Clarification of how human blood vessels are constructed is frantically needed to advance regenerative medicine. A collaborative research team from Kumamoto University, Kyoto University, and the University associated with Tokyo in Japan investigated the changes in gene functions that occur when stem cells become vascular cells. They found that the histone code, which changes the transcriptional state of the gene, changes over time because stem cells differentiate into blood vessels in response to an incitement. Furthermore, they found that a transcription factor group important for blood vessel differentiation (ETS/GATA/SOX) has a previously unknown function.

Regenerative medicine has made impressive progress due to research with embryonic stem (ES) tissue and induced pluripotent stem (iPS) cells. However , the particular mechanism of how blood vessels are constructed from these undifferentiated tissues has not yet been clarified. During the creation of new arteries, the vascular endothelial growth factor (VEGF) protein distinguishes stem cells into vascular endothelial cells and induces them to create new blood vessels. Researchers at Kumamoto College added VEGF to undifferentiated ES cells and monitored the behavior of the entire genome and epigenome changes with time in vitro.

Using ES cells created at the Center for iPS Cell Research and Software (CiRA) in Kyoto University, the research group collected RNA and histones of each cell immediately after VEGF stimulation (0 h), before differentiation (6 h), during differentiation (12 — 24 h), and after differentiation (48 h). Then they comprehensively analyzed the changes in the whole genome and epigenome using next generation deep sequencing.

In the process associated with blood vessel differentiation, the function of the protein ETS variant 2 (ETV2), which determines the differentiation directly into vascular endothelium, was first induced within 6 hours associated with differentiation stimulation. The protein GATA2, which binds in order to ETV2 and supports vascular endothelial differentiation, was caused immediately thereafter. Transcription factors SOX and FLI1, each important for endothelial differentiation, were induced between 12 plus 24 hours. At 48 hours, after differentiation into vascular endothelium was determined, a system of transcription was founded in which genes unique to vascular endothelial differentiation had been induced.

Furthermore, an examination of the histone code revealed that the regulatory genomic region of the transcribing factors (ETS/GATA/SOX) was found to have gradually switched from the “brake histone mark, ” which suppresses transcription, for an “accelerator histone mark, ” which activates transcription, whilst in the process of differentiating into the vascular endothelium. Previously, in the region that will controls the function of the transcription factor that stimulates differentiation from ES cells to a specific cell kind, bivalent modifications of histones such as the accelerator and braking system histone marks for transcription were thought to have coexisted.

In addition , when these transcription factors get rid of their function, terminal differentiation into the vascular endothelium (completion of differentiation) is completely suppressed, and genes that are crucial to differentiation into vascular endothelial cells as well as transcribing factors that maintain the undifferentiated state are adversely caused. Collectively, the transcription factors (ETS/GATA/SOX) not only induce vascular endothelial differentiation, but also suppress regression to an undifferentiated condition and differentiation into other ectodermal or endoderm-derived tissues.

It is expected that the knowledge of the features of these transcription factors, when combined with gene editing strategies, will allow for the efficient regeneration of blood vessels.

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Materials provided by Kumamoto College . Note: Content may be edited intended for style and length.