Wound healing mechanisms by distinct oral fibroblast population

不同口腔成纤维细胞群的伤口愈合机制

• 批准号: 10358611
• 负责人: KANG I KO
• 金额: $ 38.21万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10358611
• 关键词: Ablation; Anti-Inflammatory Agents; Area; Autologous Transplantation; Biological Assay; Biology; Cell division; Cells; Chronic; Cicatrix; Clinical; Coculture Techniques; Connective Tissue; Data; Dermis; Development; Diphtheria; Disease; Economic Burden; Exhibits; Failure; Fibroblasts; Functional disorder; Genetic; Gingiva; Goals; Heterogeneity; Histologic; Human; Immune; Immune response; Impaired wound healing; In Situ; In Vitro; Inflammation; Inflammatory; Joints; Knowledge; Leukocytes; Link; Mediating; Mesenchymal; Mesenchymal Stem Cells; Messenger RNA; Modeling; Molecular; Mouth Diseases; Mus; Natural regeneration; Nature; Oral; Oral cavity; Outcome; Pathogenesis; Pathology; Pathway interactions; Periodontal Diseases; Play; Population; Process; Property; Proteins; Resolution; Rheumatoid Arthritis; Role; Site; Skin; Source; Synovial Neoplasm; System; Testing; Tissues; Translating; Transplantation; Validation; Work; Wound models; base; chronic wound; cranium; cytokine; gain of function; healing; human disease; improved; in vivo; insight; interest; joint inflammation; loss of function; novel; oral fibroblast; polarized cell; postnatal; progenitor; public health relevance; response; single cell sequencing; single-cell RNA sequencing; skin fibrosis; stem cell therapy; stem cells; stem-like cell; tissue regeneration; tool; transcriptomics; translational impact; wound; wound closure; wound healing

PROJECT SUMMARY Oral wound healing is characterized by rapid resolution of inflammation and minimal scarring. As it is a prime example of ideal tissue regeneration, there is a growing interdisciplinary interest in studying the mechanisms of oral wound healing. Fibroblasts play an essential role in this process and are also implicated in oral diseases responsible for the global economic burden amounting to 442 billion dollars. Recent advances in connective tissue biology have elucidated the importance of fibroblast heterogeneity in the pathogenesis of dermal fibrosis and rheumatoid arthritis. However, the in vivo heterogeneity of oral fibroblasts and thereby a functional significance of select fibroblast population during oral wound healing is poorly understood. Here, we found that postnatal Prx1+ cells are found in mouse gingiva and express common markers of fibroblasts. Preliminary data demonstrate that wounds enriched in Prx1+ cells heal faster with minimal inflammation compared to wounds that lack these cells. Therefore we will test the overall hypothesis that Prx1+ cells represent distinct oral fibroblast progenitors and are responsible for rapid tissue regeneration through a mechanism that involves resolution of inflammation. Aim 1 will utilize an auto-transplantation approach and test the hypothesis that transplanted Prx1+ cells contribute to accelerated oral wound healing by functioning as mesenchymal progenitors in vivo. Aim 2 will investigate if lineage specific ablation of Prx1+ cells delays wound healing by causing the failure to quickly resolve inflammation in vivo, and explore mechanisms of immune cell modulation by Prx1+ fibroblasts in co- culture assays. In Aim 3, we will perform single cell RNA-sequencing to compare transcriptomic profiles of mesenchymal and leukocyte cell subtypes in Prx1+ enriched oral wounds to those in Prx1-poor wounds in mice. Moreover, we will test if Prx1-equivalent cells are found in human gingiva by single cell sequencing and in situ validation. Upon completion, the proposed studies are expected to reveal Prx1+ cells as pro-healing oral fibroblast subset and provide a significant translational value by implicating the clinical utilization of connective tissues or ex vivo stem cell therapy that are enriched with Prx1+ fibroblasts.

项目摘要 口腔伤口愈合的特征是炎症和最小疤痕的快速分辨。因为这是素数 理想组织再生的示例，研究机制的跨学科兴趣越来越大 口腔伤口愈合。成纤维细胞在此过程中起着至关重要的作用，也与口腔疾病有关 负责全球经济负担为4420亿美元。结缔组织的最新进展 组织生物学阐明了成纤维细胞异质性在真皮纤维化发病机理中的重要性 和类风湿关节炎。但是，口服成纤维细胞的体内异质性，从而实现功能 口腔伤口愈合过程中某些成纤维细胞种群的重要性知之甚少。在这里，我们发现 产后PRX1+细胞在小鼠牙龈中发现，并表达成纤维细胞的共同标记。初步数据 与伤口相比 缺乏这些细胞。因此，我们将测试PRX1+细胞代表不同口服成纤维细胞的总体假设 祖细胞，并负责通过涉及解决的机制快速组织再生 炎。 AIM 1将利用自动移植方法并检验移植的假设 PRX1+细胞通过在体内充当间充质祖细胞发挥作用，导致口腔伤口愈合加速。目的 2将调查PRX1+细胞的谱系特异性消融是否会导致未能快速延迟伤口愈合 在体内解决炎症，并探索prx1+成纤维细胞在共同体中调节免疫细胞的机制 文化测定法。在AIM 3中，我们将执行单细胞RNA序列，以比较 PRX1+富集的口腔伤口中的间充质和白细胞细胞亚型对小鼠的PRX1贫困伤口富含口腔伤口。 此外，我们将通过单细胞测序和原位测试在人牙龈中是否发现PRX1等效细胞 验证。完成后，提出的研究有望揭示PRX1+细胞为促愈合口服 成纤维细胞子集并通过暗示结缔组织的临床利用来提供显着的翻译价值 富含PRX1+成纤维细胞的组织或离体干细胞疗法。