Journal of Cytology & Histology
A small number of human embryonic stem cells, now believed to be pluripotent, may be totipotent.
The difference is fundamental. Pluripotent stem cells can give rise to almost every type of cell in the human body. But they cannot produce “extraembryonic” cells such as those in the placenta.
Totipotent stem cells can become every type of cell, including placental cells. That makes them functionally equivalent to a fertilized egg, which also possesses this property. Totipotent stem cells may be more useful for therapy than pluripotent stem cells, said Pfaff, who is also an investigator at the Howard Hughes Medical Institute.
The research also has implications for therapy with induced pluripotent stem cells; genetically reprogrammed adults cells that act much like embryonic stem cells.
Finally, the study suggests an interesting possibility in the evolution of placental mammals.
Pfaff is a professor in Salk’s Gene Expression Laboratory and senior author of the paper, published online June 13 in the journal Nature.
The researchers studied mouse embryonic stem cells, which they believe accurately reflect patterns of gene activation in human fertilized eggs and embryonic stem cells.
“We’ve identified a mechanism that resets embryonic stem cells to a more youthful state, where they are more plastic and therefore potentially more useful in therapeutics against disease, injury and aging,” Pfaff said in a Salk press release.
“Nearly 8 percent of the human genome is made up of ancient relics of viral infections that occurred in our ancestors, which have been passed from generation to generation but are unable to produce infections. Pfaff and his collaborators found that cells have used some of these viruses as a tool to regulate the on-off switches for their own genes,” the Salk press release stated.
The researchers tested mouse embryonic stem cells that exhibited genetic patterns similar to those of mouse embryos at the two-cell, or 2C, stage. They found that these cells gave rise to extraembryonic tissues. Moreover, they found that this 2C-like population was not stable; embryonic stem cells cycled in and of this state.
The study stated that “several lines of evidence indicate that 2C-like cells are required for the health and maintenance of ES cultures. Among the reasons:
Nearly all embryonic stem cells enter this state at one time or another, indicating that the state is necessary.
Removing these 2C-like cells from cultures biased them to making more ectoderm and mesoderm derivatives, presumably affecting their ability to form a complete, functional embryo
A gene called Zscan4 that is particularly active in the 2C-like cells is required for maintaining telomeres, the protective ends of chromosomes.
“Another important question that remains is whether the selection of these special ES cells can be used for practical purposes, such as reprogramming somatic nuclei,” the study stated. That was a reference to induced pluripotent stem cells. These are made by reprogramming adult cells, typically skin cells called fibroblasts, and are being intensely researched for therapy.
“This possibility is supported by the recent finding that forced Zscan4 expression in fibroblasts enhances their iPS cell reprogramming efficiency,” the study stated.
The study also suggested that transposable elements from ancient viral infections are responsible for the evolution of placental mammals, one of three main categories of mammals. (The others are marsupials, such as kangaroos, and the egg-laying monotremes, such as echidnas).
“Our findings support the notion that the co-option of retrotransposable elements by cellular genes can act as an evolutionary mechanism for coordinately linking the expression of many genes,” the study stated. “Transposon sequences have recently been shown to have a crucial role in rewiring gene regulatory networks in ES cells and in the endometrium that contributed to the evolution of pregnancy in mammals. It has also been speculated that ERVs were involved in the evolution of the placenta by providing fusogenic envelope genes adapted for formation of the syncytiotrophoblasts.
“We suggest that endogenous retroviruses, which are found in all placental mammals, may have had an equally important gene regulatory role in early mammalian development, by contributing to the specification of cell types and leading to the formation of placental tissues.”