AsianScientist (Oct. 3, 2017) – Scientists in Japan have developed a synthetic DNA-targeting molecule that can be used to convert human induced pluripotent stem cells (hiPSCs) into heart muscle cells. They published their work in the journal Nucleic Acids Research.
hiPSCs are generated from adult cells and can be programmed to change into any cell type in the body. The cell type conversion is controlled by coordinated regulation of signaling cues and genes.
Molecules that regulate these diverse signals involved in organ development have been used to control the fate of hiPSCs. However, molecules that directly switch off the desired signaling genes have not been found. Currently available protocols involve the introduction of foreign genetic material, which could be risky to patients.
In this study, first author Mr. Junichi Taniguchi and Assistant Professor Ganesh Pandian Namasivayam at Kyoto University’s Institute for Integrated Cell-Material Sciences (iCeMS) in Japan constructed a synthetic molecule that can recognize and bind with a specific DNA sequence involved in the differentiation of hiPSCs into mesoderm, an intermediary cell type that can be stimulated to change into heart muscle cells.
When the synthetic molecule, called PIP-S2, binds to its target DNA sequence, it prevents a protein, called SOX2, from binding to the same site. SOX2 is highly expressed in hiPSCs and is responsible for keeping them in their ‘pluripotent’ state, meaning it stops them from converting into other cell types.
The researchers found that PIP-S2 bound to DNA, leading to the conversion of hiPSCs to mesoderm. The team then added to the hiPSC cell culture another signaling inhibitor molecule that is a known driver for heart muscle cell formation. Heart muscle cells demonstrating the ability to contract and retract were formed within a total period of 12 days.
“To our knowledge, this work is the first report of a DNA-binding synthetic molecule capable of guiding the differentiation of hiPSCs into a particular cell lineage,” said Professor Hiroshi Sugiyama of Kyoto Univeristy, the principal investigator of the study.
This strategy could be used to design additional synthetic molecules that target various DNA sequences, inducing hiPSCs to develop into different cell types, the researchers concluded.
The article can be found at: Taniguchi et al. (2017) SA Synthetic DNA-Binding Inhibitor of SOX2 Guides Human Induced Pluripotent Stem Cells to Differentiate into Mesoderm.
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Source: Kyoto University; Photo: Sudhakar KeerthiPriyaa.
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