A better stem cell survival strategy
A simple change to protocols for hematopoietic stem cell gene therapy could see vast increases in the number and quality of cells.
In a recent study, researchers at the University of Cambridge Stem Cell Institute (CSCI; Cambridge, UK) have uncovered a new method for keeping hematopoietic stem cells alive outside the body for longer, which has the potential to improve gene therapy outcomes for a range of disorders.
Hematopoietic stem cell gene therapy (HSC GT) represents a revolutionary avenue for treating numerous genetic diseases. The process, which occurs over a period of around three days, begins with harvesting hematopoietic stem cells from a patient. The genetic defects are corrected in the cells ex vivo before they are reinfused back into the patient’s bloodstream. The technique is currently under investigation for the treatment of ten genetic diseases.
While the advent of HSC GT is broadly a great success, treatment efficacy can be constrained by the limited survival of stem cells ex vivo. When removed from the body, stem cell function deteriorates, rendering many cells inviable for therapeutic action by the time they are reinfused into the body.
In an effort to tackle this problem and boost HSC GT treatment efficacy, the CSCI researchers sought to gain a better understanding of the exact timeline and reasoning behind the loss of stem cell function occurring in lab cultures. The team monitored hematopoietic stem cells in culture over a few days and found that over half of the cells lost the essential ability to sustain life-long blood production within their first 24 hours ex vivo. Following additional analyses of stress signaling pathways, the authors attributed this loss of function to a stress response as cells attempted to adapt to the new culture environment.
“Although we expected that removing these cells from the body and culturing them on a plastic surface would alter gene expression, the extent of change we found was surprising, with over 10,000 genes altered and a significant stress response detected,” explained Carys Johnson, first author of the study.
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Luckily, the researchers were able to pinpoint a key molecular pathway that regulates the stress response and is readily targeted by Ruxolitinib – a cancer growth blocker that is already in use for cancer treatments. Through addition of this drug, the team saw a three-fold increase in cell function.
“I hope our findings will enable safer treatments for gene therapy patients. Our discovery also opens up many possibilities to better expand blood stem cells ex vivo and expand the set of disease where we can use blood stem cells to improve patients’ lives,” said Elisa Laurenti, the study’s senior author.
The team now aims to incorporate Ruxolitinib into existing HSC GT protocols to maximize the production of high-quality stem cells and improve therapeutic outcomes.
