INDIANAPOLIS — Researchers at the Indiana University School of Medicine have discovered that the damage caused to blood-forming stem cells when they are exposed to normal room air may be reversible. The findings offer promising new approaches for protecting stem cells and improving their ability to rebuild the blood system when used in transplants to treat patients with blood cancers and other blood-related diseases.
In a study recently published in the journal Blood, scientists at the Herman B Wells Center for Pediatric Research investigated hematopoietic stem cells, which produce the body's blood and immune cells. These stem cells normally reside in a low-oxygen environment within the bone marrow, but when they are collected and processed outside the body, they are routinely exposed to much higher levels of oxygen in the surrounding air.
Previous research has shown that this exposure can impair stem cell function, so the IU team wanted to understand the changes and whether the damage could be corrected.
“What surprised us was how quickly exposure to normal room oxygen changed the metabolic state of these cells,” said Xuepeng Wang, PhD, assistant research professor of pediatrics at IU and first and co-corresponding author of the study. “We found that amino acids accumulated inside the cells and activated nutrient-sensing pathways that are normally tightly controlled in blood-forming stem cells. That gave us an important clue: If we could correct that metabolic imbalance, perhaps we could restore some of the function that was lost after oxygen exposure.”
Using human blood stem cell samples, the researchers compared cells handled under low-oxygen conditions with those exposed to normal room, or ambient, oxygen. They discovered that exposure to ambient oxygen rapidly caused amino acids to accumulate inside the cells and pushed them into an over-activated metabolic state, whereas low oxygen helped the cells remain in a calm, resting state. The findings revealed an important connection between oxygen and nutrients as fundamental signals in the stem cell environment.
“Stem cells are constantly reading signals from their environment, including oxygen and nutrients,” said Ji Zhang, PhD, associate professor of pediatrics at IU and the study’s senior and co-corresponding author. “This study helps connect those two signals. It shows that changing oxygen availability can reshape nutrient metabolism and, ultimately, stem cell function. Understanding that relationship gives us new opportunities to think about how we preserve stem cells during transplantation and other therapies that require cells to be manipulated outside the body.”
To determine whether correcting this nutrient imbalance could restore stem cell function, the researchers tested two strategies. They briefly restricted the accumulation of essential amino acids while the cells were collected and processed, and used a drug to block them from entering the cells. In mouse models, both approaches helped repair the damage caused by ambient air and restored the stem cells' ability to transplant successfully.
These findings suggest that oxygen-related damage is potentially reversible, which could lead to better outcomes for future stem cell transplants in humans. Rather than focusing solely on the total number of stem cells collected, future procedures may benefit from prioritizing the health and quality of those cells during processing.
“Our long-term goal is very simple: When we give stem cells to a patient, we want those cells to retain as much of their regenerative capacity as possible,” said Reuben Kapur, PhD, director of the Wells Center and a co-corresponding senior author of the study. “This study identifies one reason that capacity can be lost during routine processing, but, importantly, it also shows us a potential way to intervene. That creates an opportunity to rethink how we handle stem cells before transplantation, with the goal of improving outcomes for both children and adults.”
While further research is required before these concepts can be tested in clinical trials, the researchers believe the findings could extend beyond traditional blood stem transplants, including for emerging gene therapies where blood-forming stem cells must spend time outside the body.
“The research illustrates how conditions outside a cell can profoundly influence what happens inside it,” Kapur said. “Protecting stem cells during the period between collection and transplantation may be another way to help preserve their ability to rebuild a patient's blood and immune system.”
IU School of Medicine’s Sankalp Srivastava, Rahul Kanumuri, Ramesh Kumar and Minghua Zhong are additional co-authors on the study.
This research was supported by funding from the National Institutes of Health.
About the Indiana University School of Medicine
The IU School of Medicine is the largest medical school in the U.S. and is annually ranked among the top medical schools in the nation by U.S. News & World Report. The school offers high-quality medical education, access to leading medical research and rich campus life in nine Indiana cities, including rural and urban locations consistently recognized for livability. According to the Blue Ridge Institute for Medical Research, the IU School of Medicine ranks No. 15 in 2025 National Institutes of Health funding among all public medical schools in the country.
Writer: Jackie Maupin, jacmaup@iu.edu
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