Uncorrelated healing response of tendon and ear injuries in MRL highlight a role for the local tendon environment in driving scarless healing

<b><i>Purpose</i></b>: Tendon tears are common injuries that heal with scar formation. Interestingly, MRL/MpJ mice heal without scar in several tissues, including tendon. Most hypotheses regarding scarless healing implicate the systemic environment. However, the tissue-specificity of this regenerative response and our previous findings showing regeneration of sub-rupture tendon injuries, which lack an overt systemic response, motivate a tissue-driven hypothesis. Our objective is to investigate the potential of the local tendon environment in driving scarless healing (1) by comparing the systemic response and the healing capacity associated with ear and tendon injuries in MRL/MpJ mice, and (2) by comparing intrinsic healing properties between MRL/MpJ and normal healer C57Bl/6 tendons. <b><i>Methods</i></b>: We examined the systemic inflammatory and local structural environments of ear and tendon punch injuries in MRL/MpJ and C57Bl/6 mice. Systemic differences were analyzed to assess effects of different injuries on the inflammatory response. Correlations were assessed between MRL/MpJ ear and tendon injuries to compare the extent of healing between regenerative tissues. <b><i>Results</i></b>: Analysis showed similarities between the systemic environment in MRL/MpJ post ear or tendon injuries. However, comparable inflammatory responses did not translate into analogous healing between tissues, suggesting that the systemic environment is not the driver of regeneration. Supporting the regenerative role of the local environment, healing MRL/MpJ tendons exhibited improved matrix and cell alignment and a distinct composition of growth factors and Hyaluronan from C57Bl/6. <b><i>Conclusion</i></b>: These findings support the tissue-driven hypothesis for MRL/MpJ tendon regeneration and motivate further investigation regarding specific roles of extracellular factors in scarless healing.

### 研究目的
肌腱撕裂是一类临床常见损伤，愈合后常伴随瘢痕形成。值得关注的是，MRL/MpJ小鼠在包括肌腱在内的多种组织中均可实现无瘢痕愈合。当前针对无瘢痕愈合的主流假说均认为该过程由全身环境介导。然而，该再生应答的组织特异性，以及我们此前发现的亚破裂肌腱损伤可实现再生且无明显全身应答的实验结果，促使我们提出组织驱动假说。本研究旨在探究局部肌腱微环境驱动无瘢痕愈合的潜力，具体通过两种方式实现：（1）对比MRL/MpJ小鼠耳部与肌腱损伤后的全身应答及愈合能力；（2）比较MRL/MpJ与正常愈合型C57Bl/6小鼠肌腱的固有愈合特性。
### 研究方法
我们检测了MRL/MpJ及C57Bl/6小鼠耳部与肌腱穿刺损伤后的全身炎症环境与局部结构微环境。通过分析全身差异，评估不同损伤类型对炎症应答的影响；通过分析MRL/MpJ小鼠耳部与肌腱损伤的相关性，对比不同再生组织的愈合程度。
### 研究结果
分析结果显示，MRL/MpJ小鼠耳部或肌腱损伤后的全身环境无显著差异。但相似的炎症应答并未在不同组织间转化为相近的愈合效果，这表明全身环境并非肌腱再生的驱动因素。支持局部环境发挥再生作用的证据包括：愈合中的MRL/MpJ肌腱相较于C57Bl/6肌腱，展现出更优的基质与细胞排列，以及生长因子与透明质酸（Hyaluronan）组成的显著差异。
### 结论
本研究结果支持MRL/MpJ小鼠肌腱再生的组织驱动假说，并为进一步探究细胞外因子在无瘢痕愈合中的特定作用提供了研究方向。