Thrombospondin-1/CD36 pathway contributes to bone marrow-derived angiogenic cell dysfunction in type 1 diabetes via Sonic hedgehog pathway suppression
Thrombospondin-1/CD36 pathway contributes to bone marrow-derived angiogenic cell dysfunction in type 1 diabetes via Sonic hedgehog pathway suppression
复制标题
Thrombospondin-1/CD36 通路通过 Sonic Hedgehog 通路抑制导致 1 型糖尿病骨髓源性血管生成细胞功能障碍
DOI：
10.1152/ajpendo.00516.2013
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发表时间：
2013-12-01
影响因子：
5.1
通讯作者：
Chen, Alex F.
中科院分区：
文献类型：
--
作者：
Wang, Jie-Mei;Isenberg, Jeffery S.;Chen, Alex F.
糖尿病患者的难治性伤口是一个重要的临床问题。Sonic hedgehog（SHH）是一种对伤口修复至关重要的形态发生蛋白，在糖尿病中缺乏。SHH在伤口愈合中的调节作用知之甚少。我们推测，血小板反应蛋白-1（TSP-1），通过其受体CD 36，有助于1型糖尿病小鼠骨髓源性血管生成细胞（BMACs）的SHH信号缺陷。从TSP-1基因敲除小鼠分离的BMAC表现出与活跃的SHH信号传导平行的管形成、迁移和粘附的改善。来自STZ诱导的1型糖尿病小鼠的BMAC显示出显著受损的基质胶管形成（n = 5; P < 0.05相对于对照），其通过TSP-I消耗（n = 5; P < 0.05 STZ-TSP-1（-/-）相对于STZ-WT）或外源性SHH（20 mg/l，24 h，n = 4; P < 0.05相对于STZ对照）来挽救。STZ组BMACs中CD 36的表达明显增加（n = 4; P < 0.05）。SHH信号在来自TSP-1（-/-）小鼠和TSP-1受体CD 36敲除小鼠（n = 6; P < 0.05 vs. WT）但不是CD 47敲除小鼠（n = 3; P > 0.05 vs. WT）的BMAC中显著更高。重组人TSP-1（2.2 nM，24 h）对BMAC Matrigel管形成的损害被CD 36缺失显著延迟（n = 5; P < 0.05）。CD 36（-/-）BMAC在具有活性SHH信号传导的正常和糖尿病条件下均表现出更好的管形成（n = 4;相对于WT BMAC P < 0.05）。结论：TSP-1/CD 36通路参与了SHH信号转导缺陷，导致1型糖尿病小鼠BMAC功能障碍。
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.