Stem cells are how organisms grow, repair and renew, the source of every new cell. Some stem cells can create any type of cell, while others are specialized. The hundreds of billions of new blood cells a human makes every day come from specialized hematopoietic stem cells in our bone marrow. A lifetime supply of hematopoietic stem cells is created before birth inside an embryo.
Espin Palazon and Campbell’s research group works on zebrafish, a common subject in medical research because they are genetically similar to humans and lay fast-developing eggs outside their bodies. By inserting fluorescence-producing reporter genes, scientists can make selected types of protein and gene expression visibly glow. Tracking real-time NF-kB expression in zebrafish embryos with a reporter line that only lights up briefly, the Iowa State-led team found that inflammatory signaling activates in two waves. Switching on and off twice acts as a biological clock, coordinating a progression that converts some of an embryo’s vascular cells into blood stem cells.
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Subscribe for FREE“By manipulating that signaling, we can create a massive amount of blood stem cells,” Espin Palazon said.
‘I nearly fell out of my chair’
Researchers had no inclination that inhibiting the reactivation phase could rev up blood stem cell production, Campbell said.
“I was the first person to see it through the microscope, and I nearly fell out of my chair. I yelled at Raquel, ‘What is this?’ It’s one of those moments you love to have in science. There are just a few times when you see something that blows you away. I expected to see maybe eight stem cells, and instead I saw hundreds,” Campbell said.
Finding a way to potentially amplify yield is intriguing because the existing methods for culturing blood stem cells produce few functional cells, Espin Palazon said. The process involves genetically reprogramming mature cells to behave like the make-anything stem cells abundant in embryos, then using those induced pluripotent stem cells to generate blood stem cells. Further study is needed to figure out how the deeper insight into inflammatory signal timing can be used to improve the protocols for creating blood stem cells in a lab.
“Now, it’s all about optimization and integration of these signals,” Campbell said.
What’s next
For years, Espin Palazon and Campbell have collaborated with the researchers at the Children’s Hospital of Philadelphia, which does extensive work on induced pluripotent stem cells. Researchers there confirmed the NF-kB signaling has similar timing patterns and effects in lab efforts to produce human blood stem cells.
While they will continue to collaborate with the hospital, the ISU researchers will soon be able to study the process in-house. A $2 million, 5-year grant from the National Institutes of Health helped fund both the newly published research and the creation of a cell culture lab on Iowa State’s campus capable of generating induced pluripotent stem cells. Campbell, who spent a month learning the protocols at the Philadelphia hospital, said the lab should be up and running by the end of the year.
Espin Palazon and Campbell said they expect the methods and findings from their latest work will translate to the study of other types of stem cells, the aging process and patient-derived immunotherapy to treat cancer. Scientists continue to learn more about the varying functions of inflammation signaling throughout life.
“Inflammatory networks are required to start life, they keep us alive by fighting infections and viruses and, in the end, can cause our demise,” Campbell said.
Reference: Campbell CA, Calderon R, Pavani G, et al. p65 signaling dynamics drive the developmental progression of hematopoietic stem and progenitor cells through cell cycle regulation. Nat Commun. 2024;15(1):7787. doi: 10.1038/s41467-024-51922-5
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