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Process Discovered That Converts Blood Vessels to Blood Stem Cells During Early Development

Scientists from the Wellcome Sanger Institute in the U.K. and the European Molecular Biology Laboratory in Rome say they found a switch that instructs blood vessel cells to become blood stem cells during embryonic development. The team discovered that two sets of specific factors in the cells work against each other, and when the balance of these changes, the vascular tube cells convert to free blood cells. 

The study (“Single-Cell Transcriptomics Reveals a New Dynamical Function of Transcription Factors during Embryonic Hematopoiesis”), published in eLife, could pave the way for further research into creating new blood cells for transplants and for understanding cancer development, according to the researchers.

“Recent advances in single-cell transcriptomics techniques have opened the door to the study of gene regulatory networks (GRNs) at the single-cell level. Here, we studied the GRNs controlling the emergence of hematopoietic stem and progenitor cells from mouse embryonic endothelium using a combination of single-cell transcriptome assays. We found that a heptad of transcription factors (Runx1, Gata2, Tal1, Fli1, Lyl1, Erg and Lmo2) is specifically co-expressed in an intermediate population expressing both endothelial and hematopoietic markers,” write the investigators.

“Within the heptad, we identified two sets of factors of opposing functions: one (Erg/Fli1) promoting the endothelial cell fate, the other (Runx1/Gata2) promoting the hematopoietic fate. Surprisingly, our data suggest that even though Fli1 initially supports the endothelial cell fate, it acquires a pro-hematopoietic role when co-expressed with Runx1. This work demonstrates the power of single-cell RNA-sequencing for characterizing complex transcription factor dynamics.” 

To understand the process of blood cell development, the scientists studied seven transcription factors, known to be important in blood cancers, using single-cell transcriptomics. They discovered that in mouse embryo cells that were transitioning between vascular cells and blood cells, all seven of these factors were expressed together. However, when they engineered various combinations of these transcription factors into embryonic stem cell lines (ESCs), used to model embryonic blood development in the dish, they discovered the factors split unexpectedly into two distinct sets, one supporting the vascular cell fate and the other the blood program.

The researchers discovered there was a balance between the two sets of transcription factors. High levels of each set of transcription factors acted as a switch for the mouse embryo to choose whether to maintain vascular cells, or to develop them into blood stem cells.

According to corresponding author Martin Hemberg, Ph.D., from the Wellcome Sanger Institute, “This was the first time that anyone has been able to show how a group of transcription factors causes a vascular cell to choose to develop into a blood stem cell, and demonstrates the power of single-cell transcriptomics for characterizing really complex systems of transcription factors. Using this technology, we could see the exact genes that were switched on in every single cell, and found that the transcription factors acted as a fork in the road of development of blood cells.”

“This was a very challenging computational problem as there was a huge network of interactions in the complex that needed to be unraveled,” added Tallulah Andrews, Ph.D., joint second author on the paper from the Wellcome Sanger Institute. “By applying recent advances in statistics to this biological question, we were able to predict that some of the transcription factors were acting in opposition to each other like a switch, rather than working together, which the study was then able to prove experimentally.”

The knowledge gained in the study could aid further research toward the creation of blood stem cells for use in transfusions or blood cancer treatments, and could also help in the understanding of metastasis, which is when cancer cells spread to other organs. 

“We have revealed the gene regulatory network responsible for switching off the vascular cell fate and switching on the blood program to generate blood stem cells,” explained Christophe Lancrin, Ph.D., a corresponding author on the paper from the European Molecular Biology Laboratory, Rome. “Interestingly, the process of metastasis in cancer also involves changes in cell states and may use a similar process to the one we have discovered. If we could better understand how the transcription factors responsible for different cell states compete with each other, we could begin to think of ways to specifically inhibit this process and improve the chance of survival of cancer patients.”

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