Scar-free healing: from embryonic mechanisms to adult therapeutic intervention
Scar-free healing: from embryonic mechanisms to adult therapeutic intervention
复制标题
DOI：
10.1098/rstb.2004.1475
复制
发表时间：
2004-05-29
影响因子：
6.3
通讯作者：
O'Kane, S
中科院分区：
文献类型：
--
作者：
Ferguson, MWJ;O'Kane, S
在人类和家畜中，创伤、手术、烧伤或运动损伤后的皮肤瘢痕形成是主要的医学问题，通常导致不良的美观、功能丧失、组织运动和/或生长的限制以及不良的心理影响。目前的治疗方法是经验性的、不可靠的和不可预测的：没有预防或治疗皮肤瘢痕的处方药。早期哺乳动物胚胎的皮肤伤口愈合良好，没有疤痕，而成年哺乳动物的伤口会留下疤痕。我们研究了胚胎伤口无瘢痕愈合和成人伤口瘢痕形成愈合之间的细胞和分子差异。重要的差异包括炎症反应，在胚胎伤口中，炎症反应由较低数量的分化程度较低的炎症细胞组成。这与参与皮肤生长和形态发生的高水平形态发生分子一起意味着愈合的胚胎伤口中的生长因子谱与成人伤口中的生长因子谱非常不同。因此，没有疤痕愈合的胚胎伤口具有低水平的TGF β 1和TGF β 2，低水平的血小板衍生生长因子和高水平的TGF β 3。我们已经在小鼠、大鼠和猪中实验性地操纵愈合成人伤口以模拟无瘢痕胚胎特征，例如中和PDGF、中和TGF β和TGF β 2或添加外源性TGF β 3。这些实验导致成人无疤痕伤口愈合。这样的实验已经允许鉴定我们已经开发的新的药物分子的治疗靶点，其显著改善或完全防止实验动物的成年伤口愈合期间的瘢痕形成。其中一些新药已经成功完成了安全性和其他研究，因此它们已经进入人体临床试验，并获得了适当监管机构的批准。最初的试验包括在双盲随机设计中将药物或安慰剂应用于人类志愿者手臂下的实验性切口或打孔活检伤口。基于这些人类志愿者研究的令人鼓舞的结果，先导药物现已进入以人类患者为基础的试验，例如在皮肤移植供体部位。我们认为伤口愈合，疤痕和再生的进化背景。我们假设，进化的压力已经施加在中等大小，广泛，肮脏的伤口与相当大的组织损伤，如咬伤，瘀伤和挫伤。由尖锐物体引起的现代伤口（例如，由创伤或手术引起的）以及在具有紧密组织贴壁的清洁或无菌环境中愈合是新发生的，以前在自然界中没有遇到过，并且进化选择的伤口愈合反应在某种程度上是不合适的。我们还证明，疤痕修复和再生都可以发生在同一动物，包括人，甚至在同一组织内，从而表明它们具有相似的机制和调节因子。因此，通过微妙地改变成人伤口愈合过程中存在的生长因子的比例，我们可以诱导成人伤口完美愈合，没有疤痕，加速愈合，并且没有不利影响，例如对伤口强度或伤口感染率。这意味着疤痕可能不再是现代损伤或手术的必然结果，并且现在有可能采用全新的药物方法来预防人类疤痕。损伤后的疤痕发生在除皮肤外的许多组织中。因此，改善疤痕的药物可能具有广泛的益处，并可以预防多种组织的并发症，例如预防因眼损伤而形成疤痕后失明，通过消除胶质疤痕促进中枢和外周神经系统中的神经元重新连接，恢复正常肠道和生殖功能通过预防胃肠道或生殖系统损伤后的狭窄和粘连，以及通过防止肌腱和韧带中的疤痕来恢复运动功能。
In man and domestic animals, scarring in the skin after trauma, surgery, burn or sports injury is a major medical problem, often resulting in adverse aesthetics, loss of function, restriction of tissue movement and/or growth and adverse psychological effects. Current treatments are empirical, unreliable and unpredictable: there are no prescription drugs for the prevention or treatment of dermal scarring. Skin wounds on early mammalian embryos heal perfectly with no scars whereas wounds to adult mammals scar. We investigated the cellular and molecular differences between scar-free healing in embryonic wounds and scar-forming healing in adult wounds. Important differences include the inflammatory response, which in embryonic wounds consists of lower numbers of less differentiated inflammatory cells. This, together with high levels of morphogenetic molecules involved in skin growth and morphogenesis, means that the growth factor profile in a healing embryonic wound is very different from that in an adult wound. Thus, embryonic wounds that heal without a scar have low levels of TGFbeta1 and TGFbeta2, low levels of platelet-derived growth factor and high levels of TGFbeta3. We have experimentally manipulated healing adult wounds in mice, rats and pigs to mimic the scar-free embryonic profile, e.g. neutralizing PDGF, neutralizing TGFbeta and TGFbeta2 or adding exogenous TGFbeta3. These experiments result in scar-free wound healing in the adult. Such experiments have allowed the identification of therapeutic targets to which we have developed novel pharmaceutical molecules, which markedly improve or completely prevent scarring during adult wound healing in experimental animals. Some of these new drugs have successfully completed safety and other studies, such that they have entered human clinical trials with approval from the appropriate regulatory authorities. Initial trials involve application of the drug or placebo in a double-blind randomized design, to experimental incision or punch biopsy wounds under the arms of human volunteers. Based on encouraging results from such human volunteer studies, the lead drugs have now entered human patient-based trials e.g. in skin graft donor sites. We consider the evolutionary context of wound healing, scarring and regeneration. We hypothesize that evolutionary pressures have been exerted on intermediate sized, widespread, dirty wounds with considerable tissue damage e.g. bites, bruises and contusions. Modern wounds (e.g. resulting from trauma or surgery) caused by sharp objects and healing in a clean or sterile environment with close tissue apposition are new occurrences, not previously encountered in nature and to which the evolutionary selected wound healing responses are somewhat inappropriate. We also demonstrate that both repair with scarring and regeneration can occur within the same animal, including man, and indeed within the same tissue, thereby suggesting that they share similar mechanisms and regulators. Consequently, by subtly altering the ratio of growth factors present during adult wound healing, we can induce adult wounds to heal perfectly with no scars, with accelerated healing and with no adverse effects, e.g. on wound strength or wound infection rates. This means that scarring may no longer be an inevitable consequence of modem injury or surgery and that a completely new pharmaceutical approach to the prevention of human scarring is now possible. Scarring after injury occurs in many tissues in addition to the skin. Thus scar-improving drugs could have widespread benefits and prevent complications in several tissues, e.g.prevention of blindness after scarring due to eye injury, facilitation of neuronal reconnections in the central and peripheral nervous system by the elimination of glial scarring, restitution of normal gut and reproductive function by preventing strictures and adhesions after injury to the gastrointestinal or reproductive systems, and restoration of locomotor function by preventing scarring in tendons and ligaments.