Old but gold: standard method for creating high-quality embryonic stem cells is more efficient than novel methods

A team of scientist from UCLA (LA, USA) have found that embryonic stem cells should be in a primed state as opposed to a naive stem cell state in order to create the highest-quality cells for differentiation.

Scientists at the UCLA Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research (LA, USA) have uncovered an important naturally occurring process in the developing human embryo that can be lost when embryonic stem cells are derived in the lab.

The research focuses on DNA methylation in the early embryo and in stem cells derived from embryos. DNA methylation is a biochemical process that occurs naturally in DNA and plays a role in how genetic information is utilized in the body. Correct DNA methylation is critical for normal human development and remains critical in maintaining healthy cells throughout a person’s lifespan. It is also known to help maintain embryonic stem cell in their pluripotent state.

The researchers made two significant discoveries about DNA methylation. First, they demonstrated that an early-stage embryo, or blastocyst, retains the DNA methylation pattern from the egg for at least six days after fertilization and not a few hours, as was previously believed.

“We know that the six days after fertilization is a very critical time in human development, with many changes happening within that period,” explained Amander Clark, study lead author and a professor and vice chair of molecular, cell and developmental biology in the life sciences at UCLA. “It’s not clear yet why the blastocyst retains methylation during this time period or what purpose it serves, 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’s second discovery reveals that utilizing a recently adopted method to derive stem cells from embryos in a petri dish results in loss of methylation. In the early embryo, the blastocyst stage of development lasts for less than 5 days. The less mature human embryonic cells that exist at the beginning of blastocyst development are called ‘naive’ embryonic cells. It is thought that at the time of implantation, these naive embryonic cells reach a more mature state. These are then called ‘primed’ embryonic cells, as they are primed 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 an alternative method that preserves the naïve stem cell state.

“In the past three years, naive stem cells have been touted as potentially superior to primed cells,” stated Clark. “But our data show that the naive method for creating stem cells results in cells that have problems, including the loss of methylation from important places in DNA. Therefore, until we have a way to create more stable naive 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.”

This discovery provides scientists with critical information regarding the best method for creating stem cells for regenerative medicine purposes. The study also provides insight into how information that is passed from an unfertilized egg to an embryo may impact the quality of the embryo and subsequently, the birth of healthy children.

To further this research, Clark and Kathrin Plath, professor of biological chemistry in UCLA Life Sciences, plan to collaborate to determine the optimal conditions for creating naive embryonic stem cells that are more stable and retain methylation at places in the genome where it is most needed.

Sources: http://newsroom.ucla.edu/releases/standard-method-for-deriving-stem-cells-may-be-better-for-use-in-regenerative-medicine;William A, Di Chen P, Liu W et al. Naive human pluripotent cells feature a methylation landscape devoid of blastocyst or germline memory. Cell Stem Cell, doi:10.1016/j.stem.2016.01.019 (2016) (Epub ahead of print).