Hanna Mikkola

UCLA-led team creates first comprehensive map of human blood stem cell development

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Human blood stem cells emerging from specialized endothelial cells in the wall of an embryonic aorta. UCLA scientists’ confirmation of this process clarifies a longstanding controversy about the stem cells’ cellular origin. Image Credit: Hanna Mikkola Lab/UCLA, Katja Schenke-Layland Lab/University of Tübingen, Nature

California researchers from UCLA and colleagues have created a first-of-its-kind roadmap that traces each step in the development of blood stem cells in the human embryo, providing scientists with a blueprint for producing fully functional blood stem cells in the lab. 

The research, published in the journal Nature, could help expand treatment options for blood cancers like leukemia and inherited blood disorders such as sickle cell disease, said UCLA’s Dr. Hanna Mikkola, who led the study. 

The California Institute for Regenerative Medicine (CIRM) has funded and supported Mikkola’s earlier blood stem cell research through various grants. 

Overcoming Limitations 

Blood stem cells, also called hematopoietic stem cells, can make unlimited copies of themselves and 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. 

Researchers have long sought 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 become self-renewing blood stem cells rather than short-lived blood progenitor cells, which can only produce limited blood cell types. 

“Nobody has succeeded in making functional blood stem cells from human pluripotent stem cells because we didn’t know enough about the cell we were trying to generate,” said Mikkola. 

A New Roadmap

The new roadmap will help researchers understand the fundamental differences between the two cell types, which is critical for creating cells that are suitable for use in transplantation therapies, said UCLA scientist Vincenzo Calvanese, a co–first author of the research, along with UCLA’s Sandra Capellera-Garcia and Feiyang Ma. 

Researchers Vincenzo Calvanese and Hanna Mikkola. | Credit: Eddy Marcos Panos (left); Reed Hutchinson/UCLA

“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,” said Calvanese, who is also a group leader at University College London.  

The research team created the resource using 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 data make it possible to follow blood stem cells as they emerge 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 research group 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. 

Through these insights into the different phases of human blood stem cell development, scientists can see how close they are to making a transplantable blood stem cell in the lab. 

A Better Understanding of Blood Cancers

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,” 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.” 

Read the full release here. 

Researchers create a better way to grow blood stem cells

/ Kevin McCormack / 1 Comment
UCLA’s Dr. Hanna Mikkola and Vincenzo Calvanese, lead scientists on the study. Photo courtesy UCLA

Blood stem cells are a vital part of us. They create all the other kinds of blood cells in our body and are used in bone marrow transplants to help people battling leukemia or other blood cancers. The problem is growing these blood stem cells outside the body has always proved challenging. Up till now.

Researchers at UCLA, with CIRM funding, have identified a protein that seems to play a key role in helping blood stem cells renew themselves in the lab. Why is this important? Because being able to create a big supply of these cells could help researchers develop new approaches to treating a wide array of life-threatening diseases.

One of the most important elements that a stem cell has is its ability to self-renew itself over long periods of time. The problem with blood stem cells has been that when they are removed from the body they quickly lose their ability to self-renew and die off.

To discover why this is the case the team at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA analyzed blood stem cells to see which genes turn on and off as those cells turn into other kinds of blood cells – red, white and platelets. They identified one gene, called MLLT3, which seemed to play a key role in helping blood stem cells self-renew.

To test this finding, the researchers took blood stem cells and, in the lab, inserted copies of the MLLT3 gene into them. The modified cells were then able to self-renew at least 12 times; a number far greater than in the past.

Dr. Hanna Mikkola, a senior author of the study says this finding could help advance the field:

“If we think about the amount of blood stem cells needed to treat a patient, that’s a significant number. But we’re not just focusing on quantity; we also need to ensure that the lab-created blood stem cells can continue to function properly by making all blood cell types when transplanted.”

Happily, that seemed to be the case. When they subjected the MLLT3-enhanced blood stem cells to further analysis they found that they appeared to self-renew at a safe rate and didn’t multiply too much or mutate in ways that could lead to leukemia or other blood cancers.

The next steps are to find more efficient and effective ways of keeping the MLLT3 gene active in blood stem cells, so they can develop ways of using this finding in a clinical setting with patients.

Their findings are published in the journal Nature.