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A research team led by University of California, Los Angeles scientists has created a single-cell transcriptome map of human hematopoietic tissues from the first trimester to birth.

Blood stem cells, or hematopoietic stem cells, have the ability to make unlimited copies of themselves and to differentiate into every type of blood cell in the human body.

For decades, doctors have used blood stem cells from the bone marrow of donors and the umbilical cords of newborns in life-saving transplant treatments for blood and immune diseases.

However, these treatments are limited by a shortage of matched donors and hampered by the low number of stem cells in cord blood.

Scientists have sought to overcome these limitations by attempting to create blood stem cells in the lab from human pluripotent stem cells, which can potentially give rise to any cell type in the body.

But success has been elusive, in part because scientists have 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 produce limited blood cell types.

“Previous efforts to make functional blood stem cells in the lab have not been successful as we did not know enough about how these cells develop,” said Dr. Vincenzo Calvanese, a researcher in the Department of Molecular, Cell and Developmental Biology and the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at the University of California, Los Angeles, and the Laboratory for Molecular Cell Biology at University College London.

“Our new roadmap will help other scientists to understand fundamental differences between blood stem cells and short-lived progenitor cells.”

“We now have a manual of how hematopoietic stem cells are made in the embryo and how they acquire the unique properties that make them useful for patients.”

Dr. Calvanese and his colleagues created the resource using single-cell RNA sequencing and spatial transcriptomics, new technologies that enable scientists to identify the unique genetic networks and functions of thousands of individual cells and to reveal the location of these cells in the embryo.

The de-identified data are available to the public on the website The Atlas of Human Hematopoietic Stem Cell Development.

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 ultimately arriving in the bone marrow.

Importantly, the map unveils specific milestones in their maturation process, including their arrival in the liver, where they acquire the special abilities of blood stem cells.

The researchers also pinpointed the exact precursor in the blood vessel wall that gives rise to blood stem cells.

This discovery clarifies a longstanding controversy about the stem cells’ cellular origin and the environment that is needed to make a blood stem cell rather than a blood progenitor cell.

Now that the authors 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 making a transplantable blood stem cell in the lab.

“Previously, if we tried to create a blood stem cell from a pluripotent cell and it didn’t transplant, we wouldn’t know where in the process we failed,” said Professor Hanna Mikkola, a researcher in the Department of Molecular, Cell and Developmental Biology and the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at the University of California, Los Angeles.

“Now, we can place the cells in our roadmap to see where we’re succeeding, where we’re falling short and fine-tune the differentiation process according to the instructions from the embryo.”

In addition, the map can help scientists understand how blood-forming cells that develop in the embryo contribute to human disease.

For example, it provides the foundation for studying why some blood cancers that begin in utero are more aggressive than those that occur after birth.

“Now that we’ve created an online resource that scientists around the world can use to guide their research, the real work is starting,” Professor Mikkola said.

“It’s a really exciting time to be in the field because we’re finally going to be seeing the fruits of our labor.”

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