Human CD133+ progenitor cells promote the healing of diabetic ischemic ulcers by paracrine stimulation of angiogenesis and activation of Wnt signaling.
Human CD133+ progenitor cells promote the healing of diabetic ischemic ulcers by paracrine stimulation of angiogenesis and activation of Wnt signaling.
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DOI：
10.1161/circresaha.108.192138
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发表时间：
2009-05-08
影响因子：
20.1
通讯作者：
Madeddu P
中科院分区：
文献类型：
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作者：
Barcelos LS;Duplaa C;Kränkel N;Graiani G;Invernici G;Katare R;Siragusa M;Meloni M;Campesi I;Monica M;Simm A;Campagnolo P;Mangialardi G;Stevanato L;Alessandri G;Emanueli C;Madeddu P
我们评估了人胎儿胰岛来源的CD 133+祖细胞及其条件培养基（CD 133 + CCM）在缺血性糖尿病溃疡新模型中的愈合潜力。链脲佐菌素诱导的糖尿病小鼠进行双侧肢体缺血和创伤。一处伤口用含有2×104个CD 133+或CD 133 −细胞的胶原蛋白或溶剂覆盖。对侧伤口，仅覆盖胶原蛋白，作为对照。胎儿CD 133+细胞表达高水平的无翅（Wnt）基因，其在分化为CD 133 −细胞后下调，沿着Wnt拮抗剂分泌的卷曲相关蛋白（sFRP）-1、-3和-4上调。与CD 133-或载体相比，CD 133+细胞加速伤口闭合，并通过旁分泌效应刺激内皮细胞增殖、迁移和存活促进血管生成。CD 133+细胞分泌高水平的血管内皮生长因子（VEGF）-A和白细胞介素（IL）-8。一致地，CD 133 + CCM加速伤口闭合和修复性血管生成，通过共同施用Wnt拮抗剂sFRP-1或针对VEGF-A或IL-8的中和抗体来消除该作用。在体外，这些作用在高葡萄糖引发的人脐静脉内皮细胞暴露于CD 133 + CCM后重现，导致刺激迁移、血管生成样网络形成和诱导Wnt表达。sFRP-1以及抗VEGF-A或IL-8的抗体减弱了CD 133 + CCM的促迁移和促血管生成作用。CD 133+细胞通过旁分泌机制激活受者的Wnt信号通路促进伤口愈合。这些临床前发现为糖尿病溃疡的治疗开辟了新的前景。
We evaluated the healing potential of human fetal aorta–derived CD133+ progenitor cells and their conditioned medium (CD133+ CCM) in a new model of ischemic diabetic ulcer. Streptozotocin-induced diabetic mice underwent bilateral limb ischemia and wounding. One wound was covered with collagen containing 2×104 CD133+ or CD133− cells or vehicle. The contralateral wound, covered with only collagen, served as control. Fetal CD133+ cells expressed high levels of wingless (Wnt) genes, which were downregulated following differentiation into CD133− cells along with upregulation of Wnt antagonists secreted frizzled-related protein (sFRP)-1, -3, and -4. CD133+ cells accelerated wound closure as compared with CD133− or vehicle and promoted angiogenesis through stimulation of endothelial cell proliferation, migration, and survival by paracrine effects. CD133+ cells secreted high levels of vascular endothelial growth factor (VEGF)-A and interleukin (IL)-8. Consistently, CD133+ CCM accelerated wound closure and reparative angiogenesis, with this action abrogated by coadministering the Wnt antagonist sFRP-1 or neutralizing antibodies against VEGF-A or IL-8. In vitro, these effects were recapitulated following exposure of high-glucose-primed human umbilical vein endothelial cells to CD133+ CCM, resulting in stimulation of migration, angiogenesis-like network formation and induction of Wnt expression. The promigratory and proangiogenic effect of CD133+ CCM was blunted by sFRP-1, as well as antibodies against VEGF-A or IL-8. CD133+ cells stimulate wound healing by paracrine mechanisms that activate Wnt signaling pathway in recipients. These preclinical findings open new perspectives for the cure of diabetic ulcers.