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Thioredoxin mitigates radiation-induced hematopoietic stem cell injury in mice.

Publication ,  Journal Article
Sundaramoorthy, P; Wang, Q; Zheng, Z; Jiao, Y; Chen, BJ; Doan, PL; Chao, NJ; Kang, Y
Published in: Stem Cell Res Ther
November 15, 2017

BACKGROUND: Radiation exposure poses a significant threat to public health. Hematopoietic injury is one of the major manifestations of acute radiation sickness. Protection and/or mitigation of hematopoietic stem cells (HSCs) from radiation injury is an important goal in the development of medical countermeasure agents (MCM). We recently identified thioredoxin (TXN) as a novel molecule that has marked protective and proliferative effects on HSCs. In the current study, we investigated the effectiveness of TXN in rescuing mice from a lethal dose of total body radiation (TBI) and in enhancing hematopoietic reconstitution following a lethal dose of irradiation. METHODS: We used in-vivo and in-vitro methods to understand the biological and molecular mechanisms of TXN on radiation mitigation. BABL/c mice were used for the survival study and a flow cytometer was used to quantify the HSC population and cell senescence. A hematology analyzer was used for the peripheral blood cell count, including white blood cells (WBCs), red blood cells (RBCs), hemoglobin, and platelets. Colony forming unit (CFU) assay was used to study the colongenic function of HSCs. Hematoxylin and eosin staining was used to determine the bone marrow cellularity. Senescence-associated β-galactosidase assay was used for cell senescence. Western blot analysis was used to evaluate the DNA damage and senescence protein expression. Immunofluorescence staining was used to measure the expression of γ-H2AX foci for DNA damage. RESULTS: We found that administration of TXN 24 h following irradiation significantly mitigates BALB/c mice from TBI-induced death: 70% of TXN-treated mice survived, whereas only 25% of saline-treated mice survived. TXN administration led to enhanced recovery of peripheral blood cell counts, bone marrow cellularity, and HSC population as measured by c-Kit+Sca-1+Lin- (KSL) cells, SLAM + KSL cells and CFUs. TXN treatment reduced cell senescence and radiation-induced double-strand DNA breaks in both murine bone marrow lineage-negative (Lin-) cells and primary fibroblasts. Furthermore, TXN decreased the expression of p16 and phosphorylated p38. Our data suggest that TXN modulates diverse cellular processes of HSCs. CONCLUSIONS: Administration of TXN 24 h following irradiation mitigates radiation-induced lethality. To the best of our knowledge, this is the first report demonstrating that TXN reduces radiation-induced lethality. TXN shows potential utility in the mitigation of radiation-induced hematopoietic injury.

Duke Scholars

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Published In

Stem Cell Res Ther

DOI

EISSN

1757-6512

Publication Date

November 15, 2017

Volume

8

Issue

1

Start / End Page

263

Location

England

Related Subject Headings

  • p38 Mitogen-Activated Protein Kinases
  • Whole-Body Irradiation
  • Thioredoxins
  • Survival Analysis
  • Recombinant Proteins
  • Radiation-Protective Agents
  • Radiation Injuries, Experimental
  • Proto-Oncogene Proteins c-kit
  • Mice, Inbred BALB C
  • Mice
 

Citation

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Sundaramoorthy, P., Wang, Q., Zheng, Z., Jiao, Y., Chen, B. J., Doan, P. L., … Kang, Y. (2017). Thioredoxin mitigates radiation-induced hematopoietic stem cell injury in mice. Stem Cell Res Ther, 8(1), 263. https://doi.org/10.1186/s13287-017-0711-2
Sundaramoorthy, Pasupathi, Qinhong Wang, Zhihong Zheng, Yiqun Jiao, Benny J. Chen, Phuong L. Doan, Nelson J. Chao, and Yubin Kang. “Thioredoxin mitigates radiation-induced hematopoietic stem cell injury in mice.Stem Cell Res Ther 8, no. 1 (November 15, 2017): 263. https://doi.org/10.1186/s13287-017-0711-2.
Sundaramoorthy P, Wang Q, Zheng Z, Jiao Y, Chen BJ, Doan PL, et al. Thioredoxin mitigates radiation-induced hematopoietic stem cell injury in mice. Stem Cell Res Ther. 2017 Nov 15;8(1):263.
Sundaramoorthy, Pasupathi, et al. “Thioredoxin mitigates radiation-induced hematopoietic stem cell injury in mice.Stem Cell Res Ther, vol. 8, no. 1, Nov. 2017, p. 263. Pubmed, doi:10.1186/s13287-017-0711-2.
Sundaramoorthy P, Wang Q, Zheng Z, Jiao Y, Chen BJ, Doan PL, Chao NJ, Kang Y. Thioredoxin mitigates radiation-induced hematopoietic stem cell injury in mice. Stem Cell Res Ther. 2017 Nov 15;8(1):263.
Journal cover image

Published In

Stem Cell Res Ther

DOI

EISSN

1757-6512

Publication Date

November 15, 2017

Volume

8

Issue

1

Start / End Page

263

Location

England

Related Subject Headings

  • p38 Mitogen-Activated Protein Kinases
  • Whole-Body Irradiation
  • Thioredoxins
  • Survival Analysis
  • Recombinant Proteins
  • Radiation-Protective Agents
  • Radiation Injuries, Experimental
  • Proto-Oncogene Proteins c-kit
  • Mice, Inbred BALB C
  • Mice