Abstract
CD47 is a widely expressed cell surface receptor that serves as a counter-receptor for signal regulatory protein-α and as a receptor for the secreted matricellular protein thrombospondin-1. Thrombospondin-1 signaling through CD47 regulates cellular signaling pathways that control cell survival, growth, motility, mitochondrial biogenesis, arterial vasoactive responses to physiologic vasodilators and blood flow, and responsiveness to growth factors. Studies employing mice lacking either thrombospondin-1 or CD47 have revealed an important role for this receptor-ligand interaction in tissue responses to injury and stress. These null mice show enhanced recovery from soft tissue fixed ischemic injuries, ischemia reperfusion injuries, and radiation injuries. These studies have led to development of antisense strategies to locally or globally suppress CD47 gene expression. A translation-blocking CD47 morpholino improves tissue survival in skin flap and hindlimb fixed ischemia models, full thickness skin grafts, and a liver ischemia/reperfusion model of organ transplantation in mice. Furthermore, the benefits of morpholino treatment extend to aged mice and mice with dysregulated fat metabolism that characteristically exhibit impaired recovery from ischemic injuries. Activity of the morpholino was also demonstrated for treatment of ischemic injury in miniature pigs. Treatment with the CD47 morpholino protects mice from major effects of ionizing radiation including alopecia, deterioration of muscle function, soft tissue and cutaneous fibrosis, and loss of hematopoietic stem cells in bone marrow. Remarkably, the same treatment does not protect tumors but instead enhances their ablation by irradiation. We discuss prospects for further development of CD47 antisense therapeutics for clinical applications including reconstructive surgery, organ transplantation, angioplasty, and cancer.
Highlights
Cell and tissue responses to stressTissue injury results in a complex array of physiological responses that limit blood loss, monitor for infection, eliminate nonviable cells, and initiate regeneration of tissue architecture and function
Several of the key elements that have emerged from these studies are the importance of maintaining blood flow, limiting inflammatory responses and the accompanying formation of reactive oxygen species (ROS), and limiting programmed cell death responses in tissues that are temporarily deprived of oxygen and nutrients
Whereas control flaps experienced ~50% tissue loss, CD47 morpholino treated tissue units enjoyed over 90% tissue survival
Summary
Tissue injury results in a complex array of physiological responses that limit blood loss, monitor for infection, eliminate nonviable cells, and initiate regeneration of tissue architecture and function. Nitric oxide (NO) and NO donor drugs have been used to increase blood flow, anti-inflammatory agents to limit recruitment or activation of neutrophils, antioxidants to scavenge ROS, and anti-apoptotic agents to minimize loss of viable cells in ischemic tissues [1,2,3,4] Such approaches to date have demonstrated limited success in clinical use [1,2]. Phase I and II trials were recently completed involving systemic administration of a morpholino oligonucleotide targeted to modify splicing of exon 51 in the human dystrophin pre-mRNA transcript, excluding exon 51 from the mature mRNA [39,40,41] The morpholino in these studies, Eteplirsen, was delivered by intravenous injection to treat patients with Duchenne muscular dystrophy. Other clinical trials employing morpholinos have tested their use to enhance patency of saphenous vein bypass grafts [43] and angioplasty stents [44] and to cross the blood brain barrier to target cancers [45]
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