The ability to reliably and safely make in the laboratory all of the different types of cells in human blood is one key step closer to reality.
A group from the University of Wisconsin-Madison reports the discovery of two genetic programs responsible for taking blank-slate stem cells and turning them into both red and the array of white cells that make up human blood. The research is important because it identifies how nature itself makes blood products at the earliest stages of development. The discovery gives scientists the tools to make the cells themselves, investigate how blood cells develop and produce clinically relevant blood products.
This is the first demonstration of the production of different kinds of cells from human pluripotent stem cells using transcription factors, the proteins that bind to DNA and control the flow of genetic information, which ultimately determines the developmental fate of undifferentiated stem cells.
During development, blood cells emerge in the aorta, a major blood vessel in the embryo. There, blood cells, including hematopoietic stem cells, are generated by budding from a unique population of what scientists call hemogenic endothelial cells. The new report identifies two distinct groups of transcription factors that can directly convert human stem cells into the hemogenic endothelial cells, which subsequently develop into various types of blood cells.
The factors identified by the group were capable of making the range of human blood cells, including white blood cells, red blood cells and megakaryocytes, commonly used blood products. By overexpressing just two transcription factors, the team reproduced the sequence of blood-making events seen in the embryo a laboratory dish.
The method developed by the group was shown to produce blood cells in abundance. For every million stem cells, the researchers were able to produce 30 million blood cells. A critical aspect of the work is the use of modified messenger RNA to direct stem cells toward particular developmental fates. The new approach makes it possible to induce cells without introducing any genetic artifacts. By co-opting nature’s method of making cells and avoiding all potential genetic artifacts, cells for therapy can be made safer.
This can be done without a virus, and genome integrity is not affected. Moreover, while the new work shows that blood can be made by manipulating genetic mechanisms, the approach is likely to be true as well for making other types of cells with therapeutic potential, including cells of the pancreas and heart.
The next step is to make hematopoietic stem cells, multipotent stem cells found in bone marrow. Hematopoietic stem cells are used to treat some cancers, including leukemia and multiple myeloma. Devising a method for producing them in the lab remains a significant challenge. With the new approach to making blood cells used to model their development in a dish and identify novel hematopoietic stem cell factors.