Mammals fail to regenerate organs when wound contraction drives scar formation.
Mammals fail to regenerate organs when wound contraction drives scar formation.
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DOI：
10.1038/s41536-021-00149-9
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发表时间：
2021-07-22
影响因子：
7.2
通讯作者：
Tzeranis DS
中科院分区：
文献类型：
--
作者：
Yannas IV;Tzeranis DS
为了理解为什么哺乳动物一般不会再生受伤的器官，我们考虑了早期羔羊胎儿自发皮肤再生的例外情况。而在胎儿早期，皮肤伤口通过再生愈合，在胎儿晚期和出生后，皮肤伤口通过瘢痕形成而愈合。我们回顾了独立的证据，伤口愈合反应的这种开关与伤口收缩的开始相吻合，这也在胎儿妊娠后期启用。在三种严重损伤的哺乳动物模型（切除的豚鼠皮肤、横断的大鼠坐骨神经、切除的兔结膜基质）中，伤口收缩在决定成人伤口愈合结果中的关键作用已经得到证实，其中用DRT（一种高度特异性结构的收缩阻断支架）移植损伤可显著改变伤口愈合结果。虽然在这些动物模型中自发愈合导致瘢痕形成，但DRT移植显著降低了创面收缩程度，阻止了瘢痕合成，并导致部分再生。这些发现，以及来自通过再生自发愈合的物种的独立数据，指向了一个惊人的假设：哺乳动物的再生过程处于休眠状态，直到被损伤适当地激活。在晚期胎儿和成年哺乳动物的自发伤口愈合中，伤口收缩阻碍了这种内源性再生机制。然而，工程治疗，如DRT，阻止伤口收缩，可以取消其效果，有利于伤口愈合再生，而不是疤痕形成。
To understand why mammals generally do not regenerate injured organs, we considered the exceptional case of spontaneous skin regeneration in the early lamb fetus. Whereas during the early fetal stage skin wounds heal by regeneration, in the late fetal stage, and after birth, skin wounds close instead by scar formation. We review independent evidence that this switch in wound healing response coincides with the onset of wound contraction, which is also enabled during late fetal gestation. The crucial role of wound contraction in determining the wound healing outcome in adults has been demonstrated in three mammalian models of severe injury (excised guinea pig skin, transected rat sciatic nerve, excised rabbit conjunctival stroma) where grafting the injury with DRT, a contraction-blocking scaffold of highly-specific structure, altered significantly the wound healing outcome. While spontaneous healing resulted in scar formation in these animal models, DRT grafting significantly reduced the extent of wound contraction, prevented scar synthesis, and resulted in partial regeneration. These findings, as well as independent data from species that heal spontaneously via regeneration, point to a striking hypothesis: The process of regeneration lies dormant in mammals until appropriately activated by injury. In spontaneous wound healing of the late fetus and in adult mammals, wound contraction impedes such endogenous regeneration mechanisms. However, engineered treatments, such as DRT, that block wound contraction can cancel its effects and favor wound healing by regeneration instead of scar formation.
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