Blockade of CD47 Increases Survival of Mice Exposed to Lethal Total Body Irradiation

Overview

Journal Sci Rep

Specialty Science

Date 2013 Jan 10

PMID 23301159

Citations 44

Authors

David R Soto-Pantoja

Lisa A Ridnour

David A Wink

David D Roberts

Affiliations

Soon will be listed here.

Abstract

Accidental or therapeutic total body exposure to ionizing radiation has profound pathophysiological consequences including acute radiation syndrome. Currently only investigational drugs are available in case of radiological or nuclear accidents or terrorism. Lack of selective radioprotectants for normal tissues also limits the therapeutic doses that can be delivered to treat cancers. CD47 is a receptor for the secreted protein thrombospondin-1. Blockade of thrombospondin-1 or CD47 provides local radioprotection of soft tissues and bone marrow. We now report that suppression of CD47 using an antisense morpholino increases survival of mice exposed to lethal total body irradiation. Increased survival is associated with increased peripheral circulating blood cell counts and increased proliferative capacity of bone marrow derived cells. Moreover, CD47 blockade decreased cell death while inducing a protective autophagy response in radiosensitive gastrointestinal tissues. Thus, CD47 is a new target for radiomitigation that prevents both hematopoietic and gastrointestinal radiation syndromes.

Citing Articles

Blockade of TSP-1/CD47 signal axis promotes donor hematopoietic engraftment by improving SEC/MK niche function.

Wang F, Liu Y, Zhang T, Hou X, Xin Y, Xie G iScience. 2025; 28(3):111952.

PMID: 40060904 PMC: 11889568. DOI: 10.1016/j.isci.2025.111952.

Cell autonomous functions of CD47 in regulating cellular plasticity and metabolic plasticity.

Polara R, Ganesan R, Pitson S, Robinson N Cell Death Differ. 2024; 31(10):1255-1266.

PMID: 39039207 PMC: 11445524. DOI: 10.1038/s41418-024-01347-w.

Predictive DNA damage signaling for low‑dose ionizing radiation.

Park J, Jung S, Song K, Lee D, Ahn J, Hwang S Int J Mol Med. 2024; 53(6).

PMID: 38695243 PMC: 11093554. DOI: 10.3892/ijmm.2024.5380.

Tolerating CD47.

Isenberg J, Montero E Clin Transl Med. 2024; 14(2):e1584.

PMID: 38362603 PMC: 10870051. DOI: 10.1002/ctm2.1584.

CD47: The Next Frontier in Immune Checkpoint Blockade for Non-Small Cell Lung Cancer.

Lau A, Khavkine Binstock S, Thu K Cancers (Basel). 2023; 15(21).

PMID: 37958404 PMC: 10649163. DOI: 10.3390/cancers15215229.

References

Isenberg J, Maxhimer J, Powers P, Tsokos M, Frazier W, Roberts D . Treatment of liver ischemia-reperfusion injury by limiting thrombospondin-1/CD47 signaling. Surgery. 2008; 144(5):752-61. PMC: 2635486. DOI: 10.1016/j.surg.2008.07.009. View

Kulkarni S, Ghosh S, Hauer-Jensen M, Kumar K . Hematological targets of radiation damage. Curr Drug Targets. 2010; 11(11):1375-85. DOI: 10.2174/1389450111009011375. View

Jahraus C, Schemera B, Rynders P, Ramos M, Powell C, Faircloth J . Rifaximin diminishes neutropenia following potentially lethal whole-body radiation. Exp Biol Med (Maywood). 2010; 235(7):900-5. DOI: 10.1258/ebm.2010.009333. View

Isenberg J, Ridnour L, Dimitry J, Frazier W, Wink D, Roberts D . CD47 is necessary for inhibition of nitric oxide-stimulated vascular cell responses by thrombospondin-1. J Biol Chem. 2006; 281(36):26069-80. DOI: 10.1074/jbc.M605040200. View

Xiao M, Inal C, Parekh V, Li X, Whitnall M . Role of NF-kappaB in hematopoietic niche function of osteoblasts after radiation injury. Exp Hematol. 2008; 37(1):52-64. DOI: 10.1016/j.exphem.2008.09.001. View

