Cell non-autonomous functions of S100a4 drive fibrotic tendon healing
Cell non-autonomous functions of S100a4 drive fibrotic tendon healing
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DOI：
10.7554/elife.45342
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发表时间：
2019-05-24
期刊：
影响因子：
7.7
通讯作者：
Loiselle, Alayna E.
中科院分区：
文献类型：
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作者：
Ackerman, Jessica E.;Nichols, Anne E. C.;Loiselle, Alayna E.
鉴定促进再生的方法以改善肌腱愈合是至关重要的，因为纤维化愈合反应损害身体功能。在本研究中，我们在小鼠模型中检验了S100 a4单倍不足或抑制S100 a4信号传导改善急性损伤和手术修复后肌腱功能的假设。我们证明S100 a4主要通过细胞非自主过程驱动纤维化肌腱愈合，S100 a4单倍不足促进再生肌腱愈合。此外，通过拮抗其推定受体S100 a4的信号传导，S100 a4信号传导的抑制也减少了瘢痕形成。从机制上讲，S100 a4单倍不足减少了损伤部位的肌成纤维细胞和巨噬细胞含量，两种细胞群都是纤维化进展的关键驱动因素。此外，S100 a4谱系细胞通过S100 a4表达的丧失变成α-SMA（+）肌成纤维细胞。使用遗传小鼠模型，小分子抑制剂和体外研究的组合，我们已经将S100 a4定义为一种新的，有前途的治疗候选物，以改善急性损伤后的肌腱功能。
Identification of pro-regenerative approaches to improve tendon healing is critically important as the fibrotic healing response impairs physical function. In the present study we tested the hypothesis that S100a4 haploinsufficiency or inhibition of S100a4 signaling improves tendon function following acute injury and surgical repair in a murine model. We demonstrate that S100a4 drives fibrotic tendon healing primarily through a cell non-autonomous process, with S100a4 haploinsufficiency promoting regenerative tendon healing. Moreover, inhibition of S100a4 signaling via antagonism of its putative receptor, RAGE, also decreases scar formation. Mechanistically, S100a4 haploinsufficiency decreases myofibroblast and macrophage content at the site of injury, with both cell populations being key drivers of fibrotic progression. Moreover, S100a4-lineage cells become alpha-SMA(+) myofibroblasts, via loss of S100a4 expression. Using a combination of genetic mouse models, small molecule inhibitors and in vitro studies we have defined S100a4 as a novel, promising therapeutic candidate to improve tendon function after acute injury.