Thrombomodulin promotes activated protein C–mediated hematopoietic recovery after radiation.
Major finding: Thrombomodulin promotes activated protein C–mediated hematopoietic recovery after radiation.
Approach: An insertional mutagenesis screen was used to identify genes that reduce radiation toxicity.
Impact: Systemic administration of THBD or aPC may protect against radiation therapy–induced injury.
Ionizing radiation induces hematopoietic and gastrointestinal tissue damage that can result in lethality; therefore, the development of new approaches to mitigate this toxicity is essential. Geiger and colleagues used an insertional mutagenesis screen in mice to identify the thrombomodulin (THBD)–activated protein C (aPC) pathway, which regulates blood coagulation and is cytoprotective in endothelial cells, as a mediator of hematopoietic recovery after radiation injury. Thbd overexpression was beneficial in hematopoietic progenitor cells and promoted the selection of these cells in response to ionizing radiation. Moreover, systemic administration of soluble, recombinant human THBD or aPC provided a survival advantage to irradiated wild-type mice, even when aPC was first injected 24 hours after exposure to lethal radiation doses. Treatment with either recombinant protein resulted in increased numbers of hematopoietic progenitor cells 10 days after irradiation, suggesting that this pathway augments the recovery and activity of bone marrow cells after radiation damage. Endogenous THBD protein also conferred a protective effect, and reconstitution experiments demonstrated that THBD expression in both hematopoietic cells and stromal endothelial cells contributed to this enhanced survival. Activated protein C is required for this protection, as the increased radiation sensitivity of mice expressing a signaling-deficient form of THBD was reversed by expression of a constitutively active protein C transgene. Furthermore, analysis using variant aPC proteins and blocking antibodies demonstrated that the radioprotective effect of aPC occurred independently of known protein C functions, including the ability to induce downstream receptor signaling and antithrombotic actions, supporting the existence of additional, unknown aPC functions. Together, these data provide evidence that administration of recombinant THBD or aPC may be a useful therapeutic strategy for cancer patients undergoing radiation therapy.