Iversen P, Arora V, Acker A, Mason D, Devi G . Efficacy of antisense morpholino oligomer targeted to c-myc in prostate cancer xenograft murine model and a Phase I safety study in humans. Clin Cancer Res. 2003; 9(7):2510-9. View

Isenberg J, Martin-Manso G, Maxhimer J, Roberts D . Regulation of nitric oxide signalling by thrombospondin 1: implications for anti-angiogenic therapies. Nat Rev Cancer. 2009; 9(3):182-94. PMC: 2796182. DOI: 10.1038/nrc2561. View

Rogers N, Thomson A, Isenberg J . Activation of parenchymal CD47 promotes renal ischemia-reperfusion injury. J Am Soc Nephrol. 2012; 23(9):1538-50. PMC: 3431420. DOI: 10.1681/ASN.2012020137. View

Frazier E, Isenberg J, Shiva S, Zhao L, Schlesinger P, Dimitry J . Age-dependent regulation of skeletal muscle mitochondria by the thrombospondin-1 receptor CD47. Matrix Biol. 2011; 30(2):154-61. PMC: 3070423. DOI: 10.1016/j.matbio.2010.12.004. View

10.

Sazani P, Weller D, Shrewsbury S . Safety pharmacology and genotoxicity evaluation of AVI-4658. Int J Toxicol. 2010; 29(2):143-56. DOI: 10.1177/1091581809359206. View

11.

Heslet L, Bay C, Nepper-Christensen S . Acute radiation syndrome (ARS) - treatment of the reduced host defense. Int J Gen Med. 2012; 5:105-15. PMC: 3273373. DOI: 10.2147/IJGM.S22177. View

12.

Isenberg J, Romeo M, Maxhimer J, Smedley J, Frazier W, Roberts D . Gene silencing of CD47 and antibody ligation of thrombospondin-1 enhance ischemic tissue survival in a porcine model: implications for human disease. Ann Surg. 2008; 247(5):860-8. PMC: 2430143. DOI: 10.1097/SLA.0b013e31816c4006. View

13.

Singh V, Ducey E, Brown D, Whitnall M . A review of radiation countermeasure work ongoing at the Armed Forces Radiobiology Research Institute. Int J Radiat Biol. 2011; 88(4):296-310. DOI: 10.3109/09553002.2012.652726. View

14.

Isenberg J, Romeo M, Abu-Asab M, Tsokos M, Oldenborg A, Pappan L . Increasing survival of ischemic tissue by targeting CD47. Circ Res. 2007; 100(5):712-20. DOI: 10.1161/01.RES.0000259579.35787.4e. View

15.

Isenberg J, Pappan L, Romeo M, Abu-Asab M, Tsokos M, Wink D . Blockade of thrombospondin-1-CD47 interactions prevents necrosis of full thickness skin grafts. Ann Surg. 2007; 247(1):180-90. PMC: 2432017. DOI: 10.1097/SLA.0b013e31815685dc. View

16.

Soto-Pantoja D, Isenberg J, Roberts D . Therapeutic Targeting of CD47 to Modulate Tissue Responses to Ischemia and Radiation. J Genet Syndr Gene Ther. 2012; 2(2). PMC: 3368437. DOI: 10.4172/2157-7412.1000105. View

17.

Dorr H, Meineke V . Acute radiation syndrome caused by accidental radiation exposure - therapeutic principles. BMC Med. 2011; 9:126. PMC: 3235966. DOI: 10.1186/1741-7015-9-126. View

18.

Soto-Pantoja D, Miller T, Pendrak M, DeGraff W, Sullivan C, Ridnour L . CD47 deficiency confers cell and tissue radioprotection by activation of autophagy. Autophagy. 2012; 8(11):1628-42. PMC: 3494592. DOI: 10.4161/auto.21562. View

19.

Isenberg J, Maxhimer J, Hyodo F, Pendrak M, Ridnour L, DeGraff W . Thrombospondin-1 and CD47 limit cell and tissue survival of radiation injury. Am J Pathol. 2008; 173(4):1100-12. PMC: 2543077. DOI: 10.2353/ajpath.2008.080237. View

20.

Berkey F . Managing the adverse effects of radiation therapy. Am Fam Physician. 2010; 82(4):381-8, 394. View