Thrombospondin-1 signaling through CD47 inhibits self-renewal by regulating c-Myc and other stem cell transcription factors

Signaling through the thrombospondin-1 receptor CD47 broadly limits cell and tissue survival of stress, but the molecular mechanisms are incompletely understood. We now show that loss of CD47 permits sustained proliferation of primary murine endothelial cells, increases asymmetric division, and enab...

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Bibliographic Details
Published in:	Scientific reports 2013-04, Vol.3 (1), p.1673-1673, Article 1673
Main Authors:	Kaur, Sukhbir, Soto-Pantoja, David R, Stein, Erica V, Liu, Chengyu, Elkahloun, Abdel G, Pendrak, Michael L, Nicolae, Alina, Singh, Satya P, Nie, Zuqin, Levens, David, Isenberg, Jeffrey S, Roberts, David D
Format:	Article
Language:	eng
Subjects:	Animals Antagonists c-Myc protein CD47 Antigen - metabolism Cell proliferation Cell survival Cells, Cultured Endothelial cells Endothelial Cells - cytology Endothelial Cells - metabolism Gene Expression Regulation - physiology Kinases KLF4 protein Lymphocytes T Mice Models, Biological Molecular modelling Myc protein Oct-4 protein Proto-Oncogene Proteins c-myc - metabolism Rodents Signal Transduction - physiology Stem cells Stem Cells - cytology Stem Cells - metabolism Thrombospondin Thrombospondin 1 - metabolism Transcription factors Transcription Factors - metabolism
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Summary:	Signaling through the thrombospondin-1 receptor CD47 broadly limits cell and tissue survival of stress, but the molecular mechanisms are incompletely understood. We now show that loss of CD47 permits sustained proliferation of primary murine endothelial cells, increases asymmetric division, and enables these cells to spontaneously reprogram to form multipotent embryoid body-like clusters. c-Myc, Klf4, Oct4, and Sox2 expression is elevated in CD47-null endothelial cells, in several tissues of CD47- and thrombospondin-1-null mice, and in a human T cell line lacking CD47. CD47 knockdown acutely increases mRNA levels of c-Myc and other stem cell transcription factors in cells and in vivo, whereas CD47 ligation by thrombospondin-1 suppresses c-Myc expression. The inhibitory effects of increasing CD47 levels can be overcome by maintaining c-Myc expression and are absent in cells with dysregulated c-Myc. Thus, CD47 antagonists enable cell self-renewal and reprogramming by overcoming negative regulation of c-Myc and other stem cell transcription factors.
ISSN:	2045-2322 2045-2322