Serum microRNAs are early indicators of survival after radiation-induced hematopoietic injury

Abstract

Accidental radiation exposure is a threat to human health that necessitates effective clinical planning and diagnosis. Minimally invasive biomarkers that can predict long-term radiation injury are urgently needed for optimal management after a radiation accident. We have identified serum microRNA (miRNA) signatures that indicate long-term impact of total body irradiation (TBI) in mice when measured within 24 hours of exposure. Impact of TBI on the hematopoietic system was systematically assessed to determine a correlation of residual hematopoietic stem cells (HSCs) with increasing doses of radiation. Serum miRNA signatures distinguished untreated mice from animals exposed to radiation and correlated with the impact of radiation on HSCs. Mice exposed to sublethal (6.5 Gy) and lethal (8 Gy) doses of radiation were indistinguishable for 3 to 4 weeks after exposure. A serum miRNA signature detectable 24 hours after radiation exposure consistently segregated these two cohorts. Furthermore, using either a radioprotective agent before, or radiation mitigation after, lethal radiation, we determined that the serum miRNA signature correlated with the impact of radiation on animal health rather than the radiation dose. Last, using humanized mice that had been engrafted with human CD34+ HSCs, we determined that the serum miRNA signature indicated radiation-induced injury to the human bone marrow cells. Our data suggest that serum miRNAs can serve as functional dosimeters of radiation, representing a potential breakthrough in early assessment of radiation-induced hematopoietic damage and timely use of medical countermeasures to mitigate the long-term impact of radiation.

Detection of Acute Radiation Sickness: A Feasibility Study in Non-Human Primates Circulating miRNAs for Triage in Radiological Events

“…Circulating miRNA-based radiation biodosimetry holds significant promise as the assay is relatively straightforward and it requires only small volumes of blood obtainable without a phlebotomist, with the aid of commercially available lancets. It has been shown by us [15] and others [22] using mouse models, that miRNA-based assays are capable of taking into account inter-individual variations as the actual dose effect could vary depending on pre-existing conditions, inherent differences in immune responses and other confounders. Recent technological advances in exosome biology and liquid biopsy, coupled with our current studies in NHPs identifying specific biomarkers altered as function of WBI dose, will help in the development of an effective radiation biodosimeter that will be minimally invasive [31,34].…”

“…Previous rodent studies have shown dose- and time-dependent alteration in serum levels of specific miRNA sequences after whole body irradiation (WBI) [15]. Particularly, a dose and time dependent decrease in miR-150 was noted, which was proposed as a novel approach for post-exposure dose estimation [22]. The lethal dose (LD 50 ) for humans when untreated or with minimal supportive care is about 4 Gy [23, 24], which is significantly lower than LD 50 for most rodents [25,26].…”

Astaxanthin attenuates total body irradiation-induced hematopoietic system injury in mice via inhibition of oxidative stress and apoptosis

“…The hematopoietic system is the most vulnerable system to the damaging effects of total body irradiation (TBI), and doses greater than 1 Gy induce bone marrow (BM) cell injury [2]. BM suppression is also the main symptom of hematopoietic systemic injury seen in the clinic when patients receive traditional cancer therapy, such as radiotherapy, and this can cause high mortality and morbidity which worsens the outcome of cancer treatment [3, 4]. TBI-induced myelosuppression, which presents mainly as pancytopenia, is due to apoptosis of the rapidly proliferating hematopoietic progenitor cells (HPCs) and the relatively quiescent hematopoietic stem cells (HSCs) [5].…”

State-of-the-Art Advances in Radiation Biodosimetry for Mass Casualty Events Involving Radiation Exposure

“…These serum miRNA signatures were found to correlate with residual hematopoietic stem cell status and demonstrate the potential for miRNA to serve as a biomarker for radiation injury in addition to dose ( 60 ).…”