Tavarez Joey R, Kenney James, Gabunia Sergo, Nelson Deirdre A, Larsen Melinda
Department of Biological Sciences and The RNA Institute, University at Albany, State University of New York, Albany, NY, United States.
Molecular, Cellular, Developmental, and Neural Biology Graduate Program, Department of Biological Sciences, University at Albany, State University of New York, Albany, NY, United States.
Front Dent Med. 2025 May 1;6:1581376. doi: 10.3389/fdmed.2025.1581376. eCollection 2025.
Extracellular matrix remodeling is a natural response to injury but, excessive extracellular matrix accumulation, or fibrosis, is a causative factor in hundreds of diseases that limit organ function, regenerative responses, and can interfere with regenerative therapies. Fibrosis is closely related to inflammation, both of which occur in the salivary glands of patients treated with radiation for head and neck cancers and in patients suffering from autoimmune conditions, such as Sjögren's Disease. Despite the known involvement of fibrosis in disease and the inhibitory effects of fibrosis on tissue regeneration, the mechanisms through which extracellular matrix is elaborated in the salivary gland are poorly understood. Stromal fibroblasts are the primary matrix-producing cells and are known to drive both fibrosis and inflammation. To define the temporal responses of fibroblasts to injury, we induced a temporary obstructive injury though ligation of the primary submandibular and sublingual salivary gland ducts and then performed single-cell RNA sequencing and pathway analysis at timepoints immediately following the injury. Using bioinformatic approaches, we identified three unique fibroblast groups that dynamically respond to the injury. We characterized the changes in matrisomal and inflammatory gene expression over a 7-day time course and identified one group of fibroblasts to be the primary injury-responsive fibrogenic cell type. Understanding how fibroblasts respond at the early and later injury timepoints, along with defining signaling pathways regulated by fibroblasts, could lead to a better understanding of the contribution of fibroblast to acute injury responses to facilitate the development of therapeutics that minimize fibrosis and promote regenerative gland responses in chronic disease states.
细胞外基质重塑是对损伤的一种自然反应，但是，细胞外基质过度积累，即纤维化，是数百种限制器官功能、再生反应并可能干扰再生疗法的疾病的致病因素。纤维化与炎症密切相关，这两种情况都发生在接受头颈部癌症放疗的患者的唾液腺以及患有自身免疫性疾病（如干燥综合征）的患者中。尽管已知纤维化与疾病有关且对组织再生有抑制作用，但唾液腺中细胞外基质形成的机制仍知之甚少。基质成纤维细胞是主要的基质产生细胞，已知其会引发纤维化和炎症。为了确定成纤维细胞对损伤的时间反应，我们通过结扎主要的下颌下腺和舌下腺导管诱导了暂时性阻塞性损伤，然后在损伤后立即的时间点进行单细胞RNA测序和通路分析。使用生物信息学方法，我们确定了三个独特的成纤维细胞组，它们对损伤有动态反应。我们在7天的时间过程中表征了基质和炎症基因表达的变化，并确定一组成纤维细胞是主要的损伤反应性纤维化细胞类型。了解成纤维细胞在损伤早期和后期的反应方式，以及确定由成纤维细胞调节的信号通路，可能有助于更好地理解成纤维细胞对急性损伤反应的贡献，从而促进开发在慢性疾病状态下最小化纤维化并促进腺体再生反应的疗法。
