Primed human embryonic stem cells (purple) surrounded by a stem-cell-surface marker (green), which would be missing in naïve embryonic stem cells.
Scientists at the UCLA Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research have discovered an important naturally occurring process in the developing human embryo that can be lost when embryonic stem cells are derived in the lab. The finding provides critical information regarding the best method for creating stem cells for regenerative-medicine purposes. The discovery also provides insight into how information that is passed from an unfertilized egg to an embryo may affect the quality of the embryo and, subsequently, the birth of healthy children.
The research focuses on DNA methylation in the early embryo and in stem cells created from embryos. DNA methylation plays a role in how genetic information is used in the body. Correct DNA methylation of particular genes is critical for normal human development, and it remains critical in maintaining healthy cells throughout a person’s lifespan. It also helps maintain an embryonic stem cell’s ability to develop into any cell in the body.
The researchers discovered that an early-stage embryo, or blastocyst, retains the DNA methylation pattern from the egg for at least six days after fertilization. “We know that the six days after fertilization is a very critical time in human development,” says Amander Clark, PhD, vice chair of molecular, cell and developmental biology. “It’s not clear yet why the blastocyst retains methylation during this time period, but this finding opens up new areas of investigation into how methylation patterns built in the egg affect embryo quality and the birth of healthy children.”
The team also revealed that using a recently adopted method to derive stem cells from embryos in a petri dish depletes methylation. In the early embryo, the blastocyst stage of development lasts for less than five days. The less-mature human embryonic cells that exist at the beginning of blastocyst development are called “naïve” embryonic cells. It is thought that at the time of implantation, these naïve embryonic cells reach a more mature state. They are then called “primed” embryonic cells, able to become every cell type in the body.
In 1998, when the first human embryonic stem cells were derived, scientists used a method that created primed stem cells. This was the standard method until recently, when scientists started using a different method that preserves the naïve stem cell state. “In the past three years, naïve stem cells have been touted as potentially superior to primed cells,” Dr. Clark says. “But our data show that the naïve method for creating stem cells results in cells that have problems, including the loss of methylation from important places in DNA. Until we have a way to create more stable naïve embryonic stem cells, the embryonic stem cells created for the purposes of regenerative medicine should be in a primed state in order to create the highest-quality cells for differentiation.”
“Naïve Human Pluripotent Cells Feature a Methylation Landscape Devoid of Blastocyst or Germline Memory,” Cell Stem Cell, January 2016