Laboratory of Tissue Repair and Regeneration, Faculty of Dentistry, University of Toronto, Toronto, ON, Canada.
PhenomicAI, MaRS Centre, Toronto, ON, Canada.
Immunol Rev. 2021 Jul;302(1):126-146. doi: 10.1111/imr.12971. Epub 2021 May 13.
Activation of fibroblasts is a key event during normal tissue repair after injury and the dysregulated repair processes that result in organ fibrosis. To most researchers, fibroblasts are rather unremarkable spindle-shaped cells embedded in the fibrous collagen matrix of connective tissues and/or deemed useful to perform mechanistic studies with adherent cells in culture. For more than a century, fibroblasts escaped thorough classification due to the lack of specific markers and were treated as the leftovers after all other cells have been identified from a tissue sample. With novel cell lineage tracing and single cell transcriptomics tools, bona fide fibroblasts emerge as only one heterogeneous sub-population of a much larger group of partly overlapping cell types, including mesenchymal stromal cells, fibro-adipogenic progenitor cells, pericytes, and/or perivascular cells. All these cells are activated to contribute to tissue repair after injury and/or chronic inflammation. "Activation" can entail various functions, such as enhanced proliferation, migration, instruction of inflammatory cells, secretion of extracellular matrix proteins and organizing enzymes, and acquisition of a contractile myofibroblast phenotype. We provide our view on the fibroblastic cell types and activation states playing a role during physiological and pathological repair and their crosstalk with inflammatory macrophages. Inflammation and fibrosis of the articular synovium during rheumatoid arthritis and osteoarthritis are used as specific examples to discuss inflammatory fibroblast phenotypes. Ultimately, delineating the precursors and functional roles of activated fibroblastic cells will contribute to better and more specific intervention strategies to treat fibroproliferative and fibrocontractive disorders.
成纤维细胞的激活是损伤后正常组织修复过程中的一个关键事件，也是导致器官纤维化的失调修复过程。对大多数研究人员来说，成纤维细胞是嵌入结缔组织纤维胶原基质中的相当不起眼的梭形细胞，或者被认为是在培养中进行贴壁细胞的机制研究有用的细胞。一个多世纪以来，由于缺乏特异性标记物，成纤维细胞未能被彻底分类，并且被视为组织样本中所有其他细胞鉴定后剩下的“残渣”。随着新型细胞谱系追踪和单细胞转录组学工具的出现，真正的成纤维细胞成为了一个更大的、部分重叠的细胞类型群体中唯一的异质亚群，包括间充质基质细胞、纤维脂肪祖细胞、周细胞和/或血管周细胞。所有这些细胞在损伤和/或慢性炎症后都会被激活，以参与组织修复。“激活”可能涉及各种功能，如增强增殖、迁移、指导炎症细胞、分泌细胞外基质蛋白和组织酶，以及获得收缩性肌成纤维细胞表型。我们提供了在生理和病理修复过程中发挥作用的成纤维细胞类型和激活状态的观点，并讨论了它们与炎症巨噬细胞的相互作用。类风湿关节炎和骨关节炎关节滑膜的炎症和纤维化被用作具体例子来讨论炎症性成纤维细胞表型。最终，明确激活的成纤维细胞的前体和功能作用将有助于更好和更特异的干预策略来治疗纤维增生性和纤维收缩性疾病。
