‘Barcoding’ cells reveals new origins of blood

BOSTON — A new way of tracking cells has revealed some surprising details about the origins of blood. Using a process called cellular “barcoding” on mice, researchers from Boston Children’s Hospital found that blood cells don’t come from one type of mother cell — they originate from two!

They add that their findings could help scientists working with blood cancers, bone marrow transplants, and also lead to new ways of improving the human immune system.

“Historically, people have believed that most of our blood comes from a very small number of cells that eventually become blood stem cells, also known as hematopoietic stem cells,” says lead researcher Fernando Camargo, PhD, a member of the Harvard Stem Cell Institute, in a media release. “We were surprised to find another group of progenitor cells that do not come from stem cells. They make most of the blood in fetal life until young adulthood, and then gradually start decreasing.”

Study authors are now working to see if this also applies to human blood cells as well. The new cells, called embryonic multipotent progenitor cells (eMPPs), could help scientists develop new treatments for aging adults.

Follow the barcode

The team has been developing this barcoding technique for years. Using either CRISPR gene editing or an enzyme known as transposase, the researchers implanted a unique genetic code into embryonic mouse cells. By doing this, all of the cells that descend from a barcoded cell will carry that same genetic sequence — making it easy for scientists to spot.

Using cellular barcoding allowed the team to observe all of the different types of blood cells emerging in the mice, from infancy to adulthood.

“Previously, people didn’t have these tools,” Camargo explains. “Also, the idea that stem cells give rise to all the blood cells was so embedded in the field that no one attempted to question it. By tracking what happened in mice over time, we were able to see new biology.”

Thanks to this process, the team discovered that eMPPs are actually a more abundant source of lymphoid cells than normal blood stem cells. Lymphoid cells play a key role in immune responses, including the activity of B cells and T cells. Camargo believes the drop off in eMPPs as someone ages explains why the immune system also weakens as people get older.

“We’re now trying to understand why these cells peter out in middle age, which could potentially allow us to manipulate them with the goal of rejuvenating the immune system,” the study author says.

Scientists believe they could accomplish this in one of two ways. They could possibly extend the life of eMPP cells by using growth factors or immune signaling molecules, or treat blood stem cells using gene therapy — to make them act more like eMPPs.

Could this lead to a cure for blood cancer?

The study authors add their breakthrough could lead to a new understanding of how blood cancers attack the human body. Specifically, Camargo suspects that myeloid leukemias, which generally strike older patients, may originate from blood stem cells. Meanwhile, lymphoid leukemias, which mainly develop in children, may originate from eMPPs.

“We are following up to try to understand the consequences of mutations that lead to leukemia by looking at their effects in both blood stem cells and eMPPs in mice,” he says. “We want to see if the leukemias that arise from these different cells of origin are different — lymphoid-like or myeloid-like.”

The findings about blood mother cells may also lead to improvements in bone marrow transplants — which are an important procedure in treating leukemia.

“When we tried to do bone marrow transplants in mice, we found that the eMPPs didn’t engraft well; they only lasted a few weeks,” Camargo concludes. “If we could add a few genes to get eMPPs to engraft long term, they could potentially be a better source for a bone marrow transplant. They are more common in younger marrow donors than blood stem cells, and they are primed to produce lymphoid cells, which could lead to better reconstitution of the immune system and fewer infection complications after the graft.”

The findings appear in the journal Nature.

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