MMR Deficiency Does Not Sensitize or Compromise the Function of Hematopoietic Stem Cells to Low and High LET Radiation

Abstract

One of the major health concerns on long‐duration space missions will be radiation exposure to the astronauts. Outside the earth's magnetosphere, astronauts will be exposed to galactic cosmic rays (GCR) and solar particle events that are principally composed of protons and He, Ca, O, Ne, Si, Ca, and Fe nuclei. Protons are by far the most common species, but the higher atomic number particles are thought to be more damaging to biological systems. Evaluation and amelioration of risks from GCR exposure will be important for deep space travel. The hematopoietic system is one of the most radiation‐sensitive organ systems, and is highly dependent on functional DNA repair pathways for survival. Recent results from our group have demonstrated an acquired deficiency in mismatch repair (MMR) in human hematopoietic stem cells (HSCs) with age due to functional loss of the MLH1 protein, suggesting an additional risk to astronauts who may have significant numbers of MMR deficient HSCs at the time of space travel. In the present study, we investigated the effects gamma radiation, proton radiation, and 56Fe radiation on HSC function in Mlh1+/+ and Mlh1‐/‐ marrow from mice in a variety of assays and have determined that while cosmic radiation is a major risk to the hematopoietic system, there is no dependence on MMR capacity. stem cells translational medicine 2018;7:513–520

DNA repair fidelity in stem cell maintenance, health, and disease

“…MSH2, MSH3 and MSH6 levels were often found to be downregulated in association with increased genomic instability in differentiated cells [34]. Conversely, the role of MMR in irradiated HSC isolated from mice did not show a dependence on MMR status [35]. Increased replication rate in stem cells has put them on increased risk to develop mismatches.…”

RNA‐Seq analysis of differentially expressed genes relevant to mismatch repair in aging hematopoietic stem‐progenitor cells

“…3 However, studies on the relationship between MMR and HSC aging are not so much. [4][5][6][7] In this paper, we used RNA-Seq technology and an old hematopoietic stem and progenitor cells (HSPCs) model in vitro to analyze differential expressions of MMR-related genes in aged HSPCs, so as to explore the mechanism of DNA MMR injury in HSC aging.…”

“…In addition, the proliferative reserves of hematopoietic progenitors and stress erythropoiesis were significantly reduced in Ercc1 (−/−) mice compared to age‐matched controls . However, studies on the relationship between MMR and HSC aging are not so much . In this paper, we used RNA‐Seq technology and an old hematopoietic stem and progenitor cells (HSPCs) model in vitro to analyze differential expressions of MMR‐related genes in aged HSPCs, so as to explore the mechanism of DNA MMR injury in HSC aging.…”