of mature cell.
Now, however, it appears that a less invasive—but still fairly intense—approach to reprogramming somatic cells can give rise to adult stem cells. What’s more, the adult stem cells may be pluripotent, as plastic as embryonic stem cells.
This approach—stimulus-triggered acquisition of pluripotency, or STAP—has been pioneered by researchers at Brigham and Women’s Hospital (BWH) in collaboration with the RIKEN Center for Developmental Biology in Japan. These researchers, rather than directly meddle with the internal workings of somatic cells, chose to alter the cells’ external environment. Specifically, the researchers stressed the cells almost to the point of death by exposing them to various stressful environments including trauma, low oxygen, and acidic conditions.
The 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.
This startling result was published online January 29 in Nature, in an article entitled “Stimulus-triggered fate conversion of somatic cells into pluripotency.” While it may be an overstatement to say “that which does not kill a somatic cell makes it pluripotent,” the authors of the Nature article did write that “somatic cells latently possess a surprising plasticity. This dynamic plasticity—the ability to become pluripotent cells—emerges when cells are transiently exposed to strong stimuli that they would not normally experience in their living environments.” The researchers also noted that STAP cells showed a substantial decrease in DNA methylation in the regulatory regions of pluripotency marker genes.
To examine the growth potential of these cells, researchers used mature blood cells from GFP+ mice, mice that had been genetically altered with a specific mutation to light up green under a specific wavelength of light. They stressed the GFP+ cells from the blood by exposing them to an acidic environment and found that in the days following the stress, those cells reverted back to an embryonic stem cell-like state. These stem cells then began growing in spherical clusters, similar to a plant callus. The cell clusters were introduced into the developing embryo of a non-GFP mouse (whose cells do not light up green) to create a mixture of cells (a chimera). The implanted clusters were able to create GFP+ tissues in all organs tested, confirming that the cells are pluripotent.
Researchers hypothesize that these findings raise the possibility that unknown cellular functions that are activated through external stress, may set mature adult cells free from their current commitment and permit them to revert to their naïve cell state.
“Our findings suggest that somehow, through part of a natural repair process, mature cells turn off some of the epigenetic controls that inhibit expression of certain nuclear genes that result in differentiation,” said Charles Vacanti, M.D., chairman of the Department of Anesthesiology, Perioperative and Pain Medicine and Director of the Laboratory for Tissue Engineering and Regenerative Medicine at BWH and senior author of the study.
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 one 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.