Image by Matthias Zepper
Murine research has provided new insight into the functionality of hematopoietic stem cells (HSCs).
Investigators found that a full complement of mini-chromosome maintenance (MCM) proteins is required to preserve HSC functionality and the proper differentiation and maturation of erythrocytes.
Downregulation of the gene MCM3 during embryonic development caused replication stress in hematopoietic progenitors and led to fetal anemia.
In adult mice, downregulation of MCM3 reduced life expectancy and promoted lymphomagenesis.
The investigators therefore believe that therapies designed to modulate replication stress could fight aging, anemia, and hematopoietic malignancies.
This research was published in Nature Communications.
A previous study revealed that replication stress drives the functional decline of HSCs that occurs with age. With the new study, investigators have managed to replicate this phenomenon in mouse embryos.
The team did this by reducing levels of MCM3, one of the components of the MCM complex that is responsible for separating the strands of the DNA double helix during replication. Cells need to maintain high levels of MCM during DNA replication or they experience replication stress.
“When we reduce the levels of the MCM3 gene in the entire organism, we observe that replication stress especially affects the stem cells that give rise to the other blood cells and, in particular, the red blood cell precursors,” explained study author Juan Méndez, PhD, of Centro Nacional de Investigaciones Oncologicas (CNIO) in Madrid, Spain.
“In adult organisms, the production and maturation of red blood cells takes place in the bone marrow, but, during embryonic development, it occurs mainly in the fetal liver. In animals with MCM3 deficiency, the stem cells of the fetal liver are deteriorated, and the embryos develop a severe form of anemia that prevents them from being born.”
“We could say that replication stress turns fetal stem cells, which should be in perfect working order, into very old cells. We have verified this finding in transplantation experiments, where fetal cells with replication stress were unable to adequately reconstitute the blood system in the recipient animals.”
However, the investigators managed to prevent embryonic lethality and reduce anemia by increasing the levels of another gene, CHK1.
“CHK1 is one of the genes responsible for protecting cells from replication stress,” Dr Méndez noted. “It supervises DNA replication. When something goes wrong, CHK1 slows down or halts cell division until the problem has been resolved.”
Embryos that were subjected to replication stress (due to loss of MCM3) but had higher levels of CHK1 showed less pronounced anemia. Four of every 10 embryos developed normally and completed their gestation.
The investigators said an interesting implication of this work is that the type of anemia caused by replication stress is very similar to the aplastic anemia that arises in patients receiving chemotherapy or radiation therapy.
Therefore, the team believes these results could aid the development of novel therapies for aplastic anemia.
