Single-Dose Administration of Recombinant Human Thrombopoietin Mitigates Total Body Irradiation-Induced Hematopoietic System Injury in Mice and Nonhuman Primates

Xing, Shuang; Shen, Xinghai; Yang, Jinkun; Wang, Xinru; Ou, Hongling; Zhang, Xuewen; Xiong, Guo-Lin; Shan, Ya-Jun; Cong, Yang; Luo, Qing-Liang; Yu, Zhen

doi:10.1016/j.ijrobp.2020.07.2325

Cited by 11 publications

(9 citation statements)

References 34 publications

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“…Our previous study showed that a single administration of rhTPO increased the probability of survival in lethally irradiated mice [ 22 ]. It showed that skin injection of rhTPO100 μg/kg 2 h after IR was the best administration scheme in the post-IR survival experiment.…”

Section: Resultsmentioning

confidence: 99%

“…Currently, rhTPO is widely used in clinical thrombocytopenia as an HGF drug, and its radiation protection potential is gradually being explored [ 25 ]. Additionally, several studies demonstrated it brought significant improvements in acute radiation sickness [ 22 , 26 , 27 ]. However, whether rhTPO improves IR-induced long-term HSC function and, if so, the associated mechanism had not been elucidated.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, the application of TPO is a potentially effective countermeasure against radiation-induced myelosuppression. Our antecedent study demonstrated that a single injection of rhTPO 2 h after irradiation significantly improved early hematopoietic injury after irradiation by alleviating DNA damage and apoptosis, enhancing HSC proliferation, and effectively avoiding the neutralizing antibody response caused by multiple injections [ 22 ]. However, its effects on long-term myelosuppression and related mechanisms have not yet been reported.…”

Section: Introductionmentioning

confidence: 99%

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rhTPO Ameliorates Radiation-Induced Long-Term Hematopoietic Stem Cell Injury in Mice

Luan

Yang²,

Wang³

et al. 2023

Molecules

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Exposure to medium and high doses of ionizing radiation (IR) can induce long-term bone marrow (BM) suppression. We previously showed that recombinant human thrombopoietin (rhTPO) significantly promotes recovery from hematopoietic-acute radiation syndrome, but its effect on long-term BM suppression remains unknown. C57BL/6 mice were exposed to 6.5 Gy γ-rays of total body irradiation (TBI) at a dose-rate of 63.01 cGy per minute, and the mice were treated with rhTPO (100 μg; intramuscular injection) or vehicle at 2 h after TBI. All mice were killed one or two months after TBI for analysis of peripheral blood cell counts, long-term hematopoietic stem cell (HSC) frequency, and BM-derived clonogenic activity. The HSC self-renewal capacity was analyzed by BM transplantation. The levels of reactive oxygen species (ROS) production and ratios of γH2AX+ and p16, p53, and p21 mRNA in HSCs were measured by flow cytometry and real-time polymerase chain reaction, respectively. Treatment with rhTPO reduced long-term myelosuppression by improving long-term hematopoietic reconstitution (p < 0.05) after transplantation and resting state maintenance of HSCs (p < 0.05). Moreover, rhTPO treatment was associated with a sustained reduction in long-term ROS production, reduction of long-term DNA damage, diminished p53/p21 mRNA expression, and prevention of senescence after TBI. This study suggests rhTPO is an effective agent for treating IR-induced long-term BM injury because it regulates hematopoietic remodeling and HSC cycle disorder through the ROS/p53/p21/p16 pathway long term after IR.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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rhTPO Ameliorates Radiation-Induced Long-Term Hematopoietic Stem Cell Injury in Mice

Luan

Yang²,

Wang³

et al. 2023

Molecules

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“…A single sc injection of rhTPO, 50 or 100 lg/kg, to C57BL/6J male mice exposed to 9 Gy 60 Co c-radiation 2 h after drug administration significantly protected treated mice. RhTPO treatment demonstrated multilineage hematopoietic recovery, increased blood cell counts, enhanced bone marrow cellularity, as well as colony-forming ability in mice exposed to 6.5 Gy (Xing et al 2020). Furthermore, a single injection of rhTPO at a dose of 10 lg/kg 2 or 24 h after 7 Gy TBI also enhanced multilineage hematopoietic recovery and survival in NHPs (Xing et al 2020).…”

Section: Tpo and Related Analogsmentioning

confidence: 92%

“…RhTPO treatment demonstrated multilineage hematopoietic recovery, increased blood cell counts, enhanced bone marrow cellularity, as well as colony-forming ability in mice exposed to 6.5 Gy (Xing et al 2020). Furthermore, a single injection of rhTPO at a dose of 10 lg/kg 2 or 24 h after 7 Gy TBI also enhanced multilineage hematopoietic recovery and survival in NHPs (Xing et al 2020). These results demonstrate that the use of rhTPO as a single dose soon after irradiation may be a promising and effective radiomitigator for victims exposed to radiation.…”

Section: Tpo and Related Analogsmentioning

confidence: 92%

Radiation countermeasures for hematopoietic acute radiation syndrome: growth factors, cytokines and beyond

Singh

Seed²

2021

International Journal of Radiation Biology

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Purpose: The intent of this article is to report the status of some of the pharmaceuticals currently in late stage development for possible use for individuals unwantedly and acutely injured as a result of radiological/nuclear exposures. The two major questions we attempt to address here are: (a) What medicinals are currently deemed by regulatory authorities (US FDA) to be safe and effective and are being stockpiled? (b) What additional agents might be needed to make the federal/ state/local medicinal repositories more robust and useful in effectively managing contingencies involving radiation overexposures? Conclusions: A limited number (precisely four) of medicinals have been deemed safe and effective, and are approved by the US FDA for the 'hematopoietic acute radiation syndrome (H-ARS).' These agents are largely recombinant growth factors (e.g. rhuG-CSF/filgrastim, rhuGM-CSF/sargramostim) that target and stimulate myeloid progenitors within bone marrow. Romiplostim, a small molecular agonist that enhances platelet production via stimulation of bone marrow megakaryocytes, has been recently approved and indicated for H-ARS. It is critical that additional agents for other major sub-syndromes of ARS (gastrointestinal-ARS) be approved. Future success in developing such medicinals will undoubtedly entail some form of a polypharmaceutical strategy, or perhaps novel, bioengineered chimeric agents with multiple, radioprotective/radiomitigative functionalities.

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A wearable gamma radiation-responsive granulocyte colony-stimulating factor microneedle system protecting against ionizing radiation-induced injury

Zhu²,

Liang

et al. 2022

Acta Biomaterialia

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Single-Dose Administration of Recombinant Human Thrombopoietin Mitigates Total Body Irradiation-Induced Hematopoietic System Injury in Mice and Nonhuman Primates

Cited by 11 publications

References 34 publications

rhTPO Ameliorates Radiation-Induced Long-Term Hematopoietic Stem Cell Injury in Mice

rhTPO Ameliorates Radiation-Induced Long-Term Hematopoietic Stem Cell Injury in Mice

Radiation countermeasures for hematopoietic acute radiation syndrome: growth factors, cytokines and beyond

A wearable gamma radiation-responsive granulocyte colony-stimulating factor microneedle system protecting against ionizing radiation-induced injury

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