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with Fanconi anemia
Image by Michael Milsom
Environmental stress is a major factor driving DNA damage in hematopoietic stem cells (HSCs), according to research published in Nature.
Investigators found that repeated exposure to such stress induces accelerated tissue aging and may cause cancer.
In examining HSCs’ response to stress, the team also gained new insight regarding Fanconi anemia.
The investigators noted that, under normal conditions, HSCs exist in a state of dormancy. They rarely divide and have very low energy demands.
“Our theory was that this state of dormancy protected hematopoietic stem cells from DNA damage and therefore protects them from premature aging,” said study author Michael Milsom, PhD, of The Heidelberg Institute for Stem Cell Technology and Experimental Medicine in Germany.
However, under conditions of stress, such as during chronic blood loss or infection, HSCs are driven into a state of rapid cell division in order to produce new blood cells and repair the damaged tissue.
“The stem cells go from a state of rest to very high activity within a short space of time, requiring them to rapidly increase their metabolic rate, synthesize new DNA, and coordinate cell division,” Dr Milsom explained. “Suddenly having to simultaneously execute these complicated functions dramatically increases the likelihood that something will go wrong.”
Indeed, the investigators’ experiments showed that the increased energy demands during stress results in elevated production of reactive metabolites that can directly damage DNA. If this happens at the same time a cell is trying to replicate its DNA, this can cause cell death or the acquisition of mutations that may cause cancer.
Normal stem cells can repair the majority of this stress-induced DNA damage, the investigators noted. However, the more HSCs are exposed to stress, the more likely they are to inefficiently repair the damage and then die or mutate.
“We believe that this model perfectly explains the gradual accumulation of DNA damage in stem cells with age and the associated reduction in the ability of a tissue to maintain and repair itself as you get older,” Dr Milsom said.
He and his colleagues also examined how this stress response impacts a mouse model of Fanconi anemia. These mice have the same DNA repair defect found in humans with the disease, but the mice never spontaneously develop the bone marrow failure observed in nearly all patients.
“We felt that stress-induced DNA damage was the missing ingredient that was required to cause hematopoietic stem cell depletion in these mice,” Dr Milsom said.
When mice with Fanconi anemia were exposed to stimulation mimicking a prolonged viral infection, they were unable to efficiently repair the resulting DNA damage, and their stem cells failed.
In the same space of time that normal mice showed a gradual decline in HSC numbers, the stem cells in Fanconi anemia mice were almost completely depleted, resulting in bone marrow failure and an inadequate production of blood cells to sustain life.
“This perfectly recapitulates what happens to Fanconi anemia patients and now gives us an opportunity to understand how this disease works and how we might better treat it,” Dr Milsom said. 
with Fanconi anemia
Image by Michael Milsom
Environmental stress is a major factor driving DNA damage in hematopoietic stem cells (HSCs), according to research published in Nature.
Investigators found that repeated exposure to such stress induces accelerated tissue aging and may cause cancer.
In examining HSCs’ response to stress, the team also gained new insight regarding Fanconi anemia.
The investigators noted that, under normal conditions, HSCs exist in a state of dormancy. They rarely divide and have very low energy demands.
“Our theory was that this state of dormancy protected hematopoietic stem cells from DNA damage and therefore protects them from premature aging,” said study author Michael Milsom, PhD, of The Heidelberg Institute for Stem Cell Technology and Experimental Medicine in Germany.
However, under conditions of stress, such as during chronic blood loss or infection, HSCs are driven into a state of rapid cell division in order to produce new blood cells and repair the damaged tissue.
“The stem cells go from a state of rest to very high activity within a short space of time, requiring them to rapidly increase their metabolic rate, synthesize new DNA, and coordinate cell division,” Dr Milsom explained. “Suddenly having to simultaneously execute these complicated functions dramatically increases the likelihood that something will go wrong.”
Indeed, the investigators’ experiments showed that the increased energy demands during stress results in elevated production of reactive metabolites that can directly damage DNA. If this happens at the same time a cell is trying to replicate its DNA, this can cause cell death or the acquisition of mutations that may cause cancer.
