Single-cell analysis reveals fibroblast heterogeneity and myeloid-derived adipocyte progenitors in murine skin wounds
Single-cell analysis reveals fibroblast heterogeneity and myeloid-derived adipocyte progenitors in murine skin wounds
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DOI：
10.1038/s41467-018-08247-x
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发表时间：
2019-02-08
影响因子：
16.6
通讯作者：
Plikus, Maksim V.
中科院分区：
文献类型：
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作者：
Guerrero-Juarez, Christian F.;Dedhia, Priya H.;Plikus, Maksim V.
在成年小鼠皮肤的伤口愈合过程中，毛囊和脂肪细胞再生。脂肪细胞从肌成纤维细胞再生，肌成纤维细胞是一种专门的收缩性伤口成纤维细胞。在这里，我们研究伤口成纤维细胞的多样性，使用单细胞RNA测序。经分析，伤口成纤维细胞分成12个簇。伪时间和RNA速度分析表明，一些集群可能代表连续分化状态的收缩表型，而其他人似乎代表不同的成纤维细胞谱系。成纤维细胞的一个子集表达造血标志物，表明它们的骨髓起源。我们使用基因标记的肌成纤维细胞的单细胞蛋白质印迹和单细胞RNA测序来验证这一发现。使用骨髓移植和基于Cre重组酶的谱系追踪实验，我们排除了细胞融合事件，并确认造血谱系细胞产生肌成纤维细胞和罕见的再生脂肪细胞的子集。总之，我们的研究表明，创伤诱导成纤维细胞之间的高度异质性，并招募高度可塑性的骨髓细胞，有助于脂肪细胞再生。
During wound healing in adult mouse skin, hair follicles and then adipocytes regenerate. Adipocytes regenerate from myofibroblasts, a specialized contractile wound fibroblast. Here we study wound fibroblast diversity using single-cell RNA-sequencing. On analysis, wound fibroblasts group into twelve clusters. Pseudotime and RNA velocity analyses reveal that some clusters likely represent consecutive differentiation states toward a contractile phenotype, while others appear to represent distinct fibroblast lineages. One subset of fibroblasts expresses hematopoietic markers, suggesting their myeloid origin. We validate this finding using single-cell western blot and single-cell RNA-sequencing on genetically labeled myofibroblasts. Using bone marrow transplantation and Cre recombinase-based lineage tracing experiments, we rule out cell fusion events and confirm that hematopoietic lineage cells give rise to a subset of myofibroblasts and rare regenerated adipocytes. In conclusion, our study reveals that wounding induces a high degree of heterogeneity among fibroblasts and recruits highly plastic myeloid cells that contribute to adipocyte regeneration.