Ionizing irradiation is harmful for many organs and tissues in the body, including the hematopoietic system. In addition to eliminating proliferating hematopoietic progenitors, irradiation affects the structure and function of the hematopoiesis-supportive niche. A lack of drugs, which normalize the function of the hematopoietic niche after ionizing irradiation, reflects gaps in our knowledge regarding fundamental stem cell biology and remains an obstacle to an optimal therapeutic approach. We have previously demonstrated that hyaluronan (HA) contributes to the structure of the hematopoietic niche in bone marrow and supports generation of all hematopoietic lineages. However, during the exposure to irradiation, HA undergoes chemical degradation, which contributes to the imbalance of hematopoietic homeostasis in the niche. This project will address the question of whether exogenous HA can be used to facilitate the recovery of hematopoiesis following various doses of irradiation.
In Specific Aim 1, we will test the effects of HA on the recovery of hematopoiesis in mice subjected to lethal irradiation and bone marrow transplantation by monitoring the number of mature hematopoietic cells in peripheral blood and hematopoietic stem cells and committed progenitors in bone marrow. Since the biological effects of HA are determined by its size, we will identify biologically active HA by testing a panel of HA polymers of defined size. In addition, we will optimize the therapeutic dose of HA and treatment schedule.
In Specific Aim 2, we will investigate the effect of HA on hematopoietic recovery following sub-lethal irradiation. Since in the scenario of massive exposure to irradiation, therapeutic interventions other then transplantation of hematopoietic stem cells are required, we will test whether the defined size HA polymers can be used to facilitate hematopoietic recovery following various doses of irradiation without transplantation of hematopoietic stem cells. In addition, we will test different drug administration routes including oral and subcutaneous. Mice will be sub-lethally irradiated with various doses (1Gy, 2Gy, 4Gy, 6Gy and 8Gy) followed by administration of HA. The dynamics of the recovery of mature hematopoietic cells in peripheral blood and hematopoietic stem/progenitor cells in bone marrow will be examined. Obtained data will provide a basis for a novel therapeutic approach to fight irradiation-induced pancytopenia by targeting the hematopoietic niche. Overall, this grant application will allow us to test a novel hypothesis and to generate data for further studies on the possibility to use HA as a therapeutic agent.
Hyaluronan (HA) has a potential to be developed as a drug to stimulate the recovery of peripheral blood cells in subjects exposed to various doses of ionizing irradiation. We will test the effects of HA on regeneration of bone marrow hematopoiesis in vivo following various doses of irradiation with or without hematopoietic stem cell support. Together, the obtained results will provide important information regarding the possibility to target the hematopoietic niche by using HA following different doses of ionizing irradiation.
| Goncharova, Valentina; Serobyan, Naira; Iizuka, Shinji et al. (2012) Hyaluronan expressed by the hematopoietic microenvironment is required for bone marrow hematopoiesis. J Biol Chem 287:25419-33 |
| Schraufstatter, Ingrid U; Discipio, Richard G; Khaldoyanidi, Sophia (2011) Mesenchymal stem cells and their microenvironment. Front Biosci (Landmark Ed) 16:2271-88 |
| Mueller, Barbara M; Schraufstatter, Ingrid U; Goncharova, Valentina et al. (2010) Hyaluronan inhibits postchemotherapy tumor regrowth in a colon carcinoma xenograft model. Mol Cancer Ther 9:3024-32 |
