Since the end of World War II, there has been significant interest in the effects of radiation following the explosions in Hiroshima and Nagasaki. The earliest lethal effect of radiation is the acute hematopoietic syndrome with the resultant pancytopenia. The hematopoietic syndrome is caused by the death of radioprotective cells from the radiation. A large body of work exists on the efficacy of hematopoietic stem cells (HSCs) to rescue subjects from lethal irradiation. These observations form the basis for the field of bone marrow transplantation and its successes in treating selected malignancies. This suggests that an important avenue of therapy for radiation-induced damage may be the delivery of hematopoietic stem cells, or the stimulation of accelerated repair of endogenous stem cells.
The recent identification of signaling modulators that can control and enhance hematopoietic stem cell growth, renewal and regeneration raise the possibility that the same modulators may be utilized to induce rapid regeneration during time of need. Our own experiments have identified the Wnt signaling pathway as a modulator of homeostatic hematopoietic stem cell growth, and as a signal that is upregulated during regeneration of HSCs after damage. Thus, we propose to test 1) Whether Wnt signaling can stimulate proliferation of human hematopoietic stem cells such that they may be expanded for delivery as a cellular therapy following radiation exposure and 2) Whether direct in vivo delivery of activators of Wnt signaling will allow enhanced regeneration of HSCs following exposure. Cumulatively the aims outlined below would allow the identification of both cellular and molecular deliverables that can be utilized rapidly in the aftermath of a nuclear disaster.
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