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Researchers reprogram stem cells after radiation, lower cancer risk.

A University of Colorado study published in the journal Stem Cells has identified a program that makes stem cells damaged by radiation differentiate into other cells that can no longer survive forever. Radiation makes a stem cell lose its stem cell properties and the body has evolved ways to get rid of faulty stem cells.  In this way the human body avoids having damaged stem cells producing other damaged cells.

The study also shows that this same safeguard of programmed mediocrity that weeds out stem cells damaged by radiation allows blood cancers to grow in cases when the full body is irradiated. And by reprogramming this safeguard the medical community may be able to prevent cancer in the aftermath of full body radiation.

The body has not yet evolved to deal with leaking nuclear reactors and CT scans. It can only deal with a few cells at a time receiving dangerous doses of radiation or other insults to their DNA.

The team explored the effects of full body radiation on the blood stem cells of mice. In this case, radiation increased the probability that cells in the hematopoietic stem cell system would differentiate. Only, while most followed this instruction, a few did not. Stem cells with a very specific mutation were able to disobey the instruction to differentiate and retain their stem cell properties.

Genetic inhibition of the gene C/EBPA allowed a few stem cells to keep the ability to act as stem cells. With competition from other, healthy stem cells removed, the stem cells with reduced C/EBPA were able to dominate the blood cell production system. In this way, the blood system transitioned from C/EBPA+ cells to primarily C/EBPA- cells.

Past studies have shown that mutations and other genetic alterations resulting in inhibition of the C/EBPA gene are associated with acute myeloid leukemia in humans. Thus, it’s not mutations caused by radiation but a blood system reengineered by faulty stem cells that creates cancer risk in people who have experienced radiation.

The team state that it’s evolution driven by natural selection.  In a healthy blood system, healthy stem cells out-compete stem cells that happen to have the C/EBPA mutation. But when radiation reduces the heath and robustness of the stem cell population, the mutated cells that have been there all along are suddenly given the opportunity to take over.

The current study shows why radiation makes hematopoietic stem cells (HSCs) differentiate and that by activating a stem cell maintenance pathway, researchers can keep it from happening. Even months after irradiation, artificially activating the NOTCH signaling pathway of irradiated HSCs reactivates their stem cell properties, restarting the blood cell assembly line in these HSCs that would have otherwise differentiated in response to radiation.

When the team activated NOTCH in previously irradiated HSCs, it kept the population of dangerous, C/EBPA cells at bay. Competition from non-C/EBPA-mutant stem cells, with their fitness restored by NOTCH activation, meant that there was no evolutionary space for C/EBPA-mutant stem cells.

The team summise that for people working in a situation in which is likely to result in full-body radiation, they should freeze their HSCs.  In this way an infusion of healthy HSCs after radiation exposure would likely allow the healthy blood system to out-compete the radiation-exposed HSC with their programmed mediocrity (increased differentiation) and even HSC with cancer-causing mutations. But there’s also hope that in the future, that the team could offer drugs that would restore the fitness of stem cells left over after radiation.

Source:  University of Colorado Cancer Center

Scanning electron microscopy picture of an intra-aortic hematopoietic cluster (collaboration with Dr. M. Mommaas and J. Onderwater, LUMC).  Credit:  Hubrecht Institute 2014.
Scanning electron microscopy picture of an intra-aortic hematopoietic cluster (collaboration with Dr. M. Mommaas and J. Onderwater, LUMC). Credit: Hubrecht Institute 2014.

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