Asai Jun, Takenaka Hideya, Kusano Kengo F, Ii Masaaki, Luedemann Corinne, Curry Cynthia, Eaton Elizabeth, Iwakura Atsushi, Tsutsumi Yoshiaki, Hamada Hiromichi, Kishimoto Saburo, Thorne Tina, Kishore Raj, Losordo Douglas W
Division of Cardiovascular Research and Medicine, St Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA, USA.
Circulation. 2006 May 23;113(20):2413-24. doi: 10.1161/CIRCULATIONAHA.105.603167. Epub 2006 May 15.
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.
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.
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.
音猬因子（Shh）是一种典型的形态发生素，已知其在胚胎发育过程中调节上皮-间充质相互作用。最近的观察表明，外源性给予Shh可诱导血管生成，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关键作用，我们推测刺猬信号通路的激活可能对皮肤伤口愈合过程中的微血管重塑产生有利影响，从而加速伤口闭合。由于糖尿病与伤口愈合受损有关，我们在皮肤伤口修复的糖尿病模型中验证了这一假设。
在Ptc1-LacZ小鼠中，皮肤损伤导致LacZ表达，表明Shh受体patched的表达被诱导，因此Shh信号通路在出生后是完整的，并且在伤口修复过程中上调。在糖尿病小鼠中，使用编码Shh的裸DNA进行局部基因治疗导致显著的局部基因表达和伤口恢复加速。伤口愈合的加速在伤口血管增多方面尤为明显。在骨髓移植模型中，伤口血管增多至少部分是由骨髓来源的内皮祖细胞募集增加介导的。在体外，Shh促进成纤维细胞产生血管生成细胞因子以及真皮成纤维细胞增殖。此外，Shh直接促进内皮祖细胞的增殖、迁移、黏附和管腔形成。
这些发现表明，局部应用Shh基因治疗这一简单策略可能对糖尿病等微循环受损患者的伤口愈合增强具有显著的治疗潜力。
