Topical sonic hedgehog gene therapy accelerates wound healing in diabetes by enhancing endothelial progenitor cell-mediated microvascular remodeling
Topical sonic hedgehog gene therapy accelerates wound healing in diabetes by enhancing endothelial progenitor cell-mediated microvascular remodeling
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DOI：
10.1161/circulationaha.105.603167
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发表时间：
2006-05-23
期刊：
影响因子：
37.8
通讯作者：
Losordo, Douglas W.
中科院分区：
文献类型：
--
作者：
Asai, Jun;Takenaka, Hideya;Losordo, Douglas W.
背景-Sonic hedgehog(Shh)是已知的在胚胎发育过程中调节上皮-间充质相互作用的典型形态因子。最近的研究表明，外源性给予Shh可以诱导血管生成，并可能加速缺血心肌和骨骼肌的修复。由于血管生成在伤口修复中起着关键作用，我们假设Hedgehog通路的激活可能促进皮肤伤口愈合过程中微血管重塑的有利作用，从而加速伤口闭合。方法和结果--在Ptc1-LacZ小鼠中，皮肤损伤导致LacZ表达，表明Shh受体Patch的表达被诱导，因此Shh信号通路在出生后是完整的，并在伤口修复过程中上调。在糖尿病小鼠中，使用编码Shh的裸露DNA的局部基因治疗导致了显著的局部基因表达，并加速了伤口的恢复。伤口愈合的加速是由于伤口血管的增加。在骨髓移植模型中，伤口血管的增强至少部分是通过促进骨髓来源的内皮祖细胞的募集来实现的。在体外，Shh促进成纤维细胞产生血管生成细胞因子，并促进真皮成纤维细胞的增殖。此外，Shh直接促进内皮祖细胞的增殖、迁移、黏附和管状形成。结论：这些发现表明，局部应用Shh基因治疗的简单策略可能对糖尿病等微循环障碍患者的伤口愈合具有显著的治疗潜力。
Background - Sonic hedgehog (Shh) is a prototypical morphogen known to regulate epithelial-mesenchymal interaction during embryonic development. Recent observations indicate that exogenous administration of Shh can induce angiogenesis and may accelerate repair of ischemic myocardium and skeletal muscle. Because angiogenesis plays a pivotal role in wound repair, we hypothesized that activation of the hedgehog pathway may promote a favorable effect on microvascular remodeling during cutaneous wound healing and thereby accelerate wound closure. Because diabetes is associated with impaired wound healing, we tested this hypothesis in a diabetic model of cutaneous wound repair.Methods and Results - In Ptc1-LacZ mice, cutaneous injury resulted in LacZ expression, indicating that expression of the Shh receptor Patched was induced and therefore that the Shh signaling pathway was intact postnatally and upregulated in the process of wound repair. In diabetic mice, topical gene therapy with the use of naked DNA encoding for Shh resulted in significant local gene expression and acceleration of wound recovery. The acceleration in wound healing was notable for increased wound vascularity. In bone marrow transplantation models, the enhanced vascularity of the wound was shown to be mediated, at least in part, by enhanced recruitment of bone marrow - derived endothelial progenitor cells. In vitro, Shh promoted production of angiogenic cytokines from fibroblasts as well as proliferation of dermal fibroblasts. Furthermore, Shh directly promoted endothelial progenitor cell proliferation, migration, adhesion, and tube formation.Conclusions - These findings suggest that a simple strategy of topically applied Shh gene therapy may have significant therapeutic potential for enhanced wound healing in patients with impaired microcirculation such as occurs in diabetes.