CIRM Scientists Discover Key to Blood Cells’ Building Blocks

Our bodies generate new blood cells—both red and white blood cells—each and every day. But reproducing that feat in a petri dish has proven far more difficult.

Pictured: sections from zebrafish embryos. Blood vessels are labeled in red, the protein complex that regulates inflammation green and cell nuclei in blue. The arrowhead indicates a potential HSC. The image at bottom right combines all channels. [Credit: UC San Diego School of Medicine]

Pictured: sections from zebrafish embryos. Blood vessels are labeled in red, the protein complex that regulates inflammation green and cell nuclei in blue. The arrowhead indicates a potential HSC. The image at bottom right combines all channels.
[Credit: UC San Diego School of Medicine]

But now, scientists have identified the missing ingredient to producing hematopoietic stem cells, or HSC’s—the type of stem cell that gives rise to all blood and immune cells in the body. The results, published last week in the journal Cell, describe how a newly discovered protein plays a key role in generating HSC’s in the developing embryo—giving scientists a more complete recipe to reproduce these cells in the lab.

The research, which was led by University of California, San Diego (UCSD) professor David Traver and supported by a grant from CIRM, offers renewed hope for the possibility of generating patient-specific blood or immune cells using induced pluripotent stem cell (iPS cell) technology.

As Traver explained in last week’s news release:

“The development of some mature cell lineages from iPS cells, such as cardiac or neural, has been reasonably straightforward, but not with HSCs. This is likely due, at least in part, to not fully understanding all the factors used by the embryo to generate HSCs.”

Indeed, the ability to generate HSCs has long challenged scientists, as outlined in a CIRM workshop from last year. But now, says Traver, they have found a crucial piece to the puzzle.

Specifically, the researchers investigated a signaling protein called tumor necrosis factor alpha—or TNFα for short— a protein known to be important for regulating inflammation and immunity. Previous research by this study’s first author, Raquel Espin-Palazon, and others also discovered it was related to the healthy function of blood vessels during embryonic development.

In this study, Traver, Espin-Palazon and the UCSD drilled down even further—and found that TNFα was required for the normal development of HSCs in the embryo. This surprised the research team, as the young embryo is generally considered to be sterile—with no need for a protein normally charged with regulating immune response to be switched on. Explained Traver:

“There was no expectation that pro-inflammatory signaling would be active at this time or in the blood-forming regions.”

While preliminary, establishing this relationship between TNFα and HSC formation will be a boon to researchers looking for new ways to generate large quantities of healthy, patient-specific red and white blood cells for those patients who so desperately need them.

Learn more about how stem cell technology could help treat blood diseases in our Thalassemia Fact Sheet.

Revealing the Invisible: Scientists Uncover the Secret Ingredient to Making Blood-Forming Stem Cells

They are among the most versatile types of stem cell types in the body. They live inside bone marrow and in the blood of the umbilical cord. They can be used to treat deadly cancers such as leukemia (Leukemia Fact Sheet) as well as many blood disorders. But no one really understood the details of how they were made.

How are blood stem cells made? Australian scientists have uncovered a missing ingredient.

How are blood stem cells made? Australian scientists have uncovered a missing ingredient.

That is, until scientists at the Australian Regenerative Medicine Institute devised an ingenious way to view the formation of these hematopoetic stem cells (HSC’s) in unprecedented detail. And in so doing, found the missing ingredient that may make it possible to grow fully functioning versions of these cells in the lab—opening the door to treating a wide range of blood and immune disorders. Attempts to grow these in the past have resulted in immature versions more like those found in a fetus than those in an adult.

One of the study’s senior authors, Dr. Peter Currie, even goes so far as to say this discovery represents a ‘Holy Grail’ for the field. As he explained in today’s news release:

“HSCs are one of the best therapeutic tools at our disposal because they can make any blood cell in the body. Potentially we could use these cells in may more ways than current transplantation strategies to treat serious blood disorders and diseases, but only if we can figure out how they are generated in the first place.”

Fortunately, this new study—published today in the journal Nature—brings researchers closer to that goal.

Using high-resolution microscopic imaging techniques, Currie and his team filmed the development of a zebra fish embryo—with a particular focus on HSCs. When they played back the video, the team saw something that no one had noticed before. In order for HSCs to develop properly, they needed a little support from another cell type known as endotomes. As Currie explained:

“Endotome cells act like a comfy sofa for pre-HSCs to snuggle into, helping them progress to become fully fledged [HSCs]. Not only did we identify some of the cells and signals required for HSC formation, we also pinpointed the genes required for endotome formation in the first place.”

It appears that this unique relationship between endotomes and HSCs is key to HSC formation, a process that had for so long evaded researchers. But armed with this newfound knowledge, the team could one day produce different types of blood cells ‘on demand’—and potentially treat many types of blood disorders. This has been such a tough nut to crack with such great potential CIRM convened an international panel of experts to produce a whitepaper on the issue.

The team’s immediate next steps, according to Currie, are to pinpoint the molecular switches themselves (within endotomes and HSCs) that trigger the production of these stem cells. And while these results are preliminary, he is cautiously optimistic about the potential power to treat a variety of illnesses:

“Potentially, it’s imaginable that you could even correct genetic defects in cells and then transplant them back into the body.”