A physiological role for connective tissue growth factor in early wound healing.
A physiological role for connective tissue growth factor in early wound healing.
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DOI：
10.1038/labinvest.2012.162
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发表时间：
2013-01
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间充质干细胞（MSC），过表达分泌卷曲相关蛋白2（sFRP 2）表现出增强的修复表型。通过液相色谱串联质谱法比较sFRP 2过表达的MSCs和载体对照MSCs的分泌物。蛋白质组学分析显示，结缔组织生长因子（CTGF; CCN 2）是过度表达sFRP 2的MSC和MSC衍生的CTGF的条件培养基中，因此可能是一个重要的旁分泌效应。将皮下植入、载MSC的聚乙烯醇（PVA）海绵和支架切除伤口用作伤口模型，以研究CTGF表达的动力学。在海绵和全层皮肤伤口内产生的肉芽组织显示出MSC和成纤维细胞对CTGF表达的瞬时上调，这意味着该分子在早期组织修复中的作用。尽管在组织修复的早期阶段（第1-6天）向海绵施用重组CTGF时胶原和COL 1A 2 mRNA没有增加，但是向PVA海绵中延长施用外源性CTGF（>15天）导致成纤维细胞增殖和实验肉芽组织内胶原沉积增加。在支持其生理作用，CTGF免疫抑制在早期修复（第0-7天）减少的数量，组织质量和海绵模型中的实验肉芽组织的血管分布。然而，CTGF单倍不足不足以减少切除伤口中的胶原沉积。与急性小鼠伤口模型相似，CTGF在人急性烧伤伤口愈合的早期阶段短暂存在。总之，这些结果进一步支持了CTGF在伤口修复中的生理作用，并证明当CTGF表达局限于早期组织修复时，它起到促修复作用。这些数据还进一步说明了MSC衍生的旁分泌调节剂增强组织修复的潜力。
Mesenchymal stem cells (MSCs) that overexpress secreted frizzled-related protein 2 (sFRP2) exhibit an enhanced reparative phenotype. The secretomes of sFRP2-overexpressing MSCs and vector control-MSCs were compared through liquid chromatography tandem mass spectrometry. Proteomic profiling revealed that connective tissue growth factor (CTGF; CCN2) was overrepresented in the conditioned media of sFRP2-overexpressing MSCs and MSC-derived CTGF could thus be an important paracrine effector. Subcutaneously implanted, MSC-loaded polyvinyl alcohol (PVA) sponges and stented excisional wounds were used as wound models to study the dynamics of CTGF expression. Granulation tissue generated within the sponges and full-thickness skin wounds showed transient upregulation of CTGF expression by MSCs and fibroblasts, implying a role for this molecule in early tissue repair. Although collagen and COL1A2 mRNA were not increased when recombinant CTGF was administered to sponges during the early phase (day 1–6) of tissue repair, prolonged administration (>15 days) of exogenous CTGF into PVA sponges resulted in fibroblast proliferation and increased deposition of collagen within the experimental granulation tissue. In support of its physiological role, CTGF immunoinhibition during early repair (days 0–7) reduced the quantity, organizational quality and vascularity of experimental granulation tissue in the sponge model. However, CTGF haploinsufficiency was not enough to reduce collagen deposition in excisional wounds. Similar to acute murine wound models, CTGF was transiently present in the early phase of human acute burn wound healing. Together, these results further support a physiological role for CTGF in wound repair and demonstrate that when CTGF expression is confined to early tissue repair, it serves a pro-reparative role. These data also further illustrate the potential of MSC-derived paracrine modulators to enhance tissue repair.
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