Normal stem cells can repair the majority of this stress-induced DNA damage, the investigators noted. However, the more HSCs are exposed to stress, the more likely they are to inefficiently repair the damage and then die or mutate.
“We believe that this model perfectly explains the gradual accumulation of DNA damage in stem cells with age and the associated reduction in the ability of a tissue to maintain and repair itself as you get older,” Dr Milsom said.
He and his colleagues also examined how this stress response impacts a mouse model of Fanconi anemia. These mice have the same DNA repair defect found in humans with the disease, but the mice never spontaneously develop the bone marrow failure observed in nearly all patients.
“We felt that stress-induced DNA damage was the missing ingredient that was required to cause hematopoietic stem cell depletion in these mice,” Dr Milsom said.
When mice with Fanconi anemia were exposed to stimulation mimicking a prolonged viral infection, they were unable to efficiently repair the resulting DNA damage, and their stem cells failed.
In the same space of time that normal mice showed a gradual decline in HSC numbers, the stem cells in Fanconi anemia mice were almost completely depleted, resulting in bone marrow failure and an inadequate production of blood cells to sustain life.
“This perfectly recapitulates what happens to Fanconi anemia patients and now gives us an opportunity to understand how this disease works and how we might better treat it,” Dr Milsom said.
with Fanconi anemia
Image by Michael Milsom
Environmental stress is a major factor driving DNA damage in hematopoietic stem cells (HSCs), according to research published in Nature.
Investigators found that repeated exposure to such stress induces accelerated tissue aging and may cause cancer.
In examining HSCs’ response to stress, the team also gained new insight regarding Fanconi anemia.
The investigators noted that, under normal conditions, HSCs exist in a state of dormancy. They rarely divide and have very low energy demands.
“Our theory was that this state of dormancy protected hematopoietic stem cells from DNA damage and therefore protects them from premature aging,” said study author Michael Milsom, PhD, of The Heidelberg Institute for Stem Cell Technology and Experimental Medicine in Germany.
However, under conditions of stress, such as during chronic blood loss or infection, HSCs are driven into a state of rapid cell division in order to produce new blood cells and repair the damaged tissue.
“The stem cells go from a state of rest to very high activity within a short space of time, requiring them to rapidly increase their metabolic rate, synthesize new DNA, and coordinate cell division,” Dr Milsom explained. “Suddenly having to simultaneously execute these complicated functions dramatically increases the likelihood that something will go wrong.”
Indeed, the investigators’ experiments showed that the increased energy demands during stress results in elevated production of reactive metabolites that can directly damage DNA. If this happens at the same time a cell is trying to replicate its DNA, this can cause cell death or the acquisition of mutations that may cause cancer.
Normal stem cells can repair the majority of this stress-induced DNA damage, the investigators noted. However, the more HSCs are exposed to stress, the more likely they are to inefficiently repair the damage and then die or mutate.
“We believe that this model perfectly explains the gradual accumulation of DNA damage in stem cells with age and the associated reduction in the ability of a tissue to maintain and repair itself as you get older,” Dr Milsom said.
He and his colleagues also examined how this stress response impacts a mouse model of Fanconi anemia. These mice have the same DNA repair defect found in humans with the disease, but the mice never spontaneously develop the bone marrow failure observed in nearly all patients.
“We felt that stress-induced DNA damage was the missing ingredient that was required to cause hematopoietic stem cell depletion in these mice,” Dr Milsom said.
When mice with Fanconi anemia were exposed to stimulation mimicking a prolonged viral infection, they were unable to efficiently repair the resulting DNA damage, and their stem cells failed.
In the same space of time that normal mice showed a gradual decline in HSC numbers, the stem cells in Fanconi anemia mice were almost completely depleted, resulting in bone marrow failure and an inadequate production of blood cells to sustain life.
“This perfectly recapitulates what happens to Fanconi anemia patients and now gives us an opportunity to understand how this disease works and how we might better treat it,” Dr Milsom said.