Protective Role of Angiogenin Against Hematopoietic Syndrome of the Acute Radiation Syndrome
Abstract
Topic Area: Illnesses Related to Radiation Exposure Radiation exposures in the range of 2-10 Gray (Gy) primarily affect the hematopoietic systems, resulting in the hematopoietic syndrome of the acute radiation syndrome (H-ARS). H-ARS is characterized by a decrease in neutrophils (neutropenia) and in platelets (thrombocytopenia) counts in the blood, which is life-threating due to infection and/or bleeding because neutrophils and platelets are the two blood components that fight for infections and help clotting, respectively. Mature, functional neutrophils are originated from a primitive cell type in the bone marrow (BM) named long-term hematopoietic stem cells (LT-HSC) through a series of steps called lineage differentiation process. This differentiation process involves multiple cell types of different maturation status, which in a simplified scheme, taking neutrophil as an example, includes the hierarchy from LT-HSC to short-term hematopoietic stem cells (ST-HSC) to multipotent progenitor cells (MPP) to common myeloid progenitors (CMP) to granulocytemacrophage progenitors (GMP) and then to neutrophils. Disruption of this differentiation process at any step of this lineage will result in abnormal development of neutrophil and other blood cells. Radiation exposure is known to damage a vital property of LT-HSC, thereby affecting the production of blood cells including neutrophils and platelets. LT-HSC normally reside in a specialized place in the BM named HSC niche. The niche keeps LT-HSC in quiescence, a vital property that endows the long-term self-renewal capacity of these cells so that they can constantly replenish blood cells. Loss of quiescence will mobilize stem cells out of the niche and subsequently lead to their exhaustion. LT-HSC from irradiated mice have increased cell cycle (an indication of loss of quiescence) and fail to engraft BM and repopulate blood cells when transplanted into proper recipients, indicating a functional defect. Loss of HSC function is believed to be the main cause of H-ARS. We have serendipitously found that angiogenin (ANG)-deficient LT-HSC behave very similarly as do the irradiated LT-HSC. Mice deficient in producing ANG, the so-called knockout (KO) mice, have an increased number of LT-HSC as do the irradiated mice. LT-HSC isolated from Ang KO mice display an increase in cell cycle (an indication of loss of quiescence) as do these from irradiated mice. More relevantly, Ang-deficient LTHSC fail to repopulate blood cells in transplantation recipient mice, a phenomenon that has also been observed in irradiated LT-HSC. These findings indicate that ANG plays an important role in maintaining the quiescence and self-renewal capacity of LT-HSC and lead us to hypothesize that ANG protein supplemental therapy might be an effective treatment for H-ARS. We will therefore use our Ang KO and ANG overexpression mice, the transgenic (TG) mice, to elucidate the role of ANG in H-ARS. We will test whether mice deficient in Ang (KO mice) are more sensitive and whether mice over-producing ANG (TG mice) are more resistant to radiation damage than wild-type (WT) mice. We will then evaluate the prophylactic and therapeutic activity of ANG protein against H-ARS. We will test whether systemic administration of ANG protein 24 hours before, immediately, and 24 hours after radiation exposure will prevent or alleviate H-ARS. ANG is a 14 kDa protein that is normal constituent of human blood at a concentration of ~200 ng/ml. It is a normal blood component, so supplemental therapy is projected to have minimal adverse effect. It is a stable protein, easy to produce and store (recombinant ANG protein has been shown to be stable as an aqueous solution at room temperature for 6 months). If a therapeutic activity of ANG against radiation exposure can be demonstrated, the outcome of this project will likely have a great impact in the treatment of H-ARS.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 29, 2016
- Source ID
- W81XWH1510207
Entities
People
- Guo-fu Hu
Organizations
- Tufts Medical Center
- United States Army