Researchers at the Indiana University Melvin and Bren Simon Comprehensive Cancer Center have found that human hematopoietic stem cells are highly sensitive to oxygen, which can dictate how the cells grow and function.
The findings published last week in Leukemia could influence future approaches for stem cell transplantation, cancer immunotherapy, gene therapy and other cancer treatments.
The research team studied human stem cells from donor umbilical cord blood, peripheral blood and bone marrow to improve the utility of stem cells used in therapies. The study was co-led by cancer center researchers James Ropa, PhD, assistant professor of medical and molecular genetics at the IU School of Medicine; Maegan Capitano, PhD, assistant professor of microbiology and immunology; and Mark Kaplan, PhD, chair of the Department of Microbiology and Immunology.
Hematopoietic stem cells can develop into all types of blood and immune cells and are designed to respond to changing environments. The research team studied the cells in oxygen levels that mimic the levels within the body, which range from about 1% in the bone marrow to 14% in circulating blood. Researchers found that even brief exposure to different oxygen levels caused major shifts in how the cells behaved.
"We found that the cells were acutely sensitive to changing oxygen levels. They changed their differentiation capacity, meaning we saw different populations of cells forming in different oxygen tensions," Ropa, study co-author, said. "The cells changed their ability to proliferate and self-renew, and most importantly, they changed their ability to engraft in a living system."
When researchers transplanted the cells into mouse models, the cells grown at the lowest oxygen tension proportionally had the most cells that were able to engraft.
"This finding suggests that those cells maintain their functional capacity, which is very interesting from a normal biology and a therapeutic standpoint," Ropa said.
Capitano said the work has direct implications for research and therapies that rely on culturing cells outside the body, including immunotherapies and cord blood transplants.
"When we collect our samples for research or clinical applications, ambient air has 21 % oxygen levels," Capitano said. "When we take those cord blood cells and we expose them to our incubators in the lab, we're stressing those stem cells out, because there's no air in your body that gets above 17 % oxygen. When you expose those cells to higher oxygen levels, they undergo stress. What we found was that the cells cultured in lower oxygen tended to be less stressed out and they were able to function better."
The study highlights how much cells respond to their environment. Researchers hope these findings lead to new ways of tailoring cells for personalized patient therapies.
"Oxygen is something that researchers may not really think about on a daily basis as having a huge environmental impact, but it is critically important for cell fate," Kaplan said.
This same approach can have a big effect on things like CAR T-cells and other therapies where there are functional cells going back into a patient and hopefully having an impact on the ability of those cells to function once they are in the patient."
Mark Kaplan, Department of Microbiology and Immunology, Indiana University School of Medicine
This research discovery was made possible by the unique capabilities of IU's Hypoxia Core, a national resource for controlled-oxygen research. The core is part of the IU School of Medicine Cooperative Center of Excellence in Hematology (CCEH) and is funded in part by a National Institutes of Health CCEH specialized center grant.
Ropa, Capitano and Kaplan served as co-corresponding authors for the study. Additional IU School of Medicine authors include Sarah Gutch, Lindsay Wathen, So Jeong Kim, Jimin Park, Jessica Newton, Gracie Whitacre, Arafat Aljoufi, and Scott Cooper.
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