Major breakthrough unlocks scalable artificial blood production

In their quest for safe, mass-producible artificial blood, geneticists have long struggled. Our limited knowledge of genetic pathways that govern the development of blood has kept us from producing artificial red blood cells even after decades of effort. A breakthrough by researchers at the University of Konstanz and Queen Mary University of London may now begin to plug some of those holes and move artificial blood forward.

Red blood cells, or erythrocytes, are formed in bone marrow through a series of complicated steps. Part of the process is turning stem cells into mature ones. The last step is important and strange—its removal of the nucleus of the cell creates space for hemoglobin to carry oxygen throughout the body. Scientists have been mystified by what exactly triggers that step for decades.

A group led by Dr. Julia Gutjahr devised an unexpected solution. Remaining within the Institute of Cellular Biology and Immunology Thurgau, she identified the role of a signaling molecule called CXCL12. This chemokine not only directs immune cells as researchers had previously thought, but it also helps red blood cells achieve their completion of maturation by triggering the removal of their nuclei.

CXCL12 functions by being sequestered with a receptor called CXCR4, found on the surface of most cells, including immune cells. Normally, this signal-receptor pair guides cells to migrate to areas of injury or infection. However, Gutjahr and colleagues illustrated that in precursors to red blood cells, or erythroblasts, this signal has a dramatically different purpose.

Rather than triggering cell migration, CXCL12 triggers changes inside the erythroblast to prepare it to lose its nucleus. This includes cell reorganization, organizing its genetic material, and causing transient calcium waves within the nucleus vicinity—changes which take place just before the nucleus is expelled. These findings have been observed in recent studies by Gutjahr's laboratory and mark a shift in researchers' understanding of the role of CXCL12.

"Our research presented an entirely new picture of cell biological processes for erythroblast responses to chemokines," says Professor Antal Rot at Queen Mary University. "While for all other cells the signaling molecule CXCL12 leads to migration, for erythroblasts this molecule is transported within the cell, even into the nucleus."

The receptor and its signal partners—such as Gαi and β-arrestin1 that's phosphorylated—translocate into the nucleus, which is rather uncommon. This defies the current understanding that chemokine receptors only act from the outside of cells. "What our work shows for the first time is that chemokine receptors not only act on the cell surface but also inside the cell," says Rot, unveiling new lines of investigation into how cells behave.

Mammalian red blood cells are unique in the fact that they extrude their nuclei during maturation. This is accomplished in order to provide more room for the hemoglobin. It only occurs in mammals and allows oxygen to be transported more efficiently. Researchers did not know exactly what prompted the signal to tell the cell to accomplish this until recently.

Gutjahr's research confirms that CXCL12 is an essential part of that signal. When researchers added CXCL12 to erythroblasts in the right stage of development, they could induce nucleus ejection in a test tube setting. This allows scientists to now more precisely mimic normal blood development outside the body.

When CXCL12 interacts with CXCR4 on erythroblasts, it triggers internal processes that help the cell to finish developing. This includes making genes concerned with energy use and chromatin structure more active. If CXCR4 is removed from the cells, red blood cell development stops at subsequent stages, and bone marrow production drops severely. That loss helps to confirm just how important the CXCL12-CXCR4 pathway is during normal blood development.

CXCL12 doesn't just send messages; it changes where the receptors and other molecules move inside the cell. After binding to CXCR4, the whole receptor complex moves into specialized compartments in the cell, including around or inside the nucleus. That's where this pathway seems to push the cell toward its final shape.

Every day, hospitals need thousands of donations of blood. In Germany alone, 15,000 units of blood are needed every day, most of which are from volunteer donors. That supply is not always sufficient, especially in cases of emergency or for those patients who have rare blood types.

Synthetic blood could potentially repair this. But getting red blood cells to be made in the lab has been challenging—namely, how to get the cells to lose their nuclei. So far, only a few 80% of stem-cell-derived red blood cells can make it through this process.

Stem cells from donors like bone marrow or umbilical cord blood can be used to form red blood cells. But they are readily available in numbers. In recent years, researchers have turned to reprogrammed cells—ordinary cells that are genetically altered to act like stem cells. These offer an almost unlimited supply, but nucleus ejection works only in 40% of the cells, so they are not highly useful.

With the recent discovery of the contribution made by CXCL12, such an obstacle can be overcome in the not-too-distant future. "Based on our new study highlighting the crucial role of CXCL12 in inducing nuclear expulsion, we can expect that using CXCL12 should show substantial improvement in producing red blood cells from reprogrammed cells," Gutjahr says.

That would speed blood manufacture in the lab, make it more reliable, and better suited to mass medical use. It could also make possible the treatment of anemia, trauma, surgery, or orphan diseases in which there is difficulty in identifying compatible blood. It could even make possible individualized therapy, in which the patient's own cells are used to create safe, matched blood.

While this breakthrough moves synthetic blood one step closer to reality, more remains to be done. Gutjahr began here in 2019 as a postdoctoral researcher in Rot's lab. She has a research group now at the University of Konstanz and continues studying how CXCL12 works.

"We are now researching how to employ CXCL12 to enhance the artificial production of human erythrocytes," she explains. She and her lab hope to optimize the conditions that yield the most red blood cells and implement them on a larger scale.

A part of their research, the team is also extending the knowledge of how chemokines function within cells. Since most chemokines are known to control cell movement, their role in modifying internal cell behavior opens avenues for the study of novel therapies, not just for blood disease, but also for other illness where cell development matters.

This discovery regarding CXCL12 can potentially reframe the way researchers think about immune and developmental signaling molecules as a whole. If receptors like CXCR4 can work inside cells, therapies in the future might be designed to act directly on those intracellular processes.

Gutjahr and her colleagues have shown the way that learning one step of cell development can echo across many domains. From boosting blood cell production to constructing cell biology, their work indicates how a single molecule is all it takes.

Research findings are available online in the journal Science Signaling.

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