Elucidating the fundamental fibrotic processes driving abdominal adhesion formation
Elucidating the fundamental fibrotic processes driving abdominal adhesion formation
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DOI：
10.1038/s41467-020-17883-1
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发表时间：
2020-08-13
影响因子：
16.6
通讯作者：
Longaker, Michael T.
中科院分区：
文献类型：
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作者：
Foster, Deshka S.;Marshall, Clement D.;Longaker, Michael T.
粘连是手术或感染后在腹部器官之间形成的纤维化瘢痕，可能导致肠梗阻、慢性疼痛或不孕。我们对粘连生物学的理解是有限的，这解释了抗粘连治疗的缺乏。在这里，我们提出了一个系统的分析小鼠和人类的粘连组织。首先，我们发现粘连主要来源于脏层腹膜，这与我们的临床经验一致，即粘连主要在剖腹手术后形成，而不是腹腔镜手术后形成。其次，粘连是由多克隆增殖的组织驻留成纤维细胞形成的。第三，使用单细胞RNA测序，我们确定了粘附成纤维细胞之间的异质性，这在早期时间点更明显。第四，JUN促进粘附形成并导致PDGFRA表达上调。通过抑制JUN，粘连形成减少。我们的研究结果支持JUN作为预防粘连的治疗靶点。可以在术中应用以防止粘连形成的抗JUN疗法可以显著改善手术患者的生活。
Adhesions are fibrotic scars that form between abdominal organs following surgery or infection, and may cause bowel obstruction, chronic pain, or infertility. Our understanding of adhesion biology is limited, which explains the paucity of anti-adhesion treatments. Here we present a systematic analysis of mouse and human adhesion tissues. First, we show that adhesions derive primarily from the visceral peritoneum, consistent with our clinical experience that adhesions form primarily following laparotomy rather than laparoscopy. Second, adhesions are formed by poly-clonal proliferating tissue-resident fibroblasts. Third, using single cell RNA-sequencing, we identify heterogeneity among adhesion fibroblasts, which is more pronounced at early timepoints. Fourth, JUN promotes adhesion formation and results in upregulation of PDGFRA expression. With JUN suppression, adhesion formation is diminished. Our findings support JUN as a therapeutic target to prevent adhesions. An anti-JUN therapy that could be applied intra-operatively to prevent adhesion formation could dramatically improve the lives of surgical patients.