A newly discovered DNA-targeting molecule could inspire the first tissue regeneration therapies. The synthetic molecule can cause stem cells to transform into heart muscle cells.
The scientists responsible for the new molecule believe their breakthrough could be used to turn stem cells into a variety of cell types — paving the way for tissue regeneration.
Human induced pluripotent stem cells are adult stem cells capable of forming any type of cell. Their transformation is dictated by a series of genetic and protein signals. This gene expression process is triggered by specific molecules.
Scientists have previously discovered molecules capable of switching on genetic signals, but have yet to find molecules with the ability to turn off specific genetic signals in pluripotent stem cells.
Researchers at Kyoto University in Japan, however, have developed a new synthetic molecule, PIP-S2, that can alter gene signaling in hiPSCs. The molecule works by binding with a specific section of genetic coding.
The molecule’s position blocks the parking spot of SOX2, a protein that keeps hiPSCs in their ‘pluripotent’ state. With SOX2 blocked, the hiPSC converts to a more easily manipulated intermediary cell type called a mesoderm. Researchers were then able to convert the mesoderm into heart muscle cells using a different signalling inhibitor molecule.
Researchers believe they can use their new molecule to convert hiPSCs into a variety of cell types.
Nucleic Acids Research – A synthetic DNA-binding inhibitor of SOX2 guides human induced pluripotent stem cells to differentiate into mesoderm
Unlike the well-studied differentiation routes to achieve cardiomyocytes, several challenges remain to attain other cell types from hiPSCs, which include the poor efficiency, need for transfection of exogenous TFs, and complex culture techniques. Over the past decade, loss-/gain-of-function studies and high-throughput sequencing studies such as ChIP-seq have identified the critical function of cell type-specific TFs and their key regulatory motifs in controlling lineage specification. Because PIPs can be designed to target preferred DNA sequences, the strategy demonstrated in this study could be expanded for rationally designing PIPs to match corresponding regulatory sequence motifs and differentiate hiPSCs into any cell type. Additionally, PIPs are amenable to the conjugation with other chemical components including epigenetic modulators such as histone deacetylase (HDAC) inhibitors and histone acetyltransferase (HAT) activators, resulting in ‘epigenetic switches’ which activate selective genes through induction of histone acetylation. Combined use of these ‘epigenetic switches’ along with simple PIPs like PIP-S2 as DNA-binding inhibitors will achieve control over more complex cell fates in our future studies. Overall, this work serves as a pioneering study for the use of gene-targeting synthetic molecules in regenerative medicine.
Targeted differentiation of human induced pluripotent stem cells (hiPSCs) using only chemicals would have value-added clinical potential in the regeneration of complex cell types including cardiomyocytes. Despite the availability of several chemical inhibitors targeting proteins involved in signaling pathways, no bioactive synthetic DNA-binding inhibitors, targeting key cell fate-controlling genes such as SOX2, are yet available. Here, we demonstrate a novel DNA-based chemical approach to guide the differentiation of hiPSCs using pyrrole–imidazole polyamides (PIPs), which are sequence-selective DNA-binding synthetic molecules. Harnessing knowledge about key transcriptional changes during the induction of cardiomyocyte, we developed a DNA-binding inhibitor termed PIP-S2, targeting the 5′-CTTTGTT-3′ and demonstrated that inhibition of SOX2–DNA interaction by PIP-S2 triggers the mesoderm induction in hiPSCs. Genome-wide gene expression analyses revealed that PIP-S2 induced mesoderm by targeted alterations in SOX2-associated gene regulatory networks. Also, employment of PIP-S2 along with a Wnt/β-catenin inhibitor successfully generated spontaneously contracting cardiomyocytes, validating our concept that DNA-binding inhibitors could drive the directed differentiation of hiPSCs. Because PIPs can be fine-tuned to target specific DNA sequences, our DNA-based approach could be expanded to target and regulate key transcription factors specifically associated with desired cell types.
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