Thrombospondin-1 and CD47 Limit Cell and Tissue Survival of Radiation Injury

Abstract

Radiation, a primary mode of cancer therapy, acutely damages cellular macromolecules and DNA and elicits stress responses that lead to cell death. The known cytoprotective activity of nitric oxide (NO) is blocked by thrombospondin-1, a potent antagonist of NO/ cGMP signaling in ischemic soft tissues, suggesting that thrombospondin-1 signaling via its receptor CD47 could correspondingly increase radiosensitivity. We show here that soft tissues in thrombospondin-1-null mice are remarkably resistant to radiation injury. Twelve hours after 25-Gy hindlimb irradiation, thrombospondin-1-null mice showed significantly less cell death in both muscle and bone marrow. Two months after irradiation, skin and muscle units in null mice showed minimal histological evidence of radiation injury and near full retention of mitochondrial function. Additionally , both tissue perfusion and acute vascular responses to NO were preserved in irradiated thrombospondin-1-null hindlimbs. The role of thrombospondin-1 in radiosensitization is specific because thrombospondin-2-null mice were not protected. However , mice lacking CD47 showed radioresistance similar to thrombospondin-1-null mice. Both thrombospondin-1-and CD47-dependent radiosensitization is cell autonomous because vascular cells isolated from the respective null mice showed dramatically increased survival and improved proliferative capacity after irradiation in vitro. Therefore , thrombospondin-1/CD47 antagonists may have selective radioprotective activity for normal tissues.

Activated CD47 regulates multiple vascular and stress responses: implications for acute kidney injury and its management

“…1). Consistent with these reports, we have found that TSP1 and CD47 null vascular cells and tissues do not undergo cell death in response to high-dose radiation (44). CD47-mediated cell and tissue death under radiation stress appears to occur in part by activation of apoptosis.…”

“…TSP1 is the only known soluble high-affinity ligand for the ubiquitous cell receptor CD47 (40), although signal regulatory protein-␣ (SIRP-␣) functions on phagocytes as a counterreceptor to CD47 (94). New findings identify CD47 as a regulator of multiple cell survival and cell death pathways (44,46,85), suggesting an important role for the TSP1-CD47 axis in renal injury.…”

Differential Interactions of Thrombospondin-1, -2, and -4 with CD47 and Effects on cGMP Signaling and Ischemic Injury Responses

“…Similarly, we recently showed that TSP2-null mice do not replicate the radioresistance phenotypes of TSP1-and CD47-null mice (47).…”

CD47 deficiency confers cell and tissue radioprotection by activation of autophagy

“…1,2 Lack of CD47 in the JinB8 clone of Jurkat T cells (CD47 − ) similarly conferred resistance to increasing doses of ionizing radiation as assessed by cell viability 72 h after exposure (Fig. 1A).…”

“…4 Agonists of this pathway such as THBS1 inhibit tumor growth and angiogenesis, but antagonists improve tissue survival of ischemic insults and radiation injuries. 2,[5][6][7] Deficiency of CD47 or THBS1 or suppression of CD47 results in radioprotection of human endothelial cells in vitro and protects soft tissue and bone marrow in vivo. 1 Moreover, suppression of CD47 in combination with IR enhances the IR-induced delay of tumor regrowth for syngeneic melanoma and squamous carcinoma models.…”