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Scientists at the University of California-Los Angeles (UCLA) have created a Roadmap one-of-a-kind that traces every step in the development of blood stem cells in the human embryo. This will provide researchers with a blueprint for producing fully functional blood stem cells in the laboratory.
The research, published this Wednesday in the journal ‘Nature’, could help expand the options for treatment for blood cancerssuch as leukemia, and inherited blood disorders, such as sickle cell diseasesays Dr. Hanna Mikkola of the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at UCLA, who led the study.
Blood stem cells, also called hematopoietic stem cells, they have the ability to make unlimited copies of themselves and to differentiate into all types of blood cells in the human body.
For decades, doctors have used blood stem cells from bone marrow of donors and the umbilical cord of newborns in life-saving transplant treatments for blood and immune diseases. However, these treatments are limited by a shortage of compatible donors and by the low amount of stem cells in the umbilical cord blood.
Researchers have sought to overcome these limitations by attempting to create blood stem cells in the laboratory from human pluripotent stem cells, which can potentially give rise to any type of cell in the body. But the success has not been as expected, in part because scientists they lacked the instructions to make lab-grown cells differentiate into self-renewing blood stem cells rather than short-lived blood progenitor cells, which can only make limited types of blood cells.
“No one has been successful in making functional blood stem cells from human pluripotent stem cells because we didn’t know enough about the cell we were trying to make,” says Mikkola, a professor of molecular, cell and developmental biology at UCLA and member of the UCLA Jonsson Comprehensive Cancer Center.
The new roadmap will help researchers understand the fundamental differences between the two cell types, which is critical to creating cells that are suitable for use in transplant therapiespoints out UCLA scientist Vincenzo Calvanese, co-author of the research, along with Sandra Capellera-García and Feiyang Ma, from the same university.
“Now we have a primer on how stem cells are made cells in the embryo and how they acquire the unique properties that make them useful to patients,” says Calvanese, who is also a group leader at University College London.
Anonymized data is publicly available on The Atlas of Human Hematopoietic Stem Cell Development website.
The research team, which included scientists from Germany’s University of Tübingen and Australia’s Murdoch Children’s Research Institute, created the resource using single-cell RNA sequencing and spatial transcriptomics, new technologies that allow scientists to identify unique genetic networks and functions of thousands of individual cells and reveal the location of these cells in the embryo.
The data make it possible to follow blood stem cells as they emerge from the hemogenic endothelium and migrate through various locations during their development, starting from the aorta and reaching the bone marrow. Importantly, the map reveals specific milestones in their maturation process, including their arrival in the liver, where they acquire the special abilities of blood stem cells.
To explain the maturation process, Mikkola compares immature blood stem cells to aspiring surgeons. Just as surgeons must go through different stages to learn how to perform surgery, immature blood stem cells must move through different places to learn how to do their jobs.
The research group also identified the exact precursor in the blood vessel wall that gives rise to stem cells sanguine. This discovery clears up a long-standing controversy over the cellular origin of stem cells and the environment needed to produce a blood stem cell rather than a blood progenitor cell.
Now that researchers have identified specific molecular signatures associated with the different phases of human blood stem cell development, scientists can use this resource to see how close they are to producing transplantable blood stem cells in the laboratory.
“Before, if we tried to create a blood stem cell from a pluripotent cell and it didn’t transplant, we didn’t know where we failed in the process,” says Mikkola. “Now, we can put the cells on our roadmap to see where we are succeeding, where we are falling short, and adjust the differentiation process according to the instructions of the embryo,” she adds.
In addition, the map can help scientists understand how the blood-forming cells that develop in the embryo contribute to human disease. For example, to study why some blood cancers that begin in the womb are more aggressive than those that occur after birth.
“Now that we have created an online resource that scientists around the world can use to guide their research, the real work is beginning. It’s a really exciting time to be in the field because we’re finally going to see the fruits of our labor,” says Mikkola.
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