Kann Allison P, Srivastava Mansi
bioRxiv. 2025 Feb 3:2025.02.03.636261. doi: 10.1101/2025.02.03.636261.
Wound healing is a fundamental property of animal life, but the extent to which large injuries can be endogenously repaired varies across phyla. In vertebrates, minor wounds can re-epithelialize on their own, but major wounds often result in imperfect re-epithelialization and fibrotic scarring. In contrast, more regenerative species are capable of both scarless healing and subsequent replacement of missing structures. Due to limitations in many animals' ability to recover from large, multi-tissue injuries, much of our understanding of wound closure comes from experiments studying gaps in epithelial monolayers. In comparison, the mechanisms by which animals can heal large wounds have been characterized primarily at the histological level, usually in non-model species that undergo substantial regeneration after wound healing. Here, we investigate the cellular dynamics of large-scale wound healing in the acoel Hofstenia miamia, an invertebrate worm capable of whole-body regeneration. H. miamia lack a traditional basement membrane and epidermal cells are not separated from underlying muscle by an organized layer of extracellular matrix - making the system incompatible with canonical mechanisms of crawling-based wound healing and raising the possibility that novel mechanisms may be driving closure. By labeling injured animals with an actin dye, we found that H. miamia epidermal cells extend long, actin-rich cytoplasmic protrusions across the wound edge until they reach the nearest epithelial layer and establish cell-cell contact. This process is dependent on muscle contraction; when animals are anesthetized and immobile, they are unable to form these cellular bridges, and epidermal cells cannot migrate independently. At injury sites that lack underlying muscle connecting the wound edge, wounds heal through the formation of organism-wide contractile purse strings. Together, this work identifies mechanisms by which multiple tissue types work together to close large wounds in vivo, indicating a deep conservation of proximate epithelial-mesenchymal interactions in morphogenetic processes.
伤口愈合是动物生命的一项基本特性，但不同门类动物内源性修复大面积损伤的程度各不相同。在脊椎动物中，小伤口能够自行重新上皮化，但大伤口往往导致不完全的重新上皮化和纤维化瘢痕形成。相比之下，更具再生能力的物种能够实现无瘢痕愈合并随后替换缺失的结构。由于许多动物从大面积多组织损伤中恢复的能力有限，我们对伤口闭合的大部分理解来自于研究上皮单层间隙的实验。相比之下，动物愈合大伤口的机制主要是在组织学水平上进行表征的，通常是在伤口愈合后经历大量再生的非模式物种中。在这里，我们研究了无肠动物霍氏涡虫（Hofstenia miamia）大规模伤口愈合的细胞动力学，这是一种能够全身再生的无脊椎蠕虫。霍氏涡虫缺乏传统的基底膜，表皮细胞与下方的肌肉没有被一层有组织的细胞外基质分隔开——这使得该系统与基于爬行的伤口愈合的经典机制不兼容，并增加了可能存在新机制驱动伤口闭合的可能性。通过用肌动蛋白染料标记受伤动物，我们发现霍氏涡虫的表皮细胞会在伤口边缘延伸出长的、富含肌动蛋白的细胞质突起，直到它们到达最近的上皮层并建立细胞间接触。这个过程依赖于肌肉收缩；当动物被麻醉且无法移动时，它们就无法形成这些细胞桥，表皮细胞也无法独立迁移。在缺乏连接伤口边缘的下方肌肉的损伤部位，伤口通过形成全身体内收缩的荷包索来愈合。这项工作共同确定了多种组织类型共同作用以在体内闭合大伤口的机制，表明在形态发生过程中近端上皮 - 间充质相互作用具有深度保守性。
