title: Thrombospondin-1/CD36 pathway contributes to bone marrow-derived angiogenic cell dysfunction in type 1 diabetes via Sonic hedgehog pathway suppression.
abstract: Refractory wounds in diabetic patients present a significant clinical problem. Sonic hedgehog (SHH), a morphogenic protein central to wound repair, is deficient in diabetes. Regulation of SHH in wound healing is poorly understood. We hypothesize that thrombospondin-1 (TSP-1), through its receptor CD36, contributes to the SHH signaling defect in bone marrow-derived angiogenic cells (BMACs) in type 1 diabetic mice. Isolated BMACs from TSP-1-knockout mice demonstrated improved tube formation, migration, and adhesion in parallel with active SHH signaling. BMACs from STZ-induced type 1 diabetic mice showed significantly impaired Matrigel tube formation (n = 5; P < 0.05 vs. control), which was rescued by TSP-1 depletion (n = 5; P < 0.05 STZ-TSP-1(-/-) vs. STZ-WT) or exogenous SHH (20 mg/l, 24 h, n = 4; P < 0.05 vs. STZ-control). The expression of CD36 was elevated in BMACs from STZ mice (n = 4; P < 0.05). SHH signaling was significantly higher in BMACs from TSP-1(-/-) mice and TSP-1 receptor CD36-knockout mice (n = 6; P < 0.05 vs. WT) but not CD47-knockout mice (n = 3; P > 0.05 vs. WT). The impairment of recombinant human TSP-1 (2.2 nM, 24 h) on BMAC Matrigel tube formation was delayed significantly by CD36 deletion (n = 5; P < 0.05). CD36(-/-) BMACs demonstrated better tube formation under both normal and diabetic conditions with active SHH signaling (n = 4; P < 0.05 vs. WT BMACs). In conclusion, The TSP-1/CD36 pathway contributes to the SHH signaling defect, resulting in BMAC dysfunction in type 1 diabetic mice.
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania;
authors.forename: Jie-Mei
authors.initials: JM
authors.lastname: Wang
authors.forename: Jeffery S
authors.initials: JS
authors.lastname: Isenberg
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Billiar
authors.forename: Alex F
authors.initials: AF
authors.lastname: Chen
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000502:physiology*; D018955:CD36 Antigens / Q000502:physiology*; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000150:complications / Q000235:genetics / Q000503:physiopathology; D003922:Diabetes Mellitus, Type 1 / Q000139:chemically induced / Q000150:complications / Q000235:genetics / Q000503:physiopathology*; D003925:Diabetic Angiopathies / Q000209:etiology / Q000503:physiopathology; D042783:Endothelial Cells / Q000502:physiology*; D020868:Gene Silencing; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000235:genetics; D015398:Signal Transduction; D013311:Streptozocin; D019700:Thrombospondin 1 / Q000502:physiology*
chemical_list: D018955:CD36 Antigens; D053823:Hedgehog Proteins; C465570:Shh protein, mouse; D019700:Thrombospondin 1; C585483:Thbs1 protein, mouse; D013311:Streptozocin
keywords: Sonic hedgehog; bone marrow-derived angiogenic cells; thrombospondin-1; type 1 diabetes