Layton Thomas B, Williams Lynn, Yang Nan, Zhang Mingjun, Lee Carl, Feldmann Marc, Trujillo Glenda, Furniss Dominic, Nanchahal Jagdeep
The Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7FY, United Kingdom.
Biotherapeutics, Bristol-Myers Squibb, San Diego, CA 92121.
Proc Natl Acad Sci U S A. 2022 Mar 29;119(13):e2120336119. doi: 10.1073/pnas.2120336119. Epub 2022 Mar 23.
SignificanceTissue fibrotic diseases, for example of the liver and lung, represent a huge unmet medical need. In this study, using single-cell RNA sequencing, cytometry by time of flight (CyTOF), tissue imaging, and functional assays, we identify a complex vascular niche in Dupuytren's disease (DD), a common localized fibrotic condition of the palm, where early-disease-stage tissue can be accessed readily. We uncover a population of myofibroblast precursors within the pericyte compartment and demonstrate that the endothelium instructs the differentiation of functionally distinct stromal cells, thereby orchestrating discrete microenvironments in the fibrotic milieu. Together, these findings provide a basis for the concept of targeting blood vessel signaling to control the progression of human fibrosis.
意义
组织纤维化疾病，例如肝脏和肺部的纤维化疾病，是巨大的未被满足的医疗需求。在本研究中，我们使用单细胞RNA测序、飞行时间流式细胞术（CyTOF）、组织成像和功能分析，在掌腱膜挛缩症（DD）中识别出一个复杂的血管微环境，掌腱膜挛缩症是一种常见的手掌局部纤维化病症，在此病症中可以很容易获取疾病早期阶段的组织。我们在周细胞区室中发现了一群肌成纤维细胞前体，并证明内皮细胞指导功能不同的基质细胞的分化，从而在纤维化环境中协调不同的微环境。这些发现共同为靶向血管信号传导以控制人类纤维化进展这一概念提供了基础。
