Applying New CRISPR Technology to Transform Skin Cells into Pluripotent Stem Cells

Recently, a research team from Finland, Switzerland, and the United Kingdom successfully converted skin cells into pluripotent stem cells by activating the genes of the cells themselves. It is reported that the team applied a class of CRISPRa gene editing technology that does not cleave DNA and activates gene expression without altering the genome. So far, it has been possible to activate cell reprogramming to convert skin cells into stem cells through artificially introducing a set of key genes called Yamanaka factor into skin cells, related result is published in Nature-Communication.

In the article, researchers claimed that CRISPR-Cas9-based gene activation (CRISPRa) is an attractive tool for cell reprogramming because of its high multiplexing capacity and ability to directly target endogenous loci. Researchers used CRISPRa to target endogenous promoters of OCT4, SOX2, KLF4, MYC and LIN28A to induce primary skin cells into pluripotent stem cells (ipsCs). Reprogramming efficiency can be increased by an order of magnitude by additionally targeting a conserved Alu motif (EEA-motif) near the gene involved in embryonic genome activation. This effect is mediated to some extent by more efficient activation of NANOG and REX1. These data indicate that human somatic cells can be reprogrammed to ipsCs using only CRISPRa technology. Furthermore, these results reveal the role of EEA (EGA-enriched Alu motif) motif-related mechanisms in cell reprogramming.

Dr. Timo Otonkoski of the University of Helsinki said that CRISPR/Cas9 can be used to activate genes, which presents an attractive possibility for cell reprogramming because multiple target genes can be targeted at the same time. Reprogramming based on endogenous gene activation rather than transgene overexpression is theoretically a more physiological way to control cell fate, and may get more normal cells. In this study, they show that it is possible to design a CRISPR activation system for powerful ipsCs reprogramming.

Researchers also confirmed that one of the important keys to achieve success is the activation of a key genetic component that was discovered in the earliest steps of regulating human embryo development after fertilization. With this technique, the researchers obtained pluripotent stem cells that are similar to the typical early embryonic cells.

The study also found that many other reprogramming tasks could be improved by addressing the typical genetic elements of the intended target cell type. Dr. Jere Weltner, the lead author of the study, said the technology could be applied in biological libraries and many other tissue technology applications. In addition, the study also revealed new insights into mechanisms related to controlling gene activation in early embryos.

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