Defining the spatial-molecular map of fibrotic tendon healing and the drivers of Scleraxis-lineage cell fate and function.
Defining the spatial-molecular map of fibrotic tendon healing and the drivers of Scleraxis-lineage cell fate and function.
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DOI：
10.1016/j.celrep.2022.111706
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发表时间：
2022-11-22
期刊：
影响因子：
8.8
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中科院分区：
文献类型：
--
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肌腱损伤通过疤痕介导的反应进行愈合，目前还没有生物学方法来促进更多的再生愈合。小鼠屈肌腱通过形成空间上不同的组织区域进行愈合：天然肌腱残端之间高度排列的组织桥，丰富了成人巩膜系谱细胞，以及与肌腱周围瘢痕形成相关的杂乱无章的外壳。然而，支撑这些空间上不同的组织轮廓的特定分子程序定义得很差。在本研究中，我们将成人巩膜轴系细胞的谱系追踪与空间转录图谱相结合，以确定支配肌腱愈合和细胞命运决定的主要分子程序。假时间分析确定了三种成纤维细胞轨迹(合成的、成纤维的和反应性的)和调节这些命运转换决定的关键转录因子，包括成年巩膜轴系细胞通过反应轨迹的进展。总的来说，这个资源定义了协调时空愈合表型的分子机制，这可以被用来为治疗候选者的选择提供信息。阿克曼等人。在小鼠肌腱愈合过程中，整合成年巩膜轴系细胞的空间转录图谱和命运图谱，以确定愈合过程的关键调控因素。这项研究提供了关于以空间依赖的方式决定细胞命运的机制的重要见解。
Tendon injuries heal via a scar-mediated response, and there are no biological approaches to promote more regenerative healing. Mouse flexor tendons heal through the formation of spatially distinct tissue areas: a highly aligned tissue bridge between the native tendon stubs that is enriched for adult Scleraxis-lineage cells and a disorganized outer shell associated with peri-tendinous scar formation. However, the specific molecular programs that underpin these spatially distinct tissue profiles are poorly defined. In the present study, we combine lineage tracing of adult Scleraxis-lineage cells with spatial transcriptomic profiling to define the overarching molecular programs that govern tendon healing and cell-fate decisions. Pseudotime analysis identified three fibroblast trajectories (synthetic, fibrotic, and reactive) and key transcription factors regulating these fate-switching decisions, including the progression of adult Scleraxis-lineage cells through the reactive trajectory. Collectively, this resource defines the molecular mechanisms that coordinate the temporo-spatial healing phenotype, which can be leveraged to inform therapeutic candidate selection. Ackerman et al. integrated spatial transcriptomic profiling and fate mapping of adult Scleraxis-lineage cells during murine tendon healing to define key regulators of the healing process. This study provides important insights regarding the mechanisms that dictate cell fate in a spatially dependent manner.
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