Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
Biomedical Research Centre, University of British Columbia, Vancouver, BC, Canada.
Cell Stem Cell. 2020 Sep 3;27(3):396-412.e6. doi: 10.1016/j.stem.2020.07.008. Epub 2020 Aug 4.
Dermal fibroblasts exhibit considerable heterogeneity during homeostasis and in response to injury. Defining lineage origins of reparative fibroblasts and regulatory programs that drive fibrosis or, conversely, promote regeneration will be essential for improving healing outcomes. Using complementary fate-mapping approaches, we show that hair follicle mesenchymal progenitors make limited contributions to wound repair. In contrast, extrafollicular progenitors marked by the quiescence-associated factor Hic1 generated the bulk of reparative fibroblasts and exhibited functional divergence, mediating regeneration in the center of the wound neodermis and scar formation in the periphery. Single-cell RNA-seq revealed unique transcriptional, regulatory, and epithelial-mesenchymal crosstalk signatures that enabled mesenchymal competence for regeneration. Integration with scATAC-seq highlighted changes in chromatin accessibility within regeneration-associated loci. Finally, pharmacological modulation of RUNX1 and retinoic acid signaling or genetic deletion of Hic1 within wound-activated fibroblasts was sufficient to modulate healing outcomes, suggesting that reparative fibroblasts have latent but modifiable regenerative capacity.
在稳态和应对损伤时，真皮成纤维细胞表现出相当大的异质性。定义修复成纤维细胞的谱系起源以及驱动纤维化或相反地促进再生的调节程序对于改善愈合结果将是至关重要的。使用互补的命运映射方法，我们表明毛囊间充质祖细胞对伤口修复的贡献有限。相比之下，由静止相关因子 Hic1 标记的毛囊外祖细胞产生了大部分修复成纤维细胞，并表现出功能上的分歧，介导了伤口真皮中心的再生和周围的瘢痕形成。单细胞 RNA-seq 揭示了独特的转录、调节和上皮-间充质串扰特征，使间充质具有再生能力。与 scATAC-seq 的整合突出了与再生相关基因座内染色质可及性的变化。最后，在伤口激活的成纤维细胞中对 RUNX1 和视黄酸信号的药理学调节或 Hic1 的基因缺失足以调节愈合结果，这表明修复成纤维细胞具有潜在但可修饰的再生能力。
