The formation of a human embryo starts with the fertilization of an egg by a sperm, resulting in a cell called a zygote, which starts dividing. Five days after fertilization a blastocyst is formed, which is a ball-shaped cluster of cells that can give rise to all the cell types of the developing embryo. These cells can be isolated in the lab and are referred to as embryonic stem cells. Scientists can use embryonic stem cells to create every cell type in the human body, making them an extremely important resource for both research and medicine.
Extensive research in the last decade showed that even though these cells are obtained ~5 days after fertilization, they are maintained in a slightly latter developmental stage. This led scientists to develop different methods that manipulate embryonic stem cells to a more immature state termed "naïve embryonic stem cells". However, the manipulation methods used for obtaining naïve embryonic stem cells also lead to unwanted side effects.
One unintended side effect that occurs in naïve embryonic stem cells is erasure of a unique information that is called "parental imprinting". Despite getting similar gene sets from our father and mother, a subset of genes is expressed only from a single parent while silenced ("imprinted") in the other. Therefore, we need both the genome of our father and our mother for proper development. Losing the information that maintains imprinting can lead to various diseases.
In this study, we used computational methods to analyze expression patterns of imprinted genes in naive cells generated by ~20 independent studies. We discovered that naive cells aberrantly express many imprinted genes from both parents’ genome, which can compromise their use in regenerative medicine and disease modeling. We also performed a global gene expression analysis of naive cells, which enabled us to recognize the most important cellular pathway that is involved in the imprint loss, and specified a unique protocol that can result in less aberrant cells.
These findings are extremely important not only because they raise red flags for using naive cells for medicine, but also because they could potentially pave the way for the creation of new techniques to generate naive cells which do not involve the manipulation of the cellular pathway which is behind the loss of imprinting information.
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