A team of researchers has discovered the timing and reasons behind how inflammatory signaling influences the development of blood stem cells in embryos. This breakthrough could significantly enhance efforts to create lab-grown, patient-specific stem cell transfusions to address blood-related disorders, potentially removing the necessity for bone marrow transplants.
Ten years ago, Raquel Espin Palazon realized that activating inflammatory signaling pathways is critical for embryos to generate blood stem cells. The latest research from her laboratory reveals that maintaining these signals in an inactive state after their initial activation can be beneficial.
The recent study, led by Espin Palazon and Clyde Campbell, assistant professors of genetics, development, and cell biology at Iowa State University, will advance the development of lab-cultured, patient-specific blood stem cells. This exciting yet ongoing progress in regenerative medicine could potentially replace bone marrow transplants for treating blood disorders like leukemia, lymphoma, and anemia using stem cell therapies.
The importance of timing is highlighted in the findings published on September 6 in Nature Communications. Espin Palazon’s previous research indicated that NF-kB, a well-known protein network involved in triggering inflammation—the body’s response to infections and injuries—is vital during the formation of blood stem cells. Gaining insights into when and why these inflammatory signals occur will aid in accurately recreating the process.
“This represents a significant advancement for the laboratory-based production of blood stem cells. The protocols we develop will be more precise and effective,” stated Espin Palazon.
Signals activate in intervals
Stem cells are crucial for growth, repair, and renewal in organisms, forming the basis for all new cell types. Some stem cells are versatile enough to develop into any cell type, while others are more specialized. The hundreds of billions of new blood cells produced daily in humans originate from specialized hematopoietic stem cells found in bone marrow. A complete supply of these stem cells is created before birth within the embryo.
The research conducted by Espin Palazon and Campbell’s team utilized zebrafish, which are frequently employed in medical research due to their genetic resemblance to humans and the rapid development of their eggs externally. By incorporating fluorescent reporter genes, scientists can observe specific proteins and gene expressions through visible fluorescence. In tracking NF-kB expression in zebrafish embryos using a reporter line that glows momentarily, the team discovered that inflammatory signaling activates in two distinct waves. This alternating activation acts like a biological timer, facilitating the transformation of some vascular cells in the embryo to become blood stem cells.
If the initial wave of signals is absent, the cells remain unprepared for the transition. Conversely, if the second wave is missing, the newly formed stem cells fail to detach from blood vessels and disperse effectively. In the time between these waves, blood stem cells emerge and multiply steadily. However, if the second wave is delayed, the existing stem cells continue to proliferate excessively.
“By manipulating this signaling, we can significantly increase the production of blood stem cells,” remarked Espin Palazon.
‘I was astonished’
The researchers were surprised to discover that inhibiting the reactivation phase could enhance blood stem cell production, Campbell noted.
“I was the first to observe it under the microscope, and I nearly fell out of my chair. I exclaimed to Raquel, ‘What is happening here?’ It’s one of those exhilarating moments in science when you witness something astonishing. I anticipated seeing maybe eight stem cells, but instead, I observed hundreds,” Campbell recounted.
The potential to increase production is exciting, considering that current techniques for culturing blood stem cells yield very few functional cells, according to Espin Palazon. The existing process involves genetically reprogramming mature cells to imitate the versatile stem cells that embryos naturally create, then using those induced pluripotent stem cells to develop blood stem cells. Continued research is necessary to learn how this newfound understanding regarding the timing of inflammatory signals can improve the lab protocols for generating blood stem cells.
“Now, we need to focus on optimizing and integrating these signals,” added Campbell.
What’s on the horizon
For years, Espin Palazon and Campbell have collaborated with researchers at the Children’s Hospital of Philadelphia, who focus extensively on induced pluripotent stem cells. Their collaborators there verified that NF-kB signaling exhibits similar timing and effects in lab-created human blood stem cells.
Although they will maintain their partnership with the hospital, the researchers at Iowa State University will soon be able to conduct their studies locally. A $2 million, five-year grant from the National Institutes of Health has funded both the recently published research and the setup of a cell culture laboratory on Iowa State’s campus, which will be capable of generating induced pluripotent stem cells. Campbell, who spent a month learning the necessary protocols at the Philadelphia hospital, stated that the lab should be operational by the year’s end.
Espin Palazon and Campbell believe that the techniques and insights from their recent research could also apply to the study of other stem cell types, the aging process, and patient-derived immunotherapy for cancer treatment. Scientists are progressively discovering more about the diverse roles of inflammatory signaling throughout life.
“Inflammatory networks are essential for initiating life, sustaining us by combating infections and viruses, and ultimately may lead to our demise,” remarked Campbell